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Point Mutations of the Topoisomerase II Gene in Patients with Small Cell Lung Cancer Treated with Etoposide¹

Department of Internal Medicine, Osaka Prefectural Habikino Hospital, 3-7-1 Habikino, Habikino City, Osaka 583 [A. K., K. N., N. M., M. T.]; Department of Respiratory Medicine, Osaka City General Hospital, 2-13-22 Miyakojimahondori, Miyakojima, Osaka 534 [M. F., A. Y., T. H.]; and First Department of Internal Medicine, Kagawa Medical School, 1750-1, Ikenobe, miki-cho, Kita-gun, Kagawa 761-07 [A. K., J. T.], Japan

Reverse transcription-PCR-single-strand conformation polymorphism analysis was performed to detect topoisomerase II mutations using total RNA from 19 bronchial biopsy specimens obtained from 13 patients with small cell lung cancer. An abnormally migrating single-strand conformation polymorphism band was observed in one tumor sample from a patient treated with etoposide-containing chemotherapy. DNA sequence analysis of this tumor showed two transversions at codons 486 (G to A) and 494 (A to G), resulting in two missense mutations (Arg to Lys and Glu to Gly, respectively). The codon 486 mutation was identical to that previously found in two cell lines selected for amsacrine resistance. These results demonstrate that mutations of topoisomerase II occur in patients with small cell lung cancer. The significance of these mutations in the development of resistance to etoposide needs further investigation.

¹ This work was supported in part by a grant-in-aid for cancer research from the Ministry of Health and Welfare (Tokyo, Japan) for the Comprehensive 10-Year Strategy for Cancer Control.

² Present address: Department of Respiratory Medicine, Takamatsu National Hospital, 8 Otsu, Shinden-cho, Takamatsu 761-01, Japan. Phone: 81-878-41-2146; Fax: 81-878-43-5545.

³ To whom requests for reprints should be addressed. Phone: 81-729-57-2121; Fax: 81-729-57-5708.

⁴ Present address: National Cancer Institute-Navy, Medical Oncology Branch, Building 8, Room 5101, Naval Hospital, bethesda, MD 20889. Phone: (301) 496-0901; Fax: (301) 496-0047.

Received 11/28/95. Accepted 1/31/96.

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