Natural Treatment for Prostate Enlargement

The 21 Day Prostate Fix

21 Day Prostate Fix written by Radu Belasco is a healthier alternative to drugs and invasive medical procedures. Radu Belasco is an early prostate problem sufferer, with a family history of prostate pain, problems and cancer. Using a unique system of natural remedies, he fixed his prostate problems and wrote them in his smash hit eBook The 21 Day Prostate Fix. It is about miraculous herbs and fruits from all over the world. These unique foods have the power to cure your prostates inflammation in record time and shrink it to a healthier size. Also, you will learn how to concoct the miracle elixir that will not just cleanse your prostate, but also burn body fat. Aside from these, youll get topnotch information on nutrition, so you can keep your prostate healthy and your sex drive at its peak. Plus, youll learn other health conditions that might be contributing to your prostate issues, so you can also remedy them and get your body in its best shape ever.

The 21 Day Prostate Fix Overview

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Author: Radu Belasco

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Prostate Specific Antigen

PSA was first purified from prostatic tissue and was shown to be prostate specific in 1979 26 . One year later, it was found to be present in serum of patients with prostate cancer 27, 28 . Although PSA was later shown to be produced also in other tissues, it is in practice a specific marker for prostate cancer and prostatic diseases. PSA is secreted by normal prostatic epithelial cells, benign prostatic hyperplasia, and prostate cancer cells, and its expression is stimulated by androgens through androgen receptor mediated transcriptional activation 26, 44, 53-55 . In LNCaP cells, which are the most widely used model for studying PSA expression, dihydrotestosterone is the most potent inducer of PSA synthesis 56 . Several growth factors and other factors have also been suggested to affect PSA expression 57, 58 . In the prostate, the secretion of PSA is directed into the prostatic ducts, and PSA occurs at very high concentrations, 0.5-2 mg ml, in human seminal fluid 45 . In seminal...

Animal Models of Human Prostate Cancer

Human Prostate Cancer After lung cancer, cancer of the prostate (CaP) is the second most common cause of cancer death in American males. A latent disease, many men have prostate cancer cells long before overt signs of the disease are apparent. The annual incidence of CaP is over 100,000 in the United States, of which over 40,000 will die of the disease. Nearly a third of patients present with locally advanced or metastatic disease, and androgen deprivation therapy forms the basis of conventional therapy for the majority of these patients. However, currently available approaches for advanced CaP are not curative 137 , primarily because the cells lose their dependence on androgenic stimulation. The mechanisms of progression of CaP cells to hormone independence under androgen ablation therapy remain unclear. To investigate the factors and mechanisms that underlie the development of androgen resistance and metastasis, reliable in vivo models that mimic human CaP progression are...

Detection of Circulating Prostate Cancer Cells by Measurement of PSA mRNA

Amplification of organ-specific mRNA by reverse transcription-polymerase chain reaction (RT-PCR) is a powerful method for detection of circulating prostate cancer cells. Many groups have reported detection of PSA mRNA in circulating cells by measurement of PSA mRNA by RT-PCR 173 and this approach is potentially useful for evaluating the prognosis of prostate cancer. It has been suggested to improve preoperative staging and prognosis of prostate cancer 174, 175 by identifying preoperatively organ-confined and extracapsular cancers, respectively 176-178 . However, at present it is not clear whether PSA mRNA levels correlate with tumor stage and grade 179 . By RT-PCR even one circulating PSA expressing cell among more than 100 million other cells may be detected 180,181 . However, the method is prone to methodological problems and false-positive results have been found to be caused by low background expression of prostate-specific genes in normal hematopoietic tissues and blood cells...

ARCAs for Prostate Cancer CV706 and CV787

We hypothesized that tropism of a virus could be redirected if expression of an essential viral gene could be controlled. Viruses generated from this approach would have the same capsid as its parental virus and they should be able to penetrate all cell types that express the CAR receptor. Presumably, in all cells containing the CAR receptor, these viruses would follow the normal cell entry process they would penetrate the endosome, fuse with the endosome membrane, reach the cytoplasm, find transport to the nucleus, and uncoat the viral DNA. In a normal adenovirus replication cycle the E1A gene is the only gene expressed during the first 2.5 h of infection 52-55 . In turn, the E1A proteins as transcription factors upregulate expression of the impending cascade of viral genes. However, we have genetically engineered prostate tissue-specific promoters and enhancers so as to drive the E1A genes. Viral replication should preferentially take place in cells that express the necessary...

The Prostate Gland

Your prostate is a walnut-shaped gland that lies immediately beneath your bladder surrounding the urethra, the tube inside the penis that carries urine out of your body. It secretes a fluid that becomes part of semen. The gland can easily become inflamed during an infection, causing soreness, swelling, frequent urination, and a burning sensation while urinating. The prostate gland also can become enlarged, a condition called benign prostatic hyperplasia, which is a common problem in older men. An enlarged prostate gland can cause a number of bothersome problems when urinating, including hesitancy or straining to urinate a weak stream of urine dribbling retention of urine or the inability to control urination, also called incontinence. Other common symptoms include frequent urination, feeling an urgent need to urinate, and excessive urination at night. If you have any of the symptoms of prostate enlargement, you should not feel embarrassed about talking them over with your doctor. You...

Prostate Cancer

There are many studies that do not support an association between body mass and incident prostate cancer (18,34-36,173), although four large recent studies found a small but statistically significant increased risk of prostate cancer among obese men (131,132,174) or a significant trend toward increasing risk with increasing BMI (96). In addition, there is accumulating evidence that obesity is associated with an increase in risk of advanced prostate cancer or death from prostate cancer (175-181). Recent studies consistently indicate that obese men with prostate cancer are more likely to have aggressive disease that recurs after radical prostatectomy than nonobese men (182-184). As with breast cancer, nonbiological issues of screening, detection, and treatment are important to the evaluation of the impact of adiposity on prostate cancer prognosis. It can be harder to perform a digital rectal examination in obese men because of their general adiposity in combination with larger prostate...

Chronic Prostatitis

An additional infection of the urinary tract that is associated with biofilm formation is chronic bacterial prostatitis in men. The most commonly encountered bacteriological agent in prostatitis is E. coli, followed by other members of the Enterobacteriaceae (Proteus and Klebsiella) and coagulase-negative Staphylococci (Domingue and Hellstrom 1998). These infections are notoriously difficult to treat with antibiotic therapy. Studies by Nickel and Costerton demonstrated that prostate biopsy samples from chronically infected patients contained exopolysaccharide-encased microcolonies that were attached to the walls of the prostate ducts (Nickel and Costerton 1993). In chronic staphylococcal prostatitis, biofilm-like microcolonies were attached to the prostate in patients that were refractory to antibiotic therapy (Nickel and Costerton 1992). Finally, in a recent study, a total of 377 E. coli isolates obtained from a variety of urinary tract infections (cystitis, pyelonephritis, and...

Tumor Specific Antigens

This category of tumor antigens, which represents non-mutated gene products that are not processed and presented on normal adult tissues, is predominantly comprised of members of the cancer testis (C T) family of genes (Table 2). The expression of C T gene products is limited in adult tissues to the normal testis, which lacks expression of HLA class I and class II molecules. The prototype for this family, MAGE-1, represents the first antigen to be identified as a target of human tumor reactive T cells, and was cloned by transfecting an autologous tumor cell line that appeared to have lost antigen expression with a cosmid library containing genomic DNA from antigen positive tumor cells (1). The cancer testis genes have been clustered into 10 families, 6 of which have been mapped to the X chromosome (3 8), and subsequent studies have lead to the identification of T cell epitopes expressed on multiple products derived from these gene families. The MAGE gene family includes 17 members,...

Preventive Healthcare

The most common tests performed in men over 40 include the PSA (prostate-specific antigen) test for prostate cancer, the fecal occult blood test for colon cancer, and a series of tests that screen for the presence of heart disease or your risk of having it. Such tests may include measuring your blood pressure and the levels of cholesterol in your blood an electrocardiogram, which measures the electrical activity in your heart and a stress test, which evaluates the heart's response to physical exercise. If you have a family history of a certain disease that has a strong hereditary component, such as diabetes (see page 365), you also may undergo a screening for that disorder. For example, in the case of diabetes, the doctor would perform a test known as a glucose tolerance test (see page 367).

Periodic Health Checkups for

To look for signs of cancer of the colon, rectum, and prostate. Includes rectal examination performed by hand by a doctor, fecal occult blood test that checks for blood in the stool, sigmoidoscopy (see page 284), and possibly a PSA (prostate-specific antigen) test. Those at risk Men with a family history of colon or rectal cancer men who have intestinal polyps or ulcerative colitis men over age 50. African American men have an increased risk of prostate cancer. Prostate Not needed Once a year beginning at age 45 if you are African American or if you are a white male with a family history of prostate cancer

Improving siRNA Pharmacokinetics by Chemical

By siRNA Conjugation attractive strategy, if not a prerequisite, to develop siRNAs into effective therapeutic drugs it minimizes the amount of required siRNA and potential side-effects. Several studies have utilized celltargeting ligands such as glycosylated molecules, peptides, antibodies, hormones, vitamines, and aptamers by conjugation to various carrier systems (reviewed in ref. (182)). Direct conjugations of siRNAs to cell-targeting ligands such as peptides, antibodies, aptamers, micelles (183), and nanoparticles (184, 185) have also been reported this strategy not only confers specificity of targeting, but may also enhance cellular uptake through receptor-mediated endocytosis of the specific ligand. The conjugation of a peptide-mimicking insulin growth factor 1 (IGF1) to the 5' end of the siRNA passenger strand resulted in a 60 KD of target gene expression in MCF7 cells that overexpresses the IGF1 receptor (186). Also, an antibody targeting the transferrin receptor expressed at...

