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A Comparison of the Biological Effects of Dichloromethotrexate and Methotrexate on Human Leukemic Cells in Culture¹

Department of Neoplastic Diseases, Mount Sinai School of Medicine of the City University of New York, New York, New York 10029

The effects of human serum albumin (HA) on the cell growth inhibition produced by dichloromethotrexate (DCM) and methotrexate (MTX) and the reversibility by leucovorin (LV) of the cell growth inhibition induced by both agents were examined in vitro using a malignant human lymphocyte line, MOLT 3. The biological activity of DCM, which was slightly higher on an equimolar basis than that of MTX in HA-free culture medium, was reduced to a much lower level than that of MTX in the presence of HA (2.5 g/dl) in the culture medium. Thus, on a basis of the dose causing 90% inhibition, the equitoxic concentration of MTX increased only about 2-fold in the presence of HA, while that of DCM increased about 5-fold. Ultrafiltration and bioassay revealed that DCM and MTX were bound to HA about 85 and 50%, respectively. HA binding with these antifolics and their consequent loss of biological activity both appeared to be reversible. The present findings explain, at least in part, why a higher equitoxic dose of DCM than of MTX is required in humans. The cell growth inhibition induced by equitoxic concentrations of both agents was reversed by an equimolar concentration of LV. This finding suggests that the LV dose required to protect or rescue DCM-induced toxicity in humans may not need to be higher than that used in the high-dose MTX and LV rescue regimen. The differences in the effects of DCM and MTX on cell growth in a culture medium containing HA warrant a further modification of the in vitro drug-screening system.

¹ Supported in part by Contract NO1-CM-53837 from the Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Md.; by USPHS Research Grant CA 15936; by the United Leukemia Fund, Inc., New York, N. Y.; and by the Chemotherapy Foundation, Inc., New York, N. Y.

² On leave of absence from the Department of Medicine, Okayama University School of Medicine, Okayama, Japan.

³ To whom requests for reprints should be addressed.

Received 8/21/78. Accepted 12/27/78.