tirapazamine and dolastatin-15

We have assessed the vascular effects of vinblastine and four other tubulin binding agents (dolastatin 10, dolastatin 15, combretastatin A1 and combretastatin A4), which are awaiting clinical evaluation. All five agents induce a reduction in tumour blood flow as measured by uptake of RbCI 24 h post drug administration. The degree of reduction ranged from 50% with combretastatin A1 to 90% with dolastatin 10. These reductions were similar to that seen with flavone acetic acid (FAA) and indicate that antivascular effects are a common feature of tubulin binding agents. We subsequently evaluated whether the blood flow reductions, induced by FAA and vinblastine, could be used to enhance the activity of the bioreductive drug tirapazamine. Since the kinetics and extent of blood flow reductions induced by the agents is comparable, similar therapeutic response was expected. Potentiation was only evident with FAA, indicating that this effect is not directly related to killing of hypoxic tumour cells induced as a consequence of blood flow reduction.

Topics: Animals; Antineoplastic Agents; Bibenzyls; Depsipeptides; Flavonoids; Mice; Mice, Inbred CBA; Neoplasms, Experimental; Oligopeptides; Regional Blood Flow; Stilbenes; Tirapazamine; Triazines; Tubulin; Tumor Necrosis Factor-alpha; Vinblastine