Methotrexate cytotoxicity for L5178Y/Asn- lymphoblasts: relationship of dose and duration of exposure to tumor cell viability.
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 to 100 microM MTX for 3 to 42 hr. Viability was determined by cloning in soft agar. While there was a linear relationship between dose and MTX cytotoxicity for exposure duration of 3 and 6 hr (r = -0.66), there was a pronounced flattening of this curve at exposure durations of 18 to 42 hr (r = -0.48). Furthermore, there was an excellent correlation (r = -0.85) between MTX cytotoxicity and durations of exposure for 6 to 42 hr (dose range, 1 to 100 microM). 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 would be equally as useful as or more useful than short-term high-dose infusions.
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007939:Leukemia L1210 / Q000188:drug therapy; D007940:Leukemia L5178 / Q000188:drug therapy* / Q000473:pathology; D007942:Leukemia, Experimental / Q000188:drug therapy*; D008214:Lymphocytes / Q000187:drug effects* / Q000473:pathology; D008727:Methotrexate / Q000494:pharmacology*; D051379:Mice; D008954:Models, Biological; D013997:Time Factors
D008727:Methotrexate