The development of combretastatin A4 phosphate as a vascular targeting agent.

PURPOSE: This overview summarizes the preclinical development of tubulin-depolymerizing agents as vascular targeting agents, leading to the identification of combretastatin A4P (CA4P). METHODS AND MATERIALS: The murine tumor CaNT was implanted s.c. in the dorsum of CBA mice. Vascular function was determined after treatment using the perfusion marker Hoechst 33342 and fluorescence microscopy. Tumor cell response was assessed by using an excision assay and by measuring the delay in growth of treated tumors. RESULTS: At doses that approximated one-half the maximum tolerated dose (MTD) in CBA mice, none of the agents evaluated-i.e., taxol, melphalan, 5-fluorouracil, doxorubicin, cisplatin, gemcitabine, and irinotecan-induced any significant reduction in perfused vascular volume within the tumor mass. In contrast, CA4P at a dose of 100 mg/kg, which approximates one-fifth the MTD, induced a greater than 80% reduction in vascular function. Although colchicine did induce vascular shutdown, this occurred only at doses approximating the MTD. Histologic evaluation demonstrated that continued growth and repopulation of the tumor mass was the result of a surviving rim of viable tumor cells at the tumor periphery. CONCLUSION: These results confirm the ability of CA4P to selectively compromise vascular function in experimental tumors, inducing extensive tumor cell death at well-tolerated doses. However, despite these effects, no growth retardation is obtained when CA4P is administered alone in a single dose. The continued growth and repopulation of the tumor mass occurs from a narrow rim of viable cells at the periphery. If, as is believed, these remaining cells are the ones most sensitive to conventional cytotoxic and macromolecular approaches, CA4P and other vascular targeting agents offer considerable potential for enhancing the effectiveness of existing and emerging cancer therapies.