Selective killing of human malignant cell lines deficient in methylthioadenosine phosphorylase, a purine metabolic enzyme.
- 1 February 1981
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 78 (2), 1219-1223
- https://doi.org/10.1073/pnas.78.2.1219
Abstract
Seven of 31 (23%) human malignant tumor cell lines had no detectable methylthioadenosine phosphorylase activity (< 0.001 nmol/min per mg of protein), assayed with 5''-chloroadenosine as substrate. The enzyme-deficient cell lines were derived from 5 leukemias, 1 melanoma and 1 breast cancer. None of 16 cell lines of nonmalignant origin, derived from lymphocytes, fibroblasts and epithelial cells, lacked the enzyme (range, 0.156-1.447 nmol/min per mg of protein). As detected by autoradiography, intact enzyme-positive cell lines, normal immature bone marrow cells, and 4 specimens of malignant tumor cells incorporated the adenine moiety of 5''-chloroadenosine into nucleic acids; however, no enzyme-deficient cell lines used 5''-chloroadenosine. When both types of cell lines were cultured in a medium containing 0.4 .mu.M methotrexate, 16 .mu.M uridine, and 16 .mu.M thymidine (or 10 .mu.M azaserine alone), no cells grew. If methylthioadenosine was added to the same medium, only enzyme-positive cells increased in number; most enzyme-deficient cells were dead after 3 days. Thus, human malignant tumor cell lines naturally deficient in methylthioadenosine phosphorylase could be selectively killed when de novo purine synthesis was inhibited and methylthioadenosine was the only exogenous source of purines. [Possible chemotherapeutic applications were discussed.].Keywords
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