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Detection of Drug Resistance in Human Tumors by in Vitro Enzymatic Amplification¹

Section of Biochemical Pharmacology, Department of Medical Oncology, City of Hope National Medical Center [M. K-S., Y. L., J. x. M., J. C., H. M., K. J. S.]; and Beckman Research Institute of the City of Hope; [J. J. R.], Duarte, California 91010

Both acquired and natural resistance to chemotherapy agents have proved problematic in the treatment of neoplasia. Thymidylate synthase, which catalyzes the synthesis of thymidine precursors, has been shown to be amplified in response to a variety of chemotherapeutic agents. The detection of such amplification could prove beneficial in the development of alternative clinical protocols. In this study we report the use of existing enzymatic amplification methods in order to detect incipient amplification of the thymidylate synthase gene upon resistance to cisplatin. The assay utilizes a modification of the polymerase chain reaction in which a sequence of the thymidylate synthase gene is amplified including two flanking oligonucleotides acting as primers for DNA synthesis. This method exhibits greater sensitivity than conventional nucleic acid detection methods and requires less than 100 ng of total RNA from patient tumors and no in vitro culturing of patient cells.

¹ This work was supported by the American Cancer Society (CH265) and Bristol-Myers Co.

² Scholar of the Leukemia Society of AMerica. To whom requests for reprints should be addressed, at Section of Biochemical Pharmacology, Department of Medical Oncology, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010-0269.

Received 2/ 9/88. Revised 5/18/88. Accepted 7/20/88.

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