Integrin Linked Kinase

Integrin-linked kinase (ILK) is an ubiquitously expressed serine threonine kinase that binds to the cytoplasmic domain of the pi integrin subunit.98 It is involved in the regulation of cell survival and plays a role in cancer, with its upregula-tion identified in cancers of the colon, breast, prostate, and lung, and in melanoma.28,35-38 ILK is upregulated, often in a stage- and grade-dependent manner, and is associated with metastases.28 ILK is a central structural and signaling protein that serves as a link between the extracellular matrix and

Organdependent Expression Of Basic Fibroblast Growth Factor By Tumor Cells

Recent clinical observations have noted antiangiogenic effects in vascular tumors, including hemangioma (65-70), Kaposi's sarcoma (71-74), melanoma (75), basal cell and squamous cell carcinoma (76), and bladder carcinoma (77), using recombinant interferons. These tumors have also been documented as producing high levels of bFGF, often detectable in the urine or serum of these patients (78,79). These findings, along with in vivo observations, prompted investigation of whether IFNs could modulate the expression of the angiogenic molecule, bFGF. The authors found that IFN-a and IFN-p, but not IFN-y, downregulated the expression of bFGF mRNA and protein in HRCC, as well as in human bladder, prostate, colon, and breast carcinoma cells (80). The inhibitory effect of IFN-a and -P on bFGF expression was cell-density dependent and independent of the antiproliferative effects of IFNs (80,81). The authors recently confirmed that IFN can inhibit bFGF production in an in vivo model system....

Tumor Escape And Future Approaches To Cancer Immunotherapy

Extensive immunization trials are on-going worldwide in patients with breast, colon, renal cell, ovarian and prostate carcinomas as well as melanoma and other malignancies. These clinical trials, largely initiated in patients with advanced metastatic disease, have been able to induce clinical responses in not more than 20 of patients. They are unlikely to yield the desired results, if only a proportion of the immunization-induced, TA-specific effector cells survive in vivo. Moreover, if a proportion of specific T cells or DC are preferentially killed, and if the level of apoptosis exceeds that of effector cell influx into the tumor or their generation within the secondary lymphoid sites, the immunization strategies (as currently applied) may prove ineffective. Likewise, it may be counterproductive to generate TA-specific effector cells in a situation where the tumor is resistant to that type of immune cell, i.e., poised to escape specific immune interventions. To avoid additional...

FGF1 and FGF2 in Tumor Development

Elevated expression of either FGF-1 or FGF-2 has been demonstrated in a variety of other tumor types in vivo, and in tumor cell lines in vitro. In some cases, FGF expression correlated significantly with advanced stages of tumor development and malignancy (reviewed in refs. 1 and 2). Examples include the expression of FGF-2 and FGF-1 in squamous cell carcinoma, human leukemic cells, human bladder carcinoma, human pancreatic carcinoma, human ovarian cancer, and gastric carcinoma and the expression of FGF-2 in pituitary tumors, renal tumors, mammary carcinoma cell lines, prostate carcinoma cell lines, colon carcinoma cell lines, hepatoma cell lines, chondrosarcoma cell lines, osteosarcoma cell lines, and the expression of FGF-1 in rat Morris hepatoma cell lines (19).

Vulnerable Plaque Elasticity Imaging

In 1991, Ophir and colleagues 42, 43 developed an elasticity imaging technique called elastography, which is based on (quasi-)static deformation of a linear elastic, isotropic material. The tissue under inspection is deformed by applying stress (i.e., force normalized by area) on a part of its boundary. The resulting distribution of strain (i.e., length of a small block of tissue after deformation, divided by its length before deformation) depends upon (i) the distribution of the tissue's material properties (Young's modulus and Poisson's ratio) and (ii) the displacement or stress conditions on the remaining tissue boundaries. The Young's modulus E kPa is a material property, which can be interpreted as the ratio between the normal stress S kPa (tensile or compressive) enforced upon a small block of tissue and its resulting strain (elongation or compression). The Poisson's ratio is also a material property and it quantifies a material's local volumetric compressibility. The resulting...

The Diagnostic Use of Isoenzymes

For example, creatine kinase (CK) occurs in different forms in different cells. An elevated serum level of CK-1 indicates a breakdown of skeletal muscle and is one of the signs of muscular dystrophy. An elevated CK-2 level indicates heart disease, because this isoenzyme comes only from cardiac muscle. There are five isoenzymes of lactate dehydrogenase (LDH). High serum levels of LDH-1 may indicate a tumor of the ovaries or testes, while LDH-5 may indicate liver disease or muscular dystrophy. Different isoenzymes of phosphatase in the blood may indicate bone or prostate disease.

Inhibition of FGF Activity

Pentosan polysulfate, another polyanionic heparin analog, has been reported to inhibit proliferation of tumor cell lines derived from breast carcinoma, prostate carcinoma, lung carcinoma, epidermoid tumors, and rhabdomyosarcomas, in culture and in athymic mice (102). Human adrenal cancer cell lines that have been transfected with FGF-4 were dramatically inhibited in their proliferation and tumor formation by pentosan polysulfate, when suramin or dextran sulfate exhibited only a slight inhibitory effect (103). However, treatment of HIV-associated KS in patients with pentosan polysulfate did not reveal a significant tumor response (104). The antitumoral effect of suramin, pentosan polysulfate, laminarin sulfate, and other polysulfated compounds was also attributed to their inhibition of heparanase activity, and hence tumor metastasis (105). Another approach to interfere with tumor growth is the ligand-specific targeting of toxins to tumor cells expressing FGFRs. For example, a fusion...

Isoforms and Splice Variants of the Human Kallikreins

The presence of more than one mRNA form for the same gene is common among kallikreins. These variant mRNAs may result from alternative splicing, a retained intronic segment, or use of an alternative transcription initiation site. To date, there are at least 49 documented splice variants of the 15 kallikrein genes (Table 4), and more are currently being investigated (our unpublished data). Some of these variants may hold significant clinical value. Slawin et al. reported the prognostic significance of a splice-variant-specific RT-PCR assay for KLK2 in detecting prostate cancer metastasis 168 . Nakamura et al. reported differential expression of the brain and prostate-types of KLK11 among benign, hyperplastic, and malignant prostate cancer cell lines 169 . A novel ovarian cancer-specific variant of hK5 has been recently reported 170 , and another KLK5 transcript with a short 5'-untranslated region and a novel KLK7 transcript with a long 3'-untranslated region were highly expressed in...

Disorders of the Reproductive System

The vas deferens is a long duct that carries sperm from the epididymis past the prostate gland and into the seminal vesicle. The prostate gland and seminal vesicle produce fluids that support the sperm and make up 98 percent of the semen that is ejaculated through the urethra during orgasm. The urethra is also part of the urinary tract and transports urine from the bladder. Prostate gland Prostate gland

Gerald W Both Fiona Cameron Anne Collins Linda J Lockett and Jan Shaw

Gene-directed enzyme prodrug therapy (GDEPT) is an emerging approach for the treatment of cancers. A variety of viral vectors have been used to deliver genes that encode the relevant enzymes, and some have been tested in clinical trials. To ensure the potency and efficacy of such vectors and to obtain regulatory approval to administer them to humans, it is necessary to develop a suite of assays that provide quality assurance. New GDEPT vectors based on ovine atadenovirus and Escherichia coli purine nucleoside phosphorylase (PNP) have been developed for first time use in humans in a phase I trial for the treatment of prostate cancer. Here we describe methods for their production together with several quality-control assays. In particular, a functional cell killing assay was devised to measure the potency of PNP-GDEPT vectors, the principles of which could easily be adapted to other systems. Key Words Ovine atadenovirus vectors PNP-GDEPT prostate cancer. 1. Introduction Vectors OAdV220...

Cancer Vaccines That Elicit

These approaches to tumor vaccination have produced encouraging results in animal models (e.g., 101). Clinical trials are now underway with pulsed DC as vaccines to immunize patients against their own tumors. Again, most such trials involve melanoma patients (25, 102-105). Other trials using DC are aimed at prostate and bladder cancer (106-108). The prostate trials have been disappointing, but a trial using DC pulsed with B-cell lymphoma antigen achieved a response rate of 75 percent (109).

Cell Lines and Viruses

PC3 human prostate cancer cells (ATCC CRL-1435) for testing virus potency were frozen down as a working cell bank (1-2.5 x 106 cells vial) at doubling 18 and used within five passages. For cell growth, RPMI with glutamine and without NaHCO3 (Gibco BRL), made according to manufacturer's instructions, was supplemented with 10 FBS and penicillin streptomycin (50 IU 50 pg L). Typically, cells were passaged twice per week at a split ratio of 1 5 by treating them lightly with trypsin. 3. Recombinant virus OAdV623 contains the wild-type genome with a gene cassette inserted in a nonessential site (III) between the E4 and RH transcription units (2). The gene cassette comprises the PSMA enhancer and rat probasin promoter (the combination provides prostate cell-specific expression) linked to the E. coli purine nucleoside phosphorylase coding sequence and bovine growth hormone polyadenylation signal (8). OAdV220 contains a similar cassette in which the RSV promoter is used. In this case the...

Role in tumor biology

CSF-1 is overexpressed by many cancers, where it is a negative prognostic factor 8 . Preclinical studies have identified a role for CSF-1-dependent macrophages in tumor angiogenesis. Tumor angiogenesis is blunted in mice that are nullizygous for CSF-1, whereas forced overexpression of CSF-1, by either the host or the tumor, caused remarkable increases in tumor infiltrating macrophages and tumor vessel densities, as well as enhanced oncogenicity 9,10 . Pharmacological intervention studies corroborate a role for CSF-1 in tumor growth. CSF-1 antisense oligonucleotides, CSF-1 antibody, FMS siRNA, and a selective FMS kinase inhibitor have reduced the growth rates of diverse xenografts 11-13 . In these studies, tumor-associated macrophages and macro-phage-derived pro-angiogenic factors were depleted in association with marked reductions in tumor microvasculature. Anti-CSF-1 reversed the chemoresistance of MCF-7 xenografts, which identified an unanticipated role for CSF-1 in chemoresistance....

