Radiation dose fractionation studies with hypoxic cell radiosensitizers using a murine tumor

Abstract

The ability of five nitroimidazoles, metronidazole (MET), misonidazole (MISO), desmethylmisonidazole (DMM), SR 2508 and SR 2555, to sensitize the KHT sarcoma to radiation treatment has been compared for drug doses in the range 0–1.5 g/Kg. Single radiation doses or two different daily fractionation schedules (4 fractions of 5 Gy each or 7 fractions of 3 Gy each) were used; the tumor cell survival was determined using either an in vivo or in vitro colony assay. Each radiation (100 kVp X rays @ 11 Gy/min) treatment was given locally, 60—70 min (MET) or 30—40 min (other drugs) after either intraperitoneal (MET, MISO, DMM) or intravenous (SR 2508, SR 2555) injection of the drugs; these times have been shown to be optimum for this tumor. For the single doses and both fractionation schedules the tumor cell survival, following the irradiation treatment, declined as the drug dose increased in the range 0 to 0.75 g/Kg for all of the drugs, but above this dose level a plateau was reached and the amount of sensitization remained essentially constant. In this plateau region the reduction in survival achieved was similar for single doses and 5 Gy fractions but was less for 3 Gy fractions, indicating that sensitization was smaller for the smaller dose fractions. For the 4 × 5 Gy fractionation schedule the plateau level of survival was lowest for MISO, DMM and SR 2508, slightly higher for SR 2555 and much higher for MET. For the 3 Gy fractions SR 2508 appeared slightly less effective than MISO and DMM. Since clinically tolerated doses of MISO are much less than that equivalent to 0.5 g/Kg, these results suggest that DMM and SR 2508 will be superior sensitizers to MISO for human tumors, provided that the lesser toxicity of these drugs in animals is confirmed by studies in man, allowing larger doses than are possible with MISO to be administered to patients.