Hypoxic cell sensitlzation by misonidazolein vivoandin vitro

Publisher Website
Google Scholar
Abstract
Maximum tumor drug concentrations in mice bearing mammary carcinoma, fibrosarcoma and osteosarcoma are 20-50% of the peak serum levels, probably because of the short biological half-life of 1-1.5 h in the mouse. In man, drug concentrations in tumors usually fall in the range of 50-100% of the peak serum level, because of the longer half-life of 8-18 h. A 2- to 3-fold high tumor concentration is achieved for the same serum level in man compared with the mouse. The drug dose that can be used clinically is limited by neurotoxic side effects to a total dose of 12 g/m2 in a fractionated course of treatment, with no single dose more than 4 g/m2. Six equal doses of 2 g/m2 or 50 mg/kg would give a peak plasma level in man of 60-70 .mu.g/ml with a corresponding tumor level of 30-70 .mu.g/g. This would give an enhancement ratio of 1.4 to 1.7 for large single doses of radiation, or tumors with high hypoxic fractions. With fractionated irradiation of tumors with unknown hypoxic fractions the enhancement ratio would be smaller. There is every reason to expect that there will be useful enhancement in the clinical range of drug dosage.