Steroids Tetracyclines and Heparins

Several studies have been reported using the Lewis lung carcinoma (LLC) growing subcutaneously in C57BL mice, with standard cytotoxic anticancer therapies, along with one or more new agents directed toward the normal cellular and extracellular compartments of the tumor (3-9). The Lewis lung tumor is relatively resistant to many cancer therapies, and, because this tumor metastasizes avidly to the lungs from subcutaneous implants, it is a suitable model for both primary and metastatic disease.

The angiostatic activity of several steroids was discovered some years ago; however, the mechanism by which these steroids inhibit vessel growth and/or produce regression of growing vessels is only now being elucidated (10-13). The most effective angiostatic steroid discovered was tetrahydrocortisol (THC), which lacks the 4,5 double bond in its A-ring, and, for this reason, lacks all of the known functions of cortisone.

In 1983, Folkman et al. (14) reported that heparin or a heparin fragment, administered in combination with cortisone, inhibited angiogenesis in the chorioallantoic membrane (CAM) assay and inhibited the growth of several solid murine tumors. The same group found that P-cyclodextrin tetradecasulfate, in combination with hydrocortisone, was 100-1000x more effective than heparin in combination with hydrocortisone in inhibiting capillary formation in the CAM assay, and in preventing neovascularization induced by endotoxin in the rabbit cornea (15).

For tumor growth-delay studies, THC and 14-sulfated-^-cyclodextrin 14(SO4)PCD were prepared in a 14-d osmotic pump, and implanted subcutaneously in the animals on d 4 posttumor cell implantation, by which time neovascularization of the tumors had begun (16,17). Administration of minocycline ip daily was also initiated on d 4 posttumor cell implantation, and continued until d 18. Neither the 14-d continuous infusion of THC-14(SO4)PCD nor daily im injection of minocycline for 2 wk altered the growth of the LLC (Table 1). The three modulators administered together (THC-14(SO4)PCD-minocycline) produced a modest tumor growth delay of 1.2 d in the LLC. Single-agent chemotherapy or radiation therapy was administered to the tumor-bearing animals beginning on d 7, when the tumors were about 100 mm3. Each treatment agent was administered at a standard dosage and schedule.

The combination of the three modulators (THC-14(SO4)PCD-minocycline) was most effective at increasing the response of the Lewis lung tumor to these cytotoxic therapies (Table 1). The tumor growth delay produced by the antitumor alkylating agents was increased by about 5.8-, 3.9-, 3.8-, and 2.3-fold for CDDP, melphalan, and single and multiple doses of cyclophosphamide, respectively. Five of 12 animals treated with the three modulator combination and multiple doses of cyclophosphamide were long-term survivors. The tumor growth delays produced by single-dose and multiple-dose radiation therapy were increased about 2.2- and 2.8-fold, respectively, in the presence of the three-modulator combination. The increases in tumor growth delay observed with adriamycin and bleomycin, with the addition of the three modulators to the regimen, were about 1.7-and 1.5-fold, compared with the antitumor agents alone.

Untreated control animals bearing the Lewis lung tumors survived 21-25 d posttumor implantation and succumbed to disease metastatic to the lungs. The number and size of lung metastases in untreated and treated animals were scored on d 20 posttumor implant (Table 2). Treatment with THC-14(SO4)PCD by continuous infusion from d 4 through

Table 1

Growth Delay of the Lewis Lung Tumor Produced by Various Anticancer Treatments Alone or in Combination with ß-Cyclodextrin Tetradecasulfate—Tetrahydrocortisol, Minocycline, or the Combination of Modulators

Treatment group

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