Strategies and Considerations

Undetectable levels and are thus Ad-refractory 24-26 . An interesting finding in this regard was recently published by Okegawa et al., who demonstrated a striking inverse correlation between the level of CAR expression by prostate cancer cell lines and their tumorigenicity, thereby suggesting that in general the most aggressive tumors may be CAR-deficient and therefore refractory to therapeutic intervention utilizing unmodified Ad2- or Ad5-derived vectors 27 . The authors have also observed the same phenomenon on human breast cancer cells. If the results of this work are further corroborated by data from other laboratories, CAR deficiency in tumors may become a major obstacle in employing Ad vectors for cancer gene therapy, therefore necessitating the derivation of Ad vectors capable of infecting these tumors in a CAR-independent fashion. Another reason to develop tropism-modified Ad vectors is the fact that many normal human tissues express high levels of CAR 7 and may thus become...

Biochemical Activities of TSP1 That Could Influence Angiogenesis

Several biochemical activities of the TSP-1 protein have been defined in vitro that could ultimately impinge on angiogenesis in vivo. Proteolysis is essential for angiogenesis, and TSP-1 has been shown to bind and inactivate the serine proteases, neutrophil elastase and cathepsin G, which are found at sites of inflammation or injury (74). Cathe-psin G is also present in new vessels forming in glioblastomas and prostate carcinomas (75). TSP-1 also binds to, and may inhibit the activity of, urokinase plasminogen activator and plasmin (74), which clearly play important roles in extracellular matrix degradation by endothelial cells, as well as by tumor and stroma (76).

Introduction Rationale of Transcriptional Targeting

Gene therapy is an innovative approach aimed at introducing genetic material into an organism for therapeutic intent. Still in its infancy, this novel concept has witnessed fundamental preclinical success with numerous ongoing clinical trials to confirm these findings. Critical to the success of gene therapy trials are issues relating to specific delivery of physiologically active biomolecules at therapeutically significant concentrations. Initially this was achieved by using direct intralesional injections of vectors to localize the delivery to the target tissue and universal promoters to maximize expression at that site. Over the past several years, we and several other investigators have investigated the potential of tumor-specific promoters to transcriptionally regulate gene expression in the laboratory and in clinical trials. The safety demonstrated by these trials using tumor tissue-specific promoters has led to the recent approval of a trial administering a conditionally...

Spectrum Of Disease

Patients with rat-bite, or Haverhill, fever develop acute onset of chills, fever, headache, vomiting, a often, severe joint pains. Febrile episodes may persist fo weeks or months.5 Within the first few days of illnessj patients develop a rash on the palms, soles of the feel* and other extremities. Complications can occur and include endocarditis, septic arthritis, pneumonia, peril carditis, brain abscess, amnionitis, prostatitis, and pancreatitis.6,8

Antioxidant nutrients

There is good epidemiological evidence for an inverse association between intake of carotenoids and lung cancer, and weaker evidence for protective effects against cancers of the alimentary tract.37 The possibility that carotenoids might express antioxidant activity in human tissues, thereby protecting cell membranes, proteins and DNA against damage by free radicals, provides a plausible rationale for these associations, but once again the causal link has not been proven and the possibility remains that carotenoids are acting as markers for fruit and vegetable intake which may be beneficial for other reasons.36 Intervention trials with beta-carotene have proved disappointing. The alpha-tocopherol beta-carotene (ATBC) study, which involved over 29000 male smokers, and included a cohort given 20 mg betacarotene daily for up to eight years, produced no evidence for a protective effect against cancer at any site. On the contrary, there was a higher incidence of lung, prostate and stomach...

Toxicity of Intravenously Administered ARCAs in the Absence or Presence of Docetaxel

A synergistic antitumor efficacy was observed when CV787 was combined with taxane in the prostate tumor xenograft 88 . To examine the toxicity of CV787 in combination with the chemotherapeutic agent docetaxel, we conducted a fourth toxicology study in C57BL 6. The 4-day and 2 8-day effects were evaluated in mice given a single daily dose of dexamethasone (Decadron) each day for 3 consecutive days, a single injection of CV787 at low (1 x 108 particles per animal), medium (3 x 109 particle per animal), or high (1 x 1011 particles per animal) dose, and a single dose of the chemotherapeutic agent, docetaxel (100 mg m2). Six different treatment groups were established using identical treatment regimens for animals in subgroups sacrificed at 4 days and at 28 days. Each treatment subgroup consisted of eight randomly assigned mice. The ARCA virus vehicle and all three doses of virus were given intravenously via tail vein injection. All virus injections were given on day 1 at 1-2 h prior to...

Clinical Development of CV706 and CV787

CV706 and CV787 are novel therapeutic agents with a novel mechanism of action. As of this writing, a phase I II clinical trial of CV706 for recurrent local prostate cancer has been completed and CV787 has entered a multicenter Phase I II clinical trial for metastatic, hormonal refractory prostate cancer. A brief summary for CV706 trial result and factors impacting clinical efficacy and safety are discussed. A. CV706 Phase I II Trial for Locally Recurrent Prostate Cancer A Phase I trial of CV706 was initiated in 1998 at the Brady Urological Institute of the Johns Hopkins Oncology Center under the direction of Jonathan Simons, MD, and Ted DeWeese, MD. The patient population consists of men with locally recurrent prostate cancer with rising PSA levels following definitive external beam irradiation. Men in this category are usually left untreated or receive androgen ablation therapy as serum PSA levels rise significantly above 10 ng mL. On average, these men have a life expectancy of 3...

Proposed Mechanism Of Angiostatin Protein Generation

Trating macrophages can generate AP from plasminogen (20). Also, several human prostate carcinoma cell lines were shown to express a serine protease(s) that could convert plasminogen to AP (19). More recently, it was shown that AP activity could be generated by the proteolysis and reduction of plasmin (21). In the generation of plasmin, plasminogen is first converted to the active serine protease plasmin by hydrolysis cleavage of the Arg561-Val562 peptide bond, and an autoproteolytic release of the amino-terminal peptide by cleavage of the Lys77-Lys78 peptide bond (Fig. 1). The five K domains (heavy chain) of plasmin are covalently attached to the serine proteinase module (light chain) by two disulfide bonds. Stathakis et al. (21) suggest that a cell-derived plasmin reductase, generated, in their case, by Chinese hamster ovary or HT1080 cells, then reduces the disulfide bonds and releases the heavy from the light chain. They then show that this reduction of plasmin disulfide bond(s)...

Natural product analogs

Gossypol is a natural product derived from cottonseed extracts that causes male infertility and has been studied extensively in humans as a male contraceptive. This compound is cytotoxic to a variety of cancer cell lines and was advanced to human clinical trial on this basis even though its mechanism of action was not clear. More recently, gossypol was discovered in a natural product library screens to bind Bcl-XL 25 . Given its clinical history and this possible mechanistic rational, gossypol has been the focus of many recent investigations 25-30 . The (-)-enantiomer, 1, is responsible for the majority of both the cytotoxic and spermicidal activities. It binds both Bcl-XL (K 0.57 mM) and Bcl-2 (K 0.46 mM) and induces cytochrome c release, caspase activation and apoptotic death in numerous cell lines. (-)-Gossypol, 1, reverses the protection afforded by both Bcl-2 and Bcl-XL overexpression in Jurkat T leukemia cells with an IC50 of 18.1 mM and 22.9 mM, respectively, and dose...

Diet Nutrition And Cancer Historical Perspectives

The development of food availability data and dietary surveys coupled with statistics on cancer incidence and mortality in many nations around the globe provided the first examples of provocative associations between human cancer risk and dietary intake (6-10). The observations that human cancers exhibit 10- to over 100-fold variations in incidence among different geographic and cultural areas suggested to some investigators that diet and nutrition was a critical etiologic factor. This concept was greatly strengthened when studies of migrant populations from low-risk areas to high-risk areas frequently showed dramatic increases in cancer incidence, suggesting that environment and lifestyle, not genetics, plays the major role in the origins of most common cancers (1618). Variations in dietary patterns and the intake of specific nutrients were among the factors most frequently found to change in migrant populations experiencing increases in several malignancies, especially those of the...

Leads discovered by virtual screening

Computational screening of a 3D structure database of natural products was the starting point for the discovery of embelin, 34, isolated from the Japanese Ardisia herb 85 . Embelin binds the BIR3 domain of XIAP with an IC50 4.1 mM and NMR analysis confirms several key interactions with residues crucial for binding to SMAC and caspase-9. Embelin (25-50 mM) induces cell death and caspase-9 activation in PC-3 prostate cancer cells with high XIAP expression levels. In XIAP-transfected Jurkat cells, embelin (50 mM) reverses the protection afforded by overexpression of XIAP against etoposide-induced apoptosis.

Leads discovered by chemical library screening

Screening of several combinatorial libraries using an enzyme de-repression assay that measures relief of XIAP-mediated suppression of caspase-3 led to the identification of a series of polyphenylureas exemplified by 35 86,87 . Unlike the peptides derived from the SMAC N-terminus, the active polyphenylureas were shown to inhibit XIAP by binding to the BIR2 domain of XIAP, consequently leading to the activation of downstream executioner caspases-3 and 7. These compounds, but not inactive controls, induced rapid apoptosis in several tumor cell lines. Urea 35 induced significant tumor growth delay in PPC1 prostate cancer and HCT116 colon cancer murine xenograft models, but displayed little toxicity to normal tissues at high concentrations.

