The new tubulin-inhibitor combretastatin A-4 enhances thermal damage in the BT4An rat glioma.

Abstract

To investigate the toxicity of combretastatin A-4 disodium phosphate (CA-4) and its vascular effects in the subcutaneous (s.c.) BT4An rat glioma, and additionally, to determine the tumor response of CA-4 combined with hyperthermia. For assessment of drug toxicity, rats were given 50, 75, or 100 mg/kg CA-4 and followed by daily registration of weight and side effects. Interstitial tumor blood flow was determined by laser Doppler flowmetry in rats injected with 50 mg/kg CA-4. In the tumor response study we administered CA-4 50 mg/kg alone or combined with hyperthermia (waterbath 44 degrees C for 60 min) 0 or 3 h later. We found that CA-4, at a well-tolerated dose of 50 mg/kg, induced a considerable time-dependent decrease in the tumor blood flow. Tumor blood flow was reduced by 47-55% during the first 110 min after injecting CA-4, and thereafter remained decreased until the measurements were terminated. Administering CA-4 3 h before hyperthermia yielded the best tumor response and increased tumor growth time significantly compared with simultaneous administration of CA-4 and hyperthermia (p = 0.03). Interestingly, CA-4 alone did not influence tumor growth. CA-4 induces a gradual reduction in tumor blood flow which can be exploited to sensitize the BT4An tumor for hyperthermia.