Modification of tumour and host response to cyclophosphamide by misonidazole and by WR 2721

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Abstract
The effect has been studied of adding either misonidazole (MISO) or the radioprotective drug, WR 2721, to cyclophosphamide (CY) treatment of mice bearing either the RIF-1 or KHT sarcomas. In RIF-1, the growth delay due to CY was increased by the addition of 1 mg/g of MISO. At doses below 75 mg/kg of CY, the effect was dose modifying but, at higher doses, the curves were parallel. When the MISO dose was reduced to 0.33 mg/g, the effect was reduced but not entirely lost. Only a small enhancement of CY response in the KHT tumour was seen with single doses, but the enhancement was greater with fractionated doses. The growth delay produced by CY in both tumour systems was reduced if WR 2721 (400 mg/kg) was given 30 min earlier. At a CY dose of 75-100 mg/kg the dose-modifying factor (DMF) was approximately 0.7-0.8 but, at least in the RIF-1 tumour, was not so low at higher doses of CY. Determination of the LD50 for CY showed a DMF of approximately 1.2-1.3 for MISO (0.33 mg/g) and approximately 0.8 for WR 2721 (400 mg/kg). Neither modifying agent appeared to cause any consistent change in the pattern of body-weight loss after CY, but WR 2721 reduced the myelosuppression seen at 3-4 days after CY. The data suggest that modification of tumour response to CY by the addition of MISO varies from tumour to tumour, and is very dependent upon the MISO dose. The protective effect of WR 2721 when combined with CY is not confined to normal tissues, and at a dose of 400 mg/kg may be as great in terms of tumour response as in terms of acute LD50 in this system. At a lower dose of WR 2721, however, some differential protection may occur.