Other Novel Antiproliferative Agents

DU145 (prostate) PC-3 (prostate) LNCaP (prostate) Screening natural products for anticancer activity remains productive, and novel compounds continue to be identified in this manner. Decursin 13 is a coumarin compound that was isolated from Korean angelica gigas root and prepared via total synthesis in 2003 36 . Like the flavonoids, it exhibits a variety of biological activities, including antibacterial, neuroprotective, and antioxidant. However, only recently has 13 been demonstrated to possess in vivo activity in murine sarcoma 180 37 and to inhibit growth and induce cell death in human prostate cancer cell lines DU145, PC-3, and LNCaP 38 . Its inhibitory mechanism appears to be associated with G1 arrest in DU145 and LNCaP cells and its apoptotic effect is linked to both caspase-dependent and -independent pathways. Notably, it has no effect on normal PWR-1E prostate epithelial cells.

Miscellaneous heterocyclic systems 351 Benzimidazoles

Benzimidazole-pyridones were among the early small molecule chemo-types described as ATP-competitive inhibitors of IGF-1R. The initial screening hit was optimized for potency and Cytochrome p-450 (CYP) inhibition to provide an early lead structure, BMS-536924, 21 52-60 . This compound inhibits both IGF-1R and IR with equal potency (IC50 120 nM), is selective versus other kinases, inhibits the phosphorylation of Akt and MAP kinase (MAPK) in cells, and blocks proliferation in a wide variety of human cancer cell lines including colon, breast, lung, pancreas, prostate, sarcoma, and multiple myeloma (IC50's of 110-460 nM). Tumor growth inhibition is observed in vivo when dosed orally in the IGF-1R Sal tumor model 46 and in a broad range of human tumor xenografts such as Colo205, Geo, and RD1 (50-100 mg kg). Oral bioavailability is observed across all species, and a twofold window between antitumor efficacy and glucose elevation at the efficacious dose was reported 55 . Benzimidazole 21...

Non Atpcompetitive Inhibitors

To date, none of the synthetic catechols or their close analogs discussed above have progressed into clinical development. The naturally occurring bis-catechol, nordihydroguaiaretic acid, 33 (NDGA, INSM-18), has advanced to phase II clinical trials using continuous oral dosing for the treatment of prostate cancer 75-77 . NDGA inhibits IGF-1R phosphorylation of a synthetic nonspecific tyrosine kinase substrate and proliferation of MCF-7 breast cell line with an IC5o of 0.9 and 24.6 p.M respectively. Some early positive clinical data is now emerging from the prostate trial with respect to reduction in prostate-specific antigen (PSA) levels and delay in PSA doubling time in patients. Doses up to 2,500 mg day are tolerated with minimal toxic effects. NDGA has Her-2 receptor kinase and 15-lipoxygenase inhibitory activity. Although there is no direct mention of 33 being a non ATP-competitive IGF-1R inhibitor, it is a non ATP-competitive inhibitor of FGFR3 tyrosine kinase 78 .

Functional Genomics Applications

Microarrays have also been used to describe the effects of overexpression of the transcription factor EGR1 on prostate carcinoma cells (22). EGR1 is naturally overexpressed in prostate cancer, and its target genes were found in the cell line to include several growth factors (including insulin-like growth factor and platelet-derived growth factor) as well as neuroendocrine genes, proteases and signalling proteins.

Have early menopause What does this mean for my bones and will I need treatment

And fragility fractures when treated with GnRH agonists for prostate cancer. GnRH agonists such as Lupron are also used to treat endometriosis in women. Bone loss is one of the major side effects of Lupron. Advanced breast cancer, advanced prostate cancer, and a cancer called multiple myeloma are all associated with bone metastases. The spread of cancer cells to the bone causes loss of strength of the bone, significant pain, and an increased risk of fracture. So those with cancer can have considerable bone loss and a significant increase in fractures, which result from the treatments for the cancer and the spread of the cancer itself.

AKT pathway inhibitors with an undefined mechanism of action

9-Methoxy-2-methylellipticinium acetate (API-59-OMe, 24) has previously been reported as an AKT kinase pathway inhibitor in human endometrial cancer cells 36 . Similar results have been shown with 24 in ovarian cancer cell lines (A2780, MDAH2774 and OVCAR-8) 37 . The A2780 and MDAH2774 lines have high levels of activated AKT, while OVCAR-8 exhibits endogenous amplification and expression of AKT-2. Treatment of the cells with 24 significantly inhibited AKTmediated phosphorylation of Bad at Ser136 and GSKa p at Ser21 9 as measured by an IP kinase assay. Chloro-2-methylellipticinium acetate (CMEP, 25) was profiled against a series of prostate cancer lines (Cl-1, LNCaP and PC-3) having high basal levels of AKT inhibition 38 . In these cell lines, 25 significantly reduced AKT-mediated phosphorylation as measured by an IP kinase assay. Compound 25 also induced apoptosis in these cells when dosed at 10 pM.

Pi3kakt Kinase Pathway Inhibitors In Clinical Trials

Perifosine (27) is a synthetic, orally available alkylphospholipid, derived from alkylphosphocholine, which targets the PI3 AKT survival pathway. Although the molecular mechanism underlying the antineoplastic activity of 27 is not fully elucidated, studies suggest that 27 interferes with turnover and synthesis of natural phospholipids. This disrupts membrane signaling at several sites resulting in the inhibition of the PI3K AKT survival pathway 42,43 . Recent preclinical evaluation in cultured human Jurkat T-leukemia cells has shown that adding low concentrations of 27 (5 mM) after treatment with the commonly used chemotherapy drug etoposide, induced cell death in a synergistic fashion. The observed increase in cell death is attributed to an inactivation of the AKT survival pathway, as treated cells showed a complete dephosphorylation of AKT 44 . Compound 27 also inhibited baseline phosphorylation of AKT in multiple myeloma cells in a time- and dose-dependent fashion 45 . Reduced...

Measurement of PSA in Circulation

PSA was first detected in the serum of prostate cancer patients in 1980 27 . After the clinical study by Stamey et al. serum PSA became a widely used marker for early detection, screening, and monitoring of prostate cancer 2, 9 . However, PSA is not tumor specific but rather organ specific. Thus, prostate cancer, BPH, and prostatitis can all cause increased PSA concentrations in circulation. Manipulation of the prostate, for example, cystoscopy and prostate biopsy, also increase the concentrations of serum PSA 98, 99 .

Radiation Proctopathy

The rectum, because of its fixed position in the pelvis and proximity to the prostate and uterus, is the most common GI site of radiation injury (50,51). In a series of 738 patients with prostate cancer treated with radiation, proctitis of at least moderate severity was seen in 5 and anorectal stricture or fibrosis in 1 (52). The incidence of severe proctitis was less than 1 , and most presented within 2-5 years after radiation exposure. Other studies have noted rates of proctitis of up to 20 . Acute radiation injury may develop during or shortly after radiation

Animal Models of Lung Cancer

Xenotransplantation of human tumors into immunocompromised mice began in the late 1960s 58 following the discovery of the nude mouse in 1962 and its characterization as an athymic mutant in 1968 59 . The morphologic and karyotypic stability of tumors serially passaged in nude mice was described 60 , and it was established that xenotransplanted tumors in nude mice often retained distinctive phenotypic and functional characteristics found in the human host 61 . However, the tumor-take rate for nude mouse xenotransplants is tumor-specific, and generally, carcinomas are more difficult to establish than melanomas or sarcomas 62 . Thus, progressive tumor growth from inoculated primary tumors (i.e., cultured directly from the patient) is observed in only 33 for lung cancers 61, 63 and is virtually nil for primary breast or prostate cancers. In addition to properties inherent to the tumor, nude-mouse-related factors also impact on tumor take. For example, mice infected with the mouse...

Antibiotic Pharmacokinetics and Pharmacodynamics

An understanding of antibiotic pharmacokinetics and pharmacodynamics is critical, but these processes are complicated and may vary among classes of antibiotics and individual agents within the class. Pharmacokinetics refer to the serum and tissue levels of antibiotics, whereas pharmacodynamics refer to the antibiotics' abilities to inhibit and or kill bacterial pathogens (17,18). Pharmacodynamic properties of specific antibiotics should be considered in selecting an optimal dosing regimen. For example, while some antibiotics penetrate well and achieve high local concentrations at specific sites, others do not. Many antibiotics do not achieve therapeutic levels in specific tissues, like the prostate (ampicillin and cephalosporins), the lung (daptomycin), or the central nervous system (first- and second-generation cephalosporins), despite being reported as sensitive by in vitro laboratory testing. Also, most beta-lactam antibiotics achieve less than 50 of their serum concentration in...

PAdrenergic Receptors

Initially, adrenergic receptors were classified as either a or p, based upon the tissue response to various sympathomimetic amines. The receptor population that mediated excitatory responses was called a, and the potency ranking was epinephrine > norepinephrine > a-methyl norepinephrine > a-methyl epinephrine > isoproterenol. The receptor population that mediated inhibitory responses was designated as p, and had an agonist order of potency of isoproterenol > epinephrine > a-methyl epinephrine > a-ethyl norepinephrine > norepinephrine. It later became recognized that although generally correct, this classification was overly simplified, and the a- and p -receptors were further subclas-sified. For p-adrenergics it is now recognized that there are three receptor groups p b p2, and p3. The p radrenergic receptors are primarily located in the brain, the heart, and the pineal gland, the p2-adrenergic receptors are primarily in the lung and prostate, and the p3-adrenergic...

