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Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity
Giannoula Klement, … , Peter Bohlen, Robert S. Kerbel
Giannoula Klement, … , Peter Bohlen, Robert S. Kerbel
Published April 15, 2000
Citation Information: J Clin Invest. 2000;105(8):R15-R24. https://doi.org/10.1172/JCI8829.
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Article Article has an altmetric score of 38

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

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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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Figure 6

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Inhibition of angiogenesis in vivo by low-dose vinblastine in combinatio...
Inhibition of angiogenesis in vivo by low-dose vinblastine in combination with anti–flk-1 antibody (DC101). Angiogenesis was induced in subcutaneously implanted Matrigel plugs (Mat) by admixing 500 ng/mL of bFGF (Mat+bFGF). The mice were treated with DC101 antibody (800 μg/mL) every 3 days, low-dose vinblastine (1 mg/m2) every 3 days, or combination therapy (Vbl/DC101). After 10 days of treatment, mice were injected intravenously with FITC-dextran; Matrigel plugs were removed; and the volume of new blood vessels was assessed by measurement of intravascular FITC content (normalized to FITC in the circulating plasma). Averages of 5 animals and their respective SDs are shown (AP = 0.05).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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