Antiangiogenic effects of camptothecin analogues 9-amino-20(S)camptothecin, topotecan, and CPT-11 studied in the mouse cornea model

Angiogenesis has been correlated with increased invasion and metastases in a variety of human neoplasms. Inadequate inhibition of the growth of tumor microvessels by anticancer agents may result in treatment failure, rated cl inically as progressive or stable disease, We have investigated the antiang iogenic properties of three camptothecin analogues, 9-amino-20(S)-camptothe cin, topotecan, and camptosar (CPT-11), currently under investigation in cl inical settings. Angiogenesis was induced by basic fibroblast growth factor in the cornea of inbred Swiss-Webster mice, with the aim of exploring the suppression of neovascularization by the analogues injected into the mice d aily over a period of 6 days. The dose range chosen is known to inhibit, in the mouse model, the growth of various human tumor xenografts or murine tu mors. The statistical analysis evaluated the association between the area o f neoangiogenesis and the dose of the drugs tested and correlated the effec ts with observed drug toxicity. It was established that, as the drug doses increased, the area of neovascularization decreased, appearing to approxima te a negative exponential curve. 9-Amino-20(S)-camptothecin at 6.89 and 8.2 6 mu mol/kg (2.5 and 3.0 mg/kg) and topotecan at 8.31 mu mol/kg (3.5 mg/kg) , both drugs being delivered over a 6 day period, had statistically signifi cant reduction (47.2-72.55) of neoangiogenesis and acceptable toxicity. At higher doses of the two analogues, toxic body-weight losses and deaths were observed. CPT-11 showed statistically significant reduction of neoangiogen esis at a dose of 359 mu mol/kg (210 mg/kg) delivered over a 6-day course. Unlike camptothecin analogues, the nontoxic dose of vincristine did not ind uce a statistically significant inhibition of angiogenesis, and there was n o dose dependent escalation of antiangiogenic effects. The results indicate that camptothecins are most Likely cytotoxic against two tumor compartment s: in addition to tumor cells of epithelial origin, the drugs act against e ndothelial cells and prevent the growth of the tumor microvessels, We have hypothesized that treatment failure in some patients is due to incomplete o r inadequate inhibition of the microvessel growth by camptothecins, Presuma bly, an intensive inhibition of the remaining tumor microvasculature in suc h patients could be achieved by combining a camptothecin with another antia ngiogenic anticancer agent or with a highly selective angiogenic inhibitor everting minimal dose-limiting toxicity, Such treatment by a camptothecin p lus a less toxic inhibitor of angiogenesis can improve antitumor efficacy. To validate this concept, preclinical studies followed hy clinical trials a re planned.