Summary and Discussion

We have presented for discussion a broad-based review of the utility of adenoviral vectors in animal models of lung cancer. Since this entire compilation is devoted to Ad-gene therapy, we have particularly embellished the sections on animal models of disease, especially as they pertain to lung and prostate cancer. These examples illustrate that the development of our approaches may need to be disease specific, especially with respect to targeting and mode of delivery. From this review, it is evident that to realize the full potential of cancer gene therapy, advances need to be made on a number of fronts. Not only do we need to construct better Ad-vectors or more relevant animal models, we also need to incorporate emerging technologies to a useful purpose within the experimental design. For example, the pathway to human clinical trials may be better paved by an improved ability to gather interim surrogate measures of gene transfer and expression in animal models.

Angiostatin and Endostatin

Angiostatin, a proteolytic fragment of plasminogen composed of kringles 1-4, originally isolated from the urine of C57Bl mice bearing the LLC, was shown to be an inhibitor of angiogenesis in several assays, and to inhibit the growth of tumor metastases, by O' Reilly et al. (109). Angiostatin can be generated in vitro by the limited proteolysis of human plasminogen by elastase (110,111). The enzymatic mechanism by which angiostatin is generated in vivo remains unknown. Angiostatin was shown to inhibit the proliferation of endothelial cells in culture, and to induce tumor dormancy as defined by a balance of apoptosis and proliferation, resulting in no growth in lung metastases (112). O'Reilly et al. (112) went on to show that systemic administration of angiostatin to SCID mice bearing human tumor xenografts could inhibit the growth of those tumors, including PC-3 prostate carcinoma, Clone A colon carcinoma, and MDA-MB breast carcinoma. Administration of human angiostatin also inhibited...

New Therapies From Existing Drugs

History is replete with examples of compounds that were originally developed for one disease and subsequently found to be beneficial in another. In contrast to the hypothesis-driven philosophy of modern drug discovery, many highly successful new treatments have been discovered by serendipity 3,5,12-14 . The phosphodiesterase (PDE-5) inhibitor, sildenafil for example was originally developed as a potential anti-angina therapy but was observed during early clinical trials to be efficacious for male erectile dysfunction, for which it was subsequently first approved. Further studies on sildenafil have expanded its label to include approval for pulmonary arterial hypertension. The alpha-2 adrenergic agonist, brimonidine, was originally synthesized as an anti-hypertensive and later discovered and marketed as an anti-glaucoma agent. Further examples of drugs with unexpected benefits beyond their initially approved indications include bupropion, which is approved as a smoking cessation drug,...

Classification Of Human Cancers Using Microrna Expression Profiles

At the other end of the spectrum, several groups have been trying to identify new miRNA genes in silico 14 . In this analysis, a comparative genomics approach was taken. By looking at the 3'-UTRs across human, mouse, rat and dog genomes, Xie et al. discovered 106 conserved motifs. These motifs were reminiscent of many miRNA binding sites based on their length, distribution and the fact that they tended to end with the nucleotide A, which is a characteristic of miRNA sequences. Further analysis of the 106 motifs by searching for complementary sequences in the miRNA database found 72 of the motifs to be complementary to known miRNAs. Additionally, 242 conserved and stable stem-loop sequences were found in the conserved sequences (across the four genomes) that were complementary to the 72 motifs mentioned above. These represented 113 sequences that encode already discovered miRNAs and 129 novel predicted miRNA genes. A representative set of 12 predicted new miRNA genes were tested in a...

Drug discovery opportunities

Generally, an imbalance between histone methylation and demethylation appears to be correlated with tumorigenesis, and several demethylases are implicated in the pathogenesis of cancer. Both LSD1 and JARID1B are overexpressed in prostate cancer, and LSD1 expression correlates with tumor recurrence during therapy 64 . LSD1 also demethylates p53, repressing p53-mediated transcriptional activation and inhibiting the role of p53 in promoting apoptosis 22 . JARID1B and JMJD2C are over-expressed in breast and testis cancer and esophageal squamous carcinoma 65 . RNAi knockdown of JMJD2C inhibited cell proliferation and highlights this isoform as a potential therapeutic target 16 .

Enhancing Utility of PSA by Multivariate Methods

PSA is a sensitive diagnostic marker for prostate cancer, but its use is hampered by a high rate of falsely elevated values. Approximately 75 of men with a PSA of 4-10 g liter do not have prostate cancer in biopsy. This causes unnecessary anxiety and costs. The proportion of free PSA in serum can be used to reduce the number of unnecessary biopsies by about 20-30 184, 185 . Many other variables, such as prostate volume, digital rectal examination findings and different molecular forms of PSA have been evaluated in order to reduce the number of unnecessary biopsies. However, for the clinician it is difficult to make an accurate biopsy decision based on many variables. With multivariate methods, that is, by using regression and neural network techniques, the utilization of several variables can be optimized and made easier. PSA-based algorithms have also been developed for staging and prognosis of prostate cancer. 7.2.1. Diagnosis of Prostate Cancer The most common type of multivariate...

Non Smoothened inhibitors 321 Hedgehog protein

Two low-molecular weight compounds, 25 (GANT58) and 26 (GANT61), were identified, which inhibit Hh signaling downstream of Smo and SuFu at the level of Gli with an IC50 of 5 p.M in a Gli-luciferase cellular assay 60 . Mechanistically, both inhibitors act at the nucleus to block Gli function, and one of them, 26, interferes with DNA binding of Gli1. Both compounds display selectivity for the Hh pathway over several unrelated signal transduction pathways such as the TNF NFkB signaling, glucocorticoid receptor gene transactivation, and the Ras-Raf-Mek-Mapk cascade. Subcutaneous application of 26, dosed at 25mg kg day for 18 days, in a human prostate cancer xenograft mouse model induced growth regression with concurrent strongly reduced mRNA levels of Ptch.

Vitamin E And Pkc Inhibition

Use of vitamin E as an antioxidant agent for potential beneficial effects in coronary disease and cancers. Results from large multicenter clinical trials are now becoming available. A study on coronary heart disease in women (113) and in men (114) showed that increased vitamin E intake was associated with a significant risk reduction for coronary heart disease. Additionally, a recently published study involving male smokers in Finland (115) showed a 32 decrease in the incidence of prostate cancer in subjects taking 50 mg vitamin E day. Interestingly, in this study there was a 23 increase in prostate cancer in those subjects randomized to P-carotene. Clinical studies aimed at characterizing the effect of vitamin E in the eye have focused primarily on the potential benefit of vitamin E in age-related macular degeneration (116,117), retinitis pigmentosa (118), and retinopathy of prematurity (119). The results from these studies are suggestive that vitamin E specifically and other...

Practical Clinical Applications

Treatment regimens are often based on the predicted clinical outcome thus, physicians differentially administer aggressive or conservative therapies. This is especially true for prostate cancer, where some men develop advanced disease at a young age and others are merely under observation for prolonged periods of time. To better characterize the immune response in prostate cancer patients, a study was conducted using HPLC and protein microarrays. 2D liquid chromatography was used to separate proteins from the prostate cancer cell line LNCaP into 1760 fractions. These fractions were spotted onto microarrays, which were then incubated with serum samples from men with prostate cancer and male controls. A bioinformatics-based decision tree with two levels of partitioning classified the samples with 98 accuracy as either prostate cancer or control. These results indicated that patterns of immune recognition generated from microarrays of fractionated proteins could be used for prostate...

Diagnostic Signatures

For diagnostic signatures to be relevant in a clinical setting, a number of factors need to be considered. Ideally, clinically useful diagnostic signatures should be measurable in a readily accessible body fluid such as serum, urine, or saliva, making diagnosis noninvasive. A recognizable signature should be evident prior to the onset of clinical symptoms. Early diagnostic signatures would be valuable for monitoring patients for postoperative infection and for population-screening, as prostate-specific antigen is used to screen for prostate cancer. Furthermore, diagnostically useful signatures should be specific for a given disease. Certain signatures may be common to diseases such as cancers or infections, but useful signatures should distinguish between tumor classes and pathogen types. Lastly, signatures are present in a dynamic biological system and normal variation among healthy individuals must be taken into account. Genetic factors, age, gender, time of day, or environmental...

History and Physical Examination

The focus initially should be to establish the quantity and color of blood and elicit any symptoms of hemodynamic instability that would require immediate intervention. The medical history can then evaluate previous GI bleeding episodes and diagnoses associated with recurrent episodes of bleeding. These include diverticulosis, angiodysplasias, hemorrhoids, ulcers, varices, or inflammatory bowel disease. Other important history findings include comorbid diseases, coagulopathies, liver disease, nonsteroidal antiinflammatory drug use (NSAID), and radiation therapy affecting the abdomen or rectum (prostate). NSAID use is a very important risk factor, now recognized as the cause of not only upper GI bleeding, but also increased lower GI bleeding.

Protein Detecting Microarrays

In another study, a screen of potential serum biomarkers of human prostrate cancer identified five proteins with significantly diVerent expression levels between 33 prostate cancer samples and 20 healthy controls (M3). These proteins were detected by antibodies spotted on either microscope slides coated with (HSAB) or acrylamide-based HydrogelTM-coated slides. One hundred and eighty-four antibodies to target serum proteins and intracellular proteins were spotted in quadruplicate. The sample proteins were labeled directly with fluorescent tags and compared to a reference sample consisting of equal volumes of all serum samples. Labeling the sample eliminates the need for paired antibodies able to detect noncompeting epitopes of a protein, but can lead to bias. To control for labeling bias, the samples and reference were alternately labeled with different fluorescent tags (reverse labeling). Labeling bias due to diVerent fluorophores can be controlled this way, but

Evaluation by the International Agency for Research on Cancer

The IARC also concluded that in experimental animals, there is sufficient or limited evidence for a cancer-preventive effect of avoidance of weight gain by calorie restriction, based on studies of spontaneous and chemically induced cancers of the mammary gland, liver, pituitary gland (adenoma), and pancreas, for chemically induced cancers of the colon, skin (nonmelanoma), and prostate, and for spontaneous and genetically induced lymphoma. An association between overweight and obesity and cancer at many sites is consistent with animal studies showing that caloric restriction dramatically decreases spontaneous and carcinogen-induced tumor incidence, multiplicity, size, and growth (28-32). Possible mechanisms for these observations include altered carcinogen metabolism, decreased oxidative DNA damage, greater DNA repair capacity (18), and a reduction of IGF-I levels in calorie-restricted animals (30).

