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

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