Azacitidine Anticancer [913

Country of Origin: Originator:

Pharmion US

Pharmion Vidaza 320-67-2 244.2

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Azacitidine is an antineoplastic agent launched last year for the treatment of myelodysplastic syndrome (MDS). MDS is a group of closely related diseases caused by abnormal blood-forming stem cells of the bone marrow. They are characterized by a hyperproliferative bone marrow, the presence of clonal blood cells with impaired morphology and maturation, and peripheral blood cytopenias resulting from ineffective blood cell production. The initial stem cell injury can be from cytotoxic chemotherapy, radiation exposure, chemical exposure, or genetic predisposition. Subsequently a clonal mutation predominates over bone marrow thereby suppressing healthy stem cells. Azacitidine is indicated for the treatment of all five subtypes of MDS, which consist of refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. Azacitidine is an analog of cytidine in which the carbon at position 5 of the pyrimidine ring has been replaced by nitrogen. It is prepared by the ribosylation of 5-azacytosine, which is derived from the condensation of amidinourea with either an alkyl orthoformate or N,N-dimethylformamide dialkyl acetal. The antineoplas-tic activity of azacitidine is derived from a combination of two different mechanisms. It inhibits DNA methyltransferase, which causes demethylation or hypomethylation of DNA. In addition, it exerts direct cytotoxicity on hyperpro-liferating abnormal stem cells in the bone marrow. After in vivo phosphorylation, azacitidine incorporates into DNA and forms covalent adducts with cellular DNA methyltransferase, thereby depleting the cells from enzyme activity and causing hypomethylation of genomic DNA. Hypomethylation restores normal function to tumor-suppressor genes, which are responsible for regulating cell differentiation and growth. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine. The recommended dosage of azacitidine is 75mg/m2 subcutaneously once daily for 7 days, and the cycle is repeated every 4 weeks. It is rapidly absorbed with peak concentrations achieved within 30 minutes of the dose. It has a bioavailability of 89% and a mean volume of distribution of 76±26 liters. Mean clearance of azacitidine is 167±49 L/hour, and the mean half-life of the parent drug is 41 ±8 minutes. The primary route of elimination for azacitidine and its metabolites is renal (85%), with a cumulative mean elimination half-life of 4 hours. The efficacy of azacitidine was demonstrated in a randomized, open-label, controlled clinical trial and two non-randomized trials involving 300 patients with any of the five subtypes of MDS. Approximately 14-19% of patients in these trials had an overall response rate (complete response + partial response) to azacitidine, which consisted of normalization of blood counts and decrease in bone marrow blasts percentage. The initial response was generally observed by the fifth cycle of treatment. The need for transfusions was also eliminated in responder patients. In all three studies, approximately 19% of patients met the criteria for improvement with a median duration of 195 days. The most common adverse events with azacitidine therapy include nausea, vomiting, myelosuppression, and infection. Dose-limiting toxicities include neutropenia and thrombocytopenia.

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