Conclusions 61 Prognosis

Highly promising prognostic value Assessment of vascularization seems to be a new relevant prognostic tool in early-stage invasive breast, NSCLC, and prostate cancers. In these three tumor types, the majority of retrospective studies found a significant correlation between vascularization of the primary tumor and clinical outcome of the patients. Therefore, prospective controlled studies to evaluate the clinical significance of angio-genesis are particularly recommended in such tumors.

Endoscopic Therapy

Bleeding from multiple telangiectatic lesions in the distal colon produced by radiation therapy for prostate or gynecologic cancers (radiation proctitis or colitis) can be effectively treated with thermal contact probes, laser therapy, or newer noncontact modalities such as the argon plasma coagulator.

How do you determine the level of anesthesia needed for different types ol surgeries What is a segmental block When is

To provide adequate surgical blockade with an epidural anesthetic, it is necessary to know the innervation of the structures stimulated during the procedure. For example, a transurethral resection of the prostate requires a T8 level because the bladder is innervated by T8 through its embryologic origins. A laparotomy such as a cesarean delivery requires a T4 level to cover the innervation of the peritoneum.

Apoptosis Programmed Cell Death

When mutations or genomic alterations cause increased levels of apoptosis-inhibiting Bcl-2 proteins, apoptosis is blocked, and cell survival is prolonged. When BCL2 gene mutations of this type occur in combination with oncogenic mutations, the likelihood of cancer is increased, because potential cancer cells are not destroyed by apoptosis. Overproduction of Bcl-2 proteins has been associated with chronic lymphocytic leukemia (CLL) and cancers of the lymph nodes, prostate, lungs, breast, nose, and throat.

Overview Of Clinical Trial Experience

Clinical trial experience with TNP-470 presently includes seven phase I and five phase II studies, in which more than 300 patients have been treated. All except one phase I study (pediatric malignancies) are for adult patient populations, including individual phase I studies in patients with hormone-refractory prostate cancer and cervical cancer, two in patients with solid tumors and two in AIDS-associated Kaposi's sarcoma (KS) patients. Three of these studies have concluded (prostate, cervical, and AIDS-associated KS), but the two solid tumor, one AIDS-associated KS and the pediatric study are ongoing. Phase II patient populations are limited to glioblastoma multiforme, locally advanced pancreatic cancer, and advanced breast, cervical, and renal cancer. Approximately two-thirds of the total number of patients exposed to TNP-470 derive from the phase I experience, and these are the data that will be discussed in this chapter. Findings in the pediatric phase I study are preliminary and...

Duration Of Treatment And Outcomes

The median duration of treatment ranged from 27 to 69 d, representing one treatment course in each of three studies (cervical cancer and two solid tumor) and two treatment courses in the prostate cancer study. Total duration of treatment ranged from 1 to 672 d. Four patients were treated for greater than 1 yr. These include two women with advanced cervical cancer (508 and 652 d), one patient with a fibrous histiocytoma (672 d), and one patient with advanced colon cancer (388 d).

The Relationship of IgE to Cancer

In what may be a myth, there exists a poorly founded notion among some physicians that allergic people may be more resistant to certain forms of cancer. This concept was initiated by a report of Cockroft et al. in 1979, which summarized a comparative survey of 392 patients with three types of malignancy and 303 controls and concluded that the patients with endodermal neoplasia (lung, gut, bladder, prostate) had lowered forms of allergic disease. The major weakness of the survey was that the sample sizes were too small to be significant. In two other notable surveys done in later years with larger patient populations, the results were largely either contrary to the earlier study or too variable to make definitive conclusion.

Doselimiting Toxicities And Determination Of Maximumtolerated Dose

DLTs were reported for three of 32 prostate cancer patients, two of 21 cervical cancer patients, and five of 68 solid tumor patients. Excepting one report of hemoptysis (grade 1), which occurred in a patient with NSCLC with a history of similar episodes, all were neurological in nature. DLTs involving complaints of gait and coordination disturbances, memory impairment, increased anxiety, and emotional lability were observed in three prostate cancer patients at two dose levels, 70.6 (two patients) and 105.9 (one patient) mg m2. In two cases, the DLTs presented within the first 3 wk of treatment in one case they were delayed and reported after the 2-wk rest period. Two cervical cancer patients experienced DLTs following treatment at 71 mg m2 for 4 wk these consisted of gait disturbance as well as dizziness and nystagmus. In the solidtumor study administering TNP-470 every MWF, a single DLT (grade 1 unsteadiness) was reported in a patient with melanoma after 102 d of treatment at 32.4 mg...

Other Safety Findings

An additional toxicology finding, the development of cataracts in dogs following 3 mo treatment with TNP-470, was monitored closely by the incorporation of serial ophthalmologic examinations into the study design. In two cases, a 69-yr-old prostate cancer patient and a 70-yr-old female patient with metastatic colon cancer, the development of cataracts was recorded. The former patient was treated with 47.2 mg m2 of TNP-470 for 126 d prior to cataract detection, and the latter received TNP-470 at 235 mg m2 for 85 d before mild cataract changes were noted. In both cases, earlier ophthalmologic examinations during treatment did not show these changes.

The Impact Of Genetic Variation And Cancer Heterogeneity On Immune Responsiveness

As we previously discussed, genetic background may influence immune responsiveness. However, the genetic background of patients has not been extensively scrutinized as a predictor of immune responsiveness (16). Obvious genetic markers that may affect immune responsiveness are the HLA complex that codes for molecules responsible for antigen presentation to T cells (51). However, correlates between HLA phenotype and treatment outcome or survival failed to provide conclusive evidence that individual variability in antigen presentation may determine immune responsiveness in the context of anti-cancer immune therapy (18 52 53). Others have pointed to other polymorphisms as harbingers of immune responsiveness. For instance polymorphisms of the IL-10 gene appears to be responsible for differential levels of expression of this cytokine in various conditions. Interestingly, individuals with a phenotype associated with low IL-2 production appear to bear an increased incidence of melanoma and...

Signaling Milieus At The Effector Sites

Systemic hormones support mucosal immune functions at several different effector sites. Ventral prostate and urethral gland epithelial cells express pIgR, and IgA+ cells populate the underlying tissue spaces, and castration decreases pIgR expression. In the rat, the effect of castration can be reversed by either estradiol or dihydrotestosterone, but neither hormone has a substantial effect on IgA+ cell content (91). In contrast, testosterone prevents the effects of castration on both pIgR expression and IgA+ cell number in the mouse prostate and urethral glands (92). To the extent data on the mouse prostate and urethral glands are available, they resemble the extensive body of data on hormonal influences on pIgR expression and IgA+ cell infiltration in the rodent lacrimal gland that has been published by Sullivan et al. (93,94). The pattern of systemic hormonal influences on secretory immune functions in the mammary glands differs markedly from the patterns in the lacrimal glands and...

Abarelix Anticancer [68

Abarelix is an antagonist of the gonadotropin releasing-hormone (GnRH) receptor, and it was launched last year as an intramuscular injection for the palliative treatment of advanced symptomatic prostate cancer. Hormonal therapy of prostate cancer is based on the modulation of testosterone to achieve medical castration levels. The inhibition of GnRH activity causes the suppression of luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion, thereby reducing the secretion of testosterone by the testes. Abarelix is the first GnRH antagonist to reach its market. Hormonal therapy with GnRH agonists such as leuprolide, buse-relin, and goserelin has been in use for over two decades. Drugs of this type achieve the suppression of LH and FSH by a feedback inhibition mechanism, which involves an initial rise in the LH and FSH levels and, consequently, in the levels of testosterone. A testosterone surge may induce a clinical tumor flare that worsens

Accessory Male Organs Add the Semen

Semen is added to the spermatozoa from a number of accessory male reproductive organs. These organs include the two seminal (SEM-ih-nal) vesicles, the two bulbourethral (BUL-boh-you-REE-thral) glands, and the single prostate (PRAH-state) gland. The seminal vesicles store the ''semen'' (semin). The bulbourethral glands (Figure 15.4) are like two tiny ''bulbs'' attached to the sides of the ''urethra.'' And the prostate gland is a large, walnut-shaped body that ''stands'' (stat) just ''before'' (pro-) the urethra.

Lincomycin and Clindamycin

Clindamycin is rapidly removed from serum to body tissues and fluids and it penetrates well into saliva, sputum, respiratory tissue, pleural fluid, soft tissues, prostate, semen, bones, and joints (62), as well as into fetal blood and tissues. No data exist to show that significant concentrations are achievable in the human brain, cerebrospinal fluid, or eye.

Reflex Control Of The Lower Urinary Tract

Onufs Nucleus

Contrast to the supraspinal organization of the bladder reflex initiated by myelinated AS fibers, the bladder reflex that is initiated by unmyelinated C-fibers is organized within the sacral spinal cord (not shown in Figure 1.) The bladder C-fibers also have their cell bodies in the sacral DRG and probably also project along Lissauer's tract and the lateral projection to activate second order neurons. However, unlike the supraspinal micturition reflex pathway, the C-fiber reflex does not depend on supraspinal communication to activate sacral parasympathetic preganglionic neurons. The parasympathetic efferent pathway of this C-fiber spinal reflex and the A8 fiber supraspinal reflex are the same. The C-fiber spinal reflex, however, is not consistently demonstrable in animals with an intact spinal cord, unless the bladder outlet is obstructed for weeks or under conditions of bladder inflammation or irritation. Importantly, loss of descending control following spinal cord injury also...

