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Methotrexate Cytotoxicity for L5178Y/Asn^- Lymphoblasts: Relationship of Dose and Duration of Exposure to Tumor Cell Viability¹

Departments of Medicine [D. A. K., R. L. C., S. A. R.], Pharmacology [R. L. C.], and Epidemiology [S. A. R.], University of North Carolina, School of Medicine, Chapel Hill, North Carolina 27514

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 µM 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 durations 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 µM). 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.

¹ Supported by Grant CH35B from the American Cancer Society and the R. J. Reynolds Medical Oncology Trust Fund (Support 5-P30-CA 16086).

² To whom requests for reprints should be addressed.

Received 7/20/81. Accepted 1/22/82.

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