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

• Published in: Cancer research (Chicago, Ill.) Vol. 57; no. 10; pp. 1829 - 1834
• Main Authors: DARK, G. G, HILL, S. A, PRISE, V. E, TOZER, G. M, PETTIT, G. R, CHAPLIN, D. J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-05-1997
• Subjects: Adenocarcinoma - blood supply; Adenocarcinoma - drug therapy; Animals; Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacology; Biological and medical sciences; Breast Neoplasms - blood supply; Breast Neoplasms - drug therapy; Chemotherapy; Endothelium, Vascular - drug effects; Hindlimb - blood supply; Humans; Medical sciences; Mice; Mice, Inbred CBA; Neoplasms - blood supply; Neoplasms - drug therapy; Neoplasms, Experimental - blood supply; Neoplasms, Experimental - drug therapy; Neovascularization, Pathologic - drug therapy; Perfusion; Pharmacology. Drug treatments; Prodrugs - pharmacology; Rats; Stilbenes - pharmacology; Antineoplastic agent; Human; Cytotoxicity; Prodrug; Malignant tumor; In vitro; Biological activity; Vascularization; Ex vivo; Vascular resistance; Combretaceae; Dicotyledones; Angiospermae; Plant origin; Spermatophyta; Antimitotic; Tumor cell
• ISSN: 0008-5472; 1538-7445

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.