Combinations of cyclophosphamide and misonidazole in the KHT sarcoma

Abstract

The effect on intramuscularly growing KHT sarcomas of combinations of the chemotherapeutic agent cyclophosphamide (CYC) and the radiosensitizer misonidazole (MISO) was determined. Tumor response was evaluated using an in vivo to in vitro clonogenic cell survival assay or an in situ tumor growth delay assay. MISO, at doses ranging from 0.25 to 1.0 mg/g, was found to be effective at enhancing the tumor response to CYC when given for times of 0–4 hr before the chemotherapeutic agent. Clonogenic cell survival studies in which a 1.0 mg/g dose of MISO was administered simultaneously with CYC demonstrated that the addition of the sensitizer increased the level of tumor cell kill assessed 24 hr after treatment by a factor of ∼4–8 for CYC doses ranging from 25–150 mg/kg. Similarly, in the in situ experiments MISO enhanced the regrowth delay resulting from CYC treatments with doses up to 150 mg/kg by ∼2–4 days. Consequently, the addition of MISO to CYC was not found to be strictly dose modifying, but rather resulted in enhancement ratios ranging from 1.3 to 1.5 depending on the dose of the chemotherapeutic agent used. Normal tissue toxicity to combinations of CYC and MISO was assessed 24 hr after treatment using a spleen colony assay. When MISO (1.0 mg/g) was administered simultaneously with a range of CYC doses, a dose modifying factor of ∼1.2 for bone marrow stem cell toxicity was observed. On the basis of these observations, the addition of MISO to CYC treatment may lead to a small therapeutic gain.