ANTIANGIOGENIC CHEMOTHERAPEUTIC-AGENTS - CHARACTERIZATION IN COMPARISON TO THEIR TUMOR-GROWTH INHIBITION IN HUMAN RENAL-CELL CARCINOMA MODELS

The mechanism of action of anticancer chemotherapeutic agents is mainl y thought to be due to a direct inhibition of tumor cell proliferation . The enhanced endothelial cell proliferation rate in tumor specimens raised the question of whether therapeutic effects of chemotherapeutic agents might be at least partially attributed to inhibition of tumor angiogenesis, In the present study, we investigated the potential effe cts of chemotherapeutic agents on human renal carcinoma angiogenesis w ith the alginate implantation model in mice, For the first time, we al so compared results from the angiogenesis model with the inhibitory ef fects on growth of s.c. xenografts in nude mice. Vincristine and bleom ycin exerted strong inhibition of tumor angiogenesis in both carcinoma lines close to the level of the standard antiangiogenic agent O-chlor oacetyl-carbamyl-fumagillol (AGM-1470; T/C 22%), Adriamycin reduced an giogenesis of Caki-2 cells (T/C 33%) but had no effect on Caki-1 angio genesis (T/C 137%). Etoposide and 5-fluorouracil reduced Caki-1 tumor angiogenesis but had no effect on Caki-2, Despite antiangiogenic effec ts in both carcinoma lines, vincristine, bleomycin, and AGM-1470 signi ficantly reduced only the growth of fast-growing Caki-1 s.c. xenograft s but not the slow-growing Caki-2, Antivascular effects by bleomycin a nd AGM-1470 were also shown by a decrease of microvessel density in nu de mouse xenografts, Our findings suggest that chemotherapeutic agents may exert inhibition of tumor angiogenesis, which could be exploitabl e by combination therapy of fast-growing tumors. The resistance of the slow-growing Caki-2 carcinoma against acute angiogenesis inhibition i ndicates a need for well-tolerated angiogenesis inhibitors. Our result s also suggest the use of fastgrowing s.c. xenografts for demonstratin g growth inhibition by antiangiogenic compounds. Further characterizat ion of antiangiogenic compounds considered for clinical application sh ould, however, have its focus on slow-growing tumors, which are not ac cessible for most therapeutic strategies.