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Isolation of Thymidine-resistant Cells from a Thymidine-sensitive Acute Lymphoblastic Leukemia Cell Line¹

Department of Pediatrics, University of Maryland School of Medicine, and Walter P. Carter Center, Baltimore, Maryland 21201

Malignant cells have enhanced sensitivity to inhibition of growth by thymidine. Cell growth of the permanent lymphoid cell line CCRF-CEM, originating from a patient with acute lymphoblastic leukemia, is inhibited by 3 x 10^-5 M thymidine, compared to 1 to 5 x 10^-3 M thymidine required to inhibit growth of normal lymphoid lines. Thymidine-resistant cells were isolated at a frequency of approximately 1/100,000 cells after cloning CCRF-CEM cells in medium containing 5 x 10^-4 M thymidine. The resistant cells lacked the enzyme thymidine kinase, had a 20-fold decrease of thymidine uptake, and were resistant to 1 x 10^-4 M 5-bromo-2-deoxyuridine. The cells were sensitive to 1 x 10^-5 M methotrexate, even in the presence of exogenously added thymidine and hypoxanthine. The data indicate that a small fraction of malignant cells may escape the toxic effect of high thymidine therapy and, therefore, require additional chemotherapy for their control.

¹ Supported in part by NIH Grant GM 23827.

Received 4/16/79. Accepted 5/22/79.