Radiosensitization by misonidazole of a human malignant melanoma grown in athymic nude mice

Abstract

A human malignant melanoma grown in the athymic mutant nude mouse was subjected to acute and fractionated irradiation in the presence and absence of the hypoxic-cell radiosensitizer misonidazole (Rp-07-0582). A 60Co therapy unit was used for local irradiation of nonanaesthetized mice. Misonidazole in doses of 500 mg/kg bodyweight was administered to the mice by i.p. injection 45 min before each exposure. In the first series of experiments the enhancement ratio of misonidazole was determined for fractionation regimes with constant interfraction time (1 day) and varying number of fractions. For a single dose of 12.50 Gy [Grey], 3 fractions of 4.52 Gy in 3 days, 4 fractions of 3.75 Gy in 4 days and 10 fractions of 2.07 Gy in 10 days, the enhancement ratio was 1.4-1.5, 1.15, 1.05 and 1.0, respectively. In the 2nd series of experiments the enhancement ratio was determined for fractionation regimes with a constant number of fractions (3) and varying interfraction times. For 3 fractions of 4.40 Gy in 8 h, 3 fractions of 4.52 Gy in 3 days, 3 fractions of 4.85 Gy in 5 days, 3 fractions of 5.06 Gy in 7 days and 3 fractions of 5.53 Gy in 15 days, the enhancement ratio was 1.30-1.35, 1.15, 1.15, 1.15 and 1.05, respectively. The human malignant melanoma studied apparently contains radioresistant hypoxic cells. The tumor reoxygenates quite efficiently during the 1st day after exposure to clinically relevant doses of .gamma.-rays. To obtain clinical benefit from misonidazole in the radiotherapy of human malignant melanomas with properties like the present one, the radiosensitizer should be used in combination with large single radiation doses, in hyperfractionated treatment regimes (within 8 h overall time), or in fractionation regimes based on few fractions and relatively high doses per fraction.