Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature

Graham G. Dark, Sally A. Hill, Vivien E. Prise, Gillian M. Tozer, George Pettit, Dai J. Chaplin

Research output: Contribution to journalArticle

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Abstract

Selective induction of vascular damage within tumors represents an emerging approach to cancer treatment. Histological studies have shown that several tubulin-binding agents can induce vascular damage within tumors but only at doses approximating the maximum tolerated dose, which has limited their clinical applicability. In this study, we show that the combretastatin A-4 prodrug induces vascular shutdown within tumors at doses less than one- tenth of the maximum tolerated dose. In vitro studies indicate that a short drug exposure results in profound long-term antiproliferative/cytotoxic effects against proliferating endothelial cells but not cells that are quiescent prior to and during drug exposure. Vascular shutdown, within experimental and human breast cancer models in vivo following systemic drug administration, was demonstrated with a reduction in functional vascular volume of 93% at 6 h following drug administration and persisted over the next 12 h, with corresponding histology consistent with hemorrhagic necrosis resulting from vascular damage. These actions against tumor vasculature and the broad therapeutic window demonstrate the clinical potential of these drugs and warrant further study to elucidate the mechanisms responsible for the antivascular effects of combretastatin A-4.

Original languageEnglish (US)
Pages (from-to)1829-1834
Number of pages6
JournalCancer Research
Volume57
Issue number10
StatePublished - May 15 1997

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Blood Vessels
Neoplasms
Pharmaceutical Preparations
Maximum Tolerated Dose
Prodrugs
Tubulin
fosbretabulin
Histology
Necrosis
Endothelial Cells
Breast Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dark, G. G., Hill, S. A., Prise, V. E., Tozer, G. M., Pettit, G., & Chaplin, D. J. (1997). Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. Cancer Research, 57(10), 1829-1834.

Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. / Dark, Graham G.; Hill, Sally A.; Prise, Vivien E.; Tozer, Gillian M.; Pettit, George; Chaplin, Dai J.

In: Cancer Research, Vol. 57, No. 10, 15.05.1997, p. 1829-1834.

Research output: Contribution to journalArticle

Dark, GG, Hill, SA, Prise, VE, Tozer, GM, Pettit, G & Chaplin, DJ 1997, 'Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature', Cancer Research, vol. 57, no. 10, pp. 1829-1834.
Dark GG, Hill SA, Prise VE, Tozer GM, Pettit G, Chaplin DJ. Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. Cancer Research. 1997 May 15;57(10):1829-1834.
Dark, Graham G. ; Hill, Sally A. ; Prise, Vivien E. ; Tozer, Gillian M. ; Pettit, George ; Chaplin, Dai J. / Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. In: Cancer Research. 1997 ; Vol. 57, No. 10. pp. 1829-1834.
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