Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity
Giannoula Klement, Sylvain Baruchel, Janusz Rak, Shan Man, Katherine Clark, Daniel J. Hicklin, Peter Bohlen, Robert S. Kerbel
Giannoula Klement, Sylvain Baruchel, Janusz Rak, Shan Man, Katherine Clark, Daniel J. Hicklin, Peter Bohlen, Robert S. Kerbel
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Article

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

Abstract

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 treatment regimen that augments the potential antivascular effects of chemotherapy, that is devoid of obvious toxic side effects, and that obstructs the development of drug resistance by tumor cells. Xenografts of 2 independent neuroblastoma cell lines were subjected to either continuous treatment with low doses of vinblastine, a monoclonal neutralizing antibody (DC101) targeting 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 formed vessels when survival signals mediated by VEGF are blocked. Both DC101 and low-dose vinblastine treatment individually resulted in significant but 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 ensuing increase in host toxicity or any signs of acquired drug resistance during the course of treatment, which lasted for >6 months.

Authors

Giannoula Klement, Sylvain Baruchel, Janusz Rak, Shan Man, Katherine Clark, Daniel J. Hicklin, Peter Bohlen, Robert S. Kerbel

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Induction of solid tumor regression by nontoxic, antiangiogenic combinat...
Induction of solid tumor regression by nontoxic, antiangiogenic combination therapy with low-dose vinblastine and anti–flk-1 antibody (DC101). Top panel: Established xenografts of human neuroblastoma (SK-N-MC) were treated by a putative antivascular regimen of low-dose vinblastine (induction: 0.75 mg/m2 bolus intraperitoneally; 1 mg/m2 per day continuous subcutaneous infusion for 3 weeks; maintenance: 1.5 mg/m2 every 3 days) alone or in combination with an anti–VEGF-R2 antibody (DC101; 800 μg every 3 days). There is an appreciable tumor growth inhibition by each of the single agents, which is comparable, at least initially, with that of the combination treatment group. The benefit of the combination treatment is most evident after prolonged treatment, when lasting and complete tumor regression is observed. The data are a compilation of 2 independent experiments, with the initial experiment lasting 34 days and the second still ongoing (> 210 days). In both sets, 20 mice were randomized into 4 groups. Bottom panel: Lack of toxicity-dependent weight loss in mice bearing SK-N-MC tumor xenografts treated with “antivascular” vinblastine regimen alone or in combination with and anti–VEGF-R2 (DC101) antibody. There are no significant differences in weight between the groups, except for a transient (14–18 days long) episode of weight loss associated with diarrhea in the combination treatment group. The episode resolved without interruption of therapy. Average body weights (g) ± SD are plotted (n = 3–10 mice). ip, intraperitoneally.