The History of Anatomical Terminology

About 90 of today's medical terms are formed from just 1,200 Greek and Latin roots. Scientific investigation began in ancient Greece and soon spread to Rome. The Greeks and Romans coined many of the words still used in human anatomy today uterus, prostate, cerebellum, diaphragm, sacrum, amnion, and others. In the Renaissance, the fast pace of anatomical discovery required a

Immunoassays for the Quantification of uPAR

Prostate Cancer In prostate cancer, uPAR is located on neutrophils and macrophages as demonstrated in tissue from 16 patients with histologically confirmed prostate adenocarcinoma 140 . uPAR protein was detected in specimens from all patients. The antibody used for immunohistochemical staining was an anti-suPAR1-277 pAb 87 and the staining pattern of the control mAb R2 was identical. In 8 of the 16 cases of prostate cancer, uPAR was identified in a subpopulation of macrophages mainly found in the interstitial tissue. In all 16 cases, the anti-uPAR pAb stained intravascular neutrophils, while none of the cases demonstrated staining in cancer cells. When benign prostate hyperplasia (BPH) from nine patients were analyzed, eight patient samples had uPAR positive macrophages, which were located in the lumen of glands, intraluminal, and in one case in the interstitial tissue. In seven cases, intravascular neutrophils stained positive for uPAR 140 . A possible correlation...

Ispinesib and related compounds

Ispinesib has also been examined in Phase Ib clinical combination with docetaxel 13 , capecitabine 14 , and carboplatin 15 . The DLT for the combination of ispinesib and docetaxel was prolonged (X5 days) grade 4 neutropenia, and the optimally tolerated regimen (OTR) was defined as 10mg m2 of ispinesib and 60mg m2 of docetaxel, each administered once every 21 days. Ispinesib and docetaxel plasma concentrations were consistent with those previously reported when each drug was given as monotherapy, suggesting no pharmacokinetic interaction between them. A total of 13 24 patients (11 prostate, 1 renal, and 1 bladder) had a best response of stable disease (duration 2.25-7.5 months) 13 . sensitive non-small cell lung cancer, ovarian cancer, hepatocellular cancer, colorectal cancer, head and neck cancer, hormone-refractory prostate cancer, and melanoma. In the ongoing breast cancer study, women with locally advanced or metastatic breast cancer, receive ispinesib as monotherapy at 18mg m2 as...

New Approaches for Detection of PSA

Immunopeptidometric assay (IPMA) is a new assay principle based on the use of PSA-binding peptides as a tracer in combination with a monoclonal capture antibody. In the assay all forms of PSA are captured by the immobilized monoclonal antibody, but only enzymatically active free PSA is recognized by the PSA-binding peptide (Fig. 3). The IPMA detects enzymat-ically active PSA, but not internally cleaved PSA or proPSA, which are enzymatically inactive. Between 1 and 10 of free PSA in serum from prostate cancer patients is detected by this assay 170 . The finding of active Charrier et al. 20, 146 have studied free PSA in serum from men with prostate cancer and BPH by two-dimensional gel electrophoresis and showed that BPH sera contain more low-molecular-weight forms of free PSA than prostate cancer sera. Jung et al. 172 reported a method, in which PSA was captured by immunoadsorption on streptavidin-coated magnetic beads with a biotinylated monoclonal antibody to PSA and separated by...

MMPs Identified in Urine of Patients with Cancer

In a subsequent study, Moses et al. (M16) reported that MMP-2 and MMP-9 in urine correlated with the presence of malignant disease, not just limited to the genitourinary tract. The presence of biologically active MMP-2 or MMP-9 alone in the urine was an independent predictor of organ-confined cancer the higher molecular weight MMP species (> 150 kDa) in the urine served as independent predictors of metastatic cancer (M16). The frequency of detection of the three MMP species in the urine was as follows normal or no evidence of disease (11-20 ), cancer (71 ), metastatic cancer (90 ). The frequency of urinary MMPs was significantly higher in patients with prostate and breast cancer, 75 and 100 , respectively. Odds of metastatic cancer were 30 times greater when the higher molecular weight MMP species were present in urine than when this marker was absent. A 125 kDa MMP was detected only in the urine of patients with breast cancer (M16). In-depth studies by Li et al. (Y2) demonstrated...

Interaction Between Venous Sinus Hypertension and CSF Pressure

92 Lam et al. 2001 Torcular epidermoid 1 (adult) 91 Lam et al. 1992 Radical neck dissection sigmoid sinus ligation 3 (adults) 91 Lam et al. 1992 CVC thrombosis 2 (adults) 53 Goldsmith et al. 1991 Ca prostate metastasis SSS compression 1 (adult) 132 Plant et al. 1991 Plasmacytoma & Ewing's sarcoma 2 (adults) 80 Keiper et al. craniectomy 5 (adults) 17 Bortoluzzi et al. 1982 Bilateral lateral sinus obstruction cause 1 (adult) 132 Plant et al. 1991 Occipital skull tumours 2 (adults) 82 Kim et al. 2000 Metastatic prostate cancer 1 (adult)

Urinary Tract Infections Urethritis Cystitis and Pyelonephritis

The structure of the urinary tract reduces the likelihood of infection by preventing urine from flowing backward toward the kidneys and by washing bacteria out of the body with the normal flow of urine. In men, the prostate gland also produces secretions that slow bacterial growth. Urine is normally sterile. obstruction of the urinary tract (such as a kidney stone or an enlarged prostate Urinary gland) also increases the risk of infection. People with diabetes, immune disor- Tract

Disorders of the Bladder and Urethra

Surgery is the most common treatment for bladder cancer. Superficial bladder cancer can be treated with transurethral resection, in which the tumor is surgically removed through a cystoscope. With invasive bladder cancer, all or part of the bladder is removed using a surgical procedure called cystectomy. Often, surrounding lymph nodes, the prostate gland, and the seminal vesicles also are removed. Additional treatment may include radiation therapy, chemotherapy (treatment with powerful anticancer drugs), or immunotherapy (treatment in which the body's immune system is stimulated to destroy cancer cells), depending on where the cancer has spread and how advanced it is. Until recently, nearly all men experienced erectile dysfunction after bladder removal surgery, but surgical improvements have reduced the likelihood of this side effect. However, men who have had their prostate gland and seminal vesicles removed no longer produce semen, so they do not ejaculate when they have an orgasm,...

Antigenic changes on malignant cells

The most common types of solid tumors for which more than 100 surgically removed primary lesions have been analyzed include head and neck squamous cell carcinoma (HNSCC), carcinomas of the breast, lung, colon, liver, kidney, cervix and prostate, melanoma, leukemia and lymphoma (20,128-130). For other tumors including stomach (131), pancreatic (132,133), bladder (134,135), ovarian (136,137), germ cell (138) and basal cell (139-141) carcinomas much less information is available regarding HLA class I antigen expression since the number of lesions analyzed is too low for one to draw definitive conclusions. With the exception of liver carcinoma (142-144), leukemia (129) and lymphoma (128,130), the frequency of HLA class I antigen loss and or downregulation has been found to range between 16 to 80 of the various types of tumors analyzed with mAb recognizing monomorphic determinants. The frequency of this phenotype varies significantly among different malignancies with breast carcinoma and...

The Arbroath Multiple Disease Study

The locations of all cases dying from ischaemic heart disease in 1966, 1971 and 1976 and of bronchitis 1966-76 were mapped. The grid coordinates of these deaths, and of the deaths from respiratory cancer, all non-respiratory cancer, gastric cancer, colorectal cancer, female breast cancer, prostate cancer and cancer of the bladder and kidney were determined. The distributions of these categories of death were illustrated using three-dimensional mapping.25 The method involves producing surfaces of the local density of cases where elevated areas relate to high density and low areas to low density. The resulting surface maps are produced by an 'optimal' smoothing method (cross-validation).26

Department of Biology Technion Israel Institute of Technology Haifa 32000 Israel

Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), high-performance liquid chromatography (HPLC), mass spectrometry (MS), tandem mass spectrometry (MS MS), post-translational modifications (PTMs), time of flight (TOF), multi-dimensional protein identification technology (MudPIT), enzyme-linked immunosorbent assay (ELISA), cancer antigen 125 (CA125), laser capture microdissection (LCM), cholamidoprophy dimethalammonio-1-propanesufonate (CHAPS), polymerase chain reaction (PCR), Human Proteome Organization (HUPO), Proteomics Standards Initiative (PSI), hematoxylin and eosin (H& E), Terry's Polychrome, (TP), Toluidine Blue (TB), Nuclear Fast Red (NFR), Cresyl Violet (CV), Methylene Blue (MB), tumor-specific antigens (TSAs), tumor-associated antigen (TAA), hepatocellular carcinoma (HCC), prostate specific antigen (PSA), graft-versus-host disease (GVHD), CD8 anti-viral factor (CAF), human immunodeficiency virus (HIV).

Urinary Tract and Genitourinary Suppurative Infections

Anaerobes have been involved in many different types of urinary tract infection (UTI). The types of infections of the urinary tract in which anaerobes have been involved include para- or periurethral cellulitis or abscess, acute and chronic urethritis, cystitis, acute and chronic prostatitis, prostatic and scrotal abscesses, periprostatic phlegmon, ureteritis, periur-eteritis, pyelitis, pyelonephritis, renal abscess, scrotal gangrene, metastatic renal infection pyonephrosis, perinephric abscess, retroperitoneal abscess, and other infections.

