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Decreased Accumulation as a Mechanism of Resistance to cis-Diamminedichloroplatinum(II) in Human Non-Small Cell Lung Cancer Cell Lines: Relation to DNA Damage and Repair¹

Pharmacology Division, National Cancer Center Research Institute [M. B., Y. F., K. K., N. S.], Department of Internal Medicine, National Cancer Center Hospital [K. N., