Combined effects of an angiogenesis inhibitor (TNP-470) and hyperthermia

TNP-470, a synthetic analogue of fumagillin first isolated from Aspergillus fumigatus, is known to be a potent anti-angiogenic compound. The combined effects on tumour growth and tumour angiogenesis of TNP-470 and hyperthermia were investigated. The tumour used was SCCVII carcinoma of the C3H/He mouse. The tumour response was evaluated by the tumour growth (TG) time assay. The TG time is the time required for one-half of the treated tumours to reach three times the initial tumour volume. Significant delay of tumour growth was observed by TNP-470 alone (100 mg kg-1 x 2 or x 4), indicating that TNP-470 alone has antitumour effect in vivo. When TNP-470 (100 mg kg-1 x 2 or x 4) was administered after hyperthermia at 44 degrees C, the TG times of the combined treatment were significantly longer than those of heat alone (44 degrees C) or TNP-470 (100 mg kg-1 x 2 or x 4) alone. However, the TG time of combined treatment with TNP-470 and hyperthermia at 42 degrees C was quite similar to that of TNP-470 alone. This conflicting result on the combined effect of TNP-470 and hyperthermia may be related to the temperature-dependent vascular damage by hyperthermia. Dose-dependent inhibition of angiogenesis by TNP-470 was demonstrated in microangiograms obtained 4 days and 7 days after hyperthermia (44 degrees C for 30 min). It is, thus, suggested that the combined effect of TNP-470 and hyperthermia is attributable to the inhibition of angiogenesis by TNP-470 following heat-induced vascular damage.