Adjunctive Cryotherapy

Nevertheless, advantage from the use of adjunctive chemotherapy is likely. Cooper et al., in animal experiments, concluded that the administration of cyclophosphamide potentiated cell-mediated immunity.113 Clarke et al.,23 24 freezing prostate cancer cells in vitro, demonstrated that a combination of freezing and 5-fluouracil was associated with a greater reduction in cell survival than either freezing or the drug alone. Mir and Rubinsky,109 freezing melanoma cells in vitro, and exposing them to bleomycin, reported that the cold injury made the cells permeable to the drug, which is of therapeutic interest because bleomycin does not normally enter the cells.

Androgen Metabolism Within the Skin

DHT is produced from testosterone within peripheral tissues such as the skin by the action of the 5a -reductase enzyme. Two isozymes of 5a -reductase have been identified (19). The type 1 isozyme is active within the sebaceous gland (20,21). The type 2 isozyme is most active in the prostate gland, where it can be inhibited by drugs such as finasteride. Activity of 5a-reductase and 17 -HSD exhibits regional differences depending upon the source of the sebaceous glands (9). In skin that is prone to acne, such as facial skin, activity of the type 1 5a-reductase in sebaceous glands is greater than in sebaceous glands obtained from nonacne-prone skin (20). This implies that more DHT is being produced in sebaceous glands from facial skin compared with other areas of the body that are not prone to develop acne. The net effect of the activity of these two enzymes is the greater production of potent androgens such as testosterone and DHT within sebaceous glands of facial areas, which may in...

Synergy of ARCA and Conventional Therapy

Although conventional cancer therapies (surgery, chemotherapy, and radiation) are effective at curing early-stage disease, few human cancers are curable with a single modality. The utilization of a replication-competent cytolytic adenovirus as a therapeutic modality shows much promise. In our laboratory and clinical trials, CV706 and CV787 have been shown to be effective against human prostate tumors 21-23 . However, single-dose total eradication of human LNCaP xenografts in our animal model required as much as one-third of the lethal dose of virus alone 22, 75 . To set the bar for efficacy high, namely single-dose efficacy, is deliberate. While multiple doses Radiation therapy, either administered through external beam or seed implantation (brachytherapy), is one of the most widely used therapeutic modalities for treatment of clinically localized prostate cancer 76, 77 . However, nearly 30 of patients treated with potentially curative radiation doses suffer relapse as defined as...

Mmp Inhibitors In Clinical Trials For Cancer

Prinomastat (AG-3340, 30) is being developed for the treatment of cancer and age-related macular degeneration. In May of 1999, 30 entered Phase III trials for lung and prostate cancers. The recommended dose for these trials was 5 to 25 mg, b.i.d. Following the demonstration of an enhanced efficacy of chemotherapy when supplemented with 30, pilot combination studies and double-blinded, placebo-controlled Phase III trials in 700 patients are in progress for the treatment of non-small cell lung cancer (NSCLC) or advanced hormone-refractory prostate cancer (69). A Phase III clinical trial of 30 in combination with chemotherapy in patients with advanced NSCLC has been initiated. This trial is designed to evaluate the safety and efficacy of 30 as part of first-line therapy in combination with chemotherapy. This trial advances the ongoing clinical development of 30 in combination with the anticancer drugs paclitaxel carboplatin for the treatment of advanced NSCLC and with mitoxantrone...

Asymptomatic Bacteriuria

Asymptomatic bacteriuria or asymptomatic UTI is the isolation of a specified quantitative count of bacteria in an appropriately collected urine specimen obtained from a person without symptoms or signs of urinary infection. Asymptomatic bacteriuria is common but its prevalence varies widely with age, gender, and the presence of genitourinary abnormalities or underlying diseases. For example, the prevalence of bacteriuria increases with age in healthy women from as low as about 1 among school girls to greater than or equal to 20 among women 80 years of age or older living in the community while bacteriuria is rare in healthy young men.13 Because its clinical significance was controversial (asymptomatic bacteriuria precedes UTI but does not always lead to asymptomatic infection), guidelines were recently published for the diagnosis and treatment of asymptomatic bacteriuria in adults older than 18 years of age.13 The foundation of these guidelines rests on the premise that screening of...

Dietary Lipids And Fatty Acid Patterns

The human and laboratory evidence is most convincing for a stimulatory effect of dietary lipid concentration, particularly a diet rich in saturated fats, on cancers of the colon and rectum (6,7,21). Less certain, but supported by many studies, are the positive relationships between diets rich in fat and cancers of the prostate, breast, lung, ovary, and endometrium (6,7,21). The possibility that diets rich in omega-3 fatty acids from marine sources have inhibitor properties for cancers has been postulated, and is currently an area of active investigation (6,7,21,109-114).

Interactions Between Food Energy Consumption Tumor Growth And Angiogenesis

Thus far, few studies have focused on the role of energy intake and tumor vascular biology. A recent report showed that the transplantable Englebreth-Holm-Swarm (EHS) sarcoma (46), grown in young mice fed reduced-energy intake, contained fewer blood vessels and increased matrix, compared to those fed ad libitum (47). These observations are supported by the authors' recent unpublished experiments. The authors have completed a series of studies employing total diet or energy restriction with a variety of rodent tumor models, and assessed tumor growth and its relationship to microvessel density, based on factor VIII staining. These studies show that energy or diet restriction significantly reduces microvessel density in several transplantable tumor models, including murine MB49 bladder cancer, RT2 rat glioma, Dunning R3327H rat prostate cancer, and LNCaP human prostate carcinoma grown in nude mice (48).

Approaches of Transcriptional Regulation

Prostate Prostated cancer Prostate Prostate Prostate 3. Prostate-Specific Antigen (PSA) Promoter a. Rationale The gene for prostate-specific antigen, a member of the glandular kallikrein family, was independently characterized by Riegman et al. 32, 33 and Lundwall 34 from a human genomic library. The gene contains five exons and is located on the long arm of chromosome 19, in the region ql3.3-qter 33 . The gene is 7130 bp long and includes 633 bp of 5' and 639 bp of 3' flanking sequence. The promoter region contains a variant TATA box (TTTATA) at position -28 to -23, a GC box at -53 to -48, a CACCC box at -129 to -125. An imperfect palindromic sequence (AGAACAGCAAGTGCT) closely related to the reverse complement of the consensus sequence for steroid hormone receptor binding (TGTACANNNTGTC TCT), is found at position -170 to 156. In addition, GGGAGGG and CAGCCTC repeats are located in the region 123 to 72. Expression of PSA is primarily detected in human prostate 35-37 . Further, PSA...

Emergence of MDR Pathogens

There has been a continued emergence of antibiotic resistance among numerous bacteria, mycobacteria, viruses, fungi, and parasites. Many bacterial resistance studies have focused primarily on trends toward greater in vitro resistance among different species of bacteria. In vitro or laboratory-related antibiotic sensitivities, as measured by MIC, represents the concentration of antibiotic required to prevent the growth of a selected inoculum of bacteria in a test tube or on an agar plate. The MIC thus represents the concentration of antibiotic that should be present for treating bacteremia, and does not account for penetration of the antibiotic into tissues, such as the central nervous system, lung, prostate, or bone (23). It is important to emphasize that such in vitro data may not be applicable to infections involving invasive devices, such as central venous or urinary catheters or endo-tracheal tubes that may have bacteria embedded in biofilm, impairing antibiotic penetration or...

Cross Talk Between Kallikreins A Possible Novel Enzymatic Cascade Pathway

The cross-talk between kallikreins and the hypothesis that they are involved in a cascade enzymatic pathway are supported by strong, but mostly circumstantial evidence, as follows many kallikreins are coexpressed in the same tissue (e.g., the adjacently localized kallikrein genes KLK2, KLK3, KLK4, and KLK5 are all highly expressed in the prostate) some kallikreins have the ability to activate each other and the ability of other serine proteases to activate kallikreins (see following) the common patterns of steroid hormonal regulation the parallel pattern of differential expression of many kallikreins in different malignancies (e.g., at least seven kallikrein genes are up-regulated in ovarian cancer, and at least seven kallikreins are down-regulated in breast cancer) and serine proteases commonly use other serine proteases as substrates.

Hormonal Regulation of Kallikreins

An interesting observation is the tissue-specific pattern of hormonal regulation of several of these genes in different tissues. For example, KLK4 is upregulated by androgen in prostate and breast cancer cell lines 148 and by estrogen in endometrial cancer cell lines 147 . Also, KLK12 was found to be upregulated by androgens and progestins in prostate cancer cell lines and by estrogens and progestins in breast cancer cell lines 156 . KLK14 and KLK15 are mainly regulated by androgens. Recent preliminary kinetic and blocking

Sequence Variations of Human Kallikrein Genes

Published mRNA sequences of KLK3 revealed infrequent and inconsistent sequence variations. Baffa et al. found no evidence of mutations in the KLK3 mRNA sequence in prostate cancer compared to matched normal tissues from the same patient 53 . Similarly, no mutations were found in the coding portion of the KLK3 gene in breast cancer tissues and cell lines, with the exception of a polymorphism in exon 2 in some breast tumors 54 . Three distinct forms of KLK1 mRNA, differing in one or two amino acid substitutions, were identified in different tissues 1, 55, 56 . Experimental evidence, however, indicates that the protein products of these variants have no difference in their protein activity 57 . Probably the most polymorphic sequence of KLK4 is that deposited by Hu et al. 41 . In addition to a large insertion in the 3' untranslated region, there are 18 differences between their sequence and those deposited by others. These probable polymorphisms will affect the derived amino acid product...