Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity

Various conventional chemotherapeutic drugs can block angiogenesis or even kill activated, dividing endothelial cells. Such effects may contribute to the antitumor efficacy of chemotherapy in vivo and may delay or prevent the acquisition of drug-resistance by cancer cells. We have implemented a trea tment regimen that augments the potential antivascular effects of chemother apy, that is devoid of obvious toxic side effects, and that obstructs the d evelopment of drug resistance by tumor cells. Xenografts of 2 independent n euroblastoma cell lines were subjected to either continuous treatment with low doses of vinblastine, a monoclonal neutralizing antibody (DC101) target ing the flk-1/KDR (type 2) receptor for VEGF, or both agents together. The rationale for this combination was that any antivascular effects of the low -dose chemotherapy would be selectively enhanced in cells of newly newly fo rmed vessels when survival signals mediated by VEGF are blocked. Both DC101 and low-dose vinblastine treatment individually resulted in significant bu t transient xenograft regression, diminished tumor vascularity, and direct inhibition of angiogenesis. Remarkably, the combination therapy resulted in full and sustained regressions of large established tumors, without an ens uing increase in host toxicity or any signs of acquired drug resistance dur ing the course of treatment, which lasted for >6 months.