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Modes of Uptake of Methotrexate by Normal and Leukemic Human Leukocytes in Vitro and Their Relation to Drug Response¹

Laboratories of Pharmacology, The Children's Cancer Research Foundation, and the Departments of Pathology and Medicine, Harvard Medical School, Boston, Massachusetts 02115

Characteristics of Methotrexate transport by normal and leukemic human leukocytes were measured in vitro. At high external drug levels (20 µM) drug uptake by all cell types was temperature-insensitive, nonsaturable, and nonconcentrative. The steady-state cell/medium drug distribution ratio was about 0.03. During clinical treatment with Methotrexate, plasma drug levels generally reach 0.2 µM. At this lower drug level: (a) A temperature-sensitive and saturable mode of transport was demonstrable in all cell types except small lymphocytes. In normal granulocytes the steady-state drug distribution ratio reached 0.2. (b) Leukemic cell types showed a wide variation in capacity for uptake of the drug, and an association was seen between this capacity and clinical response to the drug.

¹ Supported by Contracts PH 43-62-169 and PH 43-66-541 of the Cancer Chemotherapy National Service Center, and by Grant C 6516, all from the National Cancer Institute, NIH.

Received 6/28/67. Accepted 11/23/67.