METHOTREXATE CYTO-TOXICITY FOR L5178Y/ASN-LYMPHOBLASTS - RELATIONSHIP OF DOSE AND DURATION OF EXPOSURE TO TUMOR-CELL VIABILITY

Abstract

To determine the relative contribution of dose and duration of exposure to methotrexate (MTX) cytotoxicity, suspension cultures of L5178Y/Asn- murine leukemic cells were exposed to 0.1-100 .mu.M MTX for 3-42 h. Viability was determined by cloning in soft agar. While there was a linear relationship between dose and MTX cytotoxicity for exposure durations of 3 and 6 h (r = -0.66), there was a pronounced flattening of this curve at exposure durations of 18-42 h (r = -0.48). There was an excellent correlation (r - -0.85) between MTX cytotoxicity and durations of exposure for 6-42 h (dose range, 1-100 .mu.M). Using the linear least-squares method, a best-fit equation for the kinetics of MTX cytotoxicity was determined to be: log viability = 2.25-1.76 (log duration) -0.31 (log dose). In practice, this equation predicts that a 1-log increase in duration of exposure results in almost a 2-log increase in cytotoxicity, whereas a 1-log increase in dose results in only a 0.3-log increase in cytotoxicity. The clinical utility of these data suggest that protracted infusions of lower doses of MTX [in cancer patients] would be equally as useful as or more useful than short-term high-dose infusions.