ENHANCEMENT OF TUMOR RADIATION RESPONSE BY THE ANTIVASCULAR AGENT 5,6-DIMETHYLXANTHENONE-4-ACETIC ACID

Purpose: 5,6-dimethylxanthenone-4-acetic acid (DMXAA) selectively dama ges tumor vasculature and is currently in clinical trial as an antitum or agent. Its ability to induce synthesis of tumor necrosis factor (TN F), and its apparent selectivity for poorly-perfused regions in tumors , suggests it possible use in combination with radiotherapy. This inve stigation examines activity of DMXAA as a radiation modifier using two murine tumors. Methods and Materials: Tumor growth delay was evaluate d using i.m. RIP-1 and MDAH-MCa-4 tumors irradiated in unanaesthetised , restrained mice (cobalt-60) using single dose or multiple fractions (8 x 2.5 Gy over 4 days) with DMXAA administered i.p. at various times in relation to irradiation. Results: Administration of DMXAA (80 mu m ol/kg, itp.) immediately after radiation resulted in a large increase in tumor growth delay, giving a radiation dose modifying factor of 2.3 for RIP-1 and 3.9 for MDAH-MCa-4. The combination was less active whe n radiation was given 1-4 h after DMXAA, but was highly active 12-48 h after DMXAA. At the latter times, clamping the tumor blood supply cau sed a large increase in radioresistance. These studies suggest that ce lls surviving DMXAA are hypoxic for only a short period. DMXAA increas ed overall growth delay when administered daily during fractionated ir radiation, giving an approximately additive response. Conclusions: The marked synergy between DMXAA and single dose ionising radiation may r eflect the complementarity of these agents at the microregional level, with DMXAA preferentially killing hypoxic cells in poorly perfused re gions. Despite additional hypoxia shortly after DMXAA treatment, survi ving cells appear to reoxygenate quickly which makes it feasible to us e DMXAA before and during fractionated radiotherapy. The combination o f fractionated radiation and DMXAA appears to be less effective than f or single dose radiation (possibly because of the smaller contribution of hypoxia under these conditions), but may be therapeutically useful . (C) 1998 Elsevier Science Inc.