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

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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Vinblastine, DC101, or combination therapy induces tumor cell apoptosis ...
Vinblastine, DC101, or combination therapy induces tumor cell apoptosis in perivascular cuffs of SK-N-MC tumor xenografts. H&E stain of formalin-fixed, paraffin-embedded sections. The typical tissue architecture (control, top two panels) shows perivascular cuffing by neoplastic cells and normal endothelial cell lining (arrows). Apoptotic cells (ap) are seen only at the periphery of the cuff, and their presence is confirmed by TUNEL staining (right-sided panels). In both single-treatment groups (vinblastine and DC101), widening of the apoptotic rims, and extension of the apoptotic figures into the cuff can be observed after 35 and 50 days of treatment, respectively. Viable malignant cells are still present within the tumor cuff in both single-agent groups. In contrast, histology of the combined therapy group reveals diffuse tumor cell death and total loss of preexisting architecture (bottom left-hand panel), a finding supported by the diffuse TUNEL stain in corresponding specimens (bottom right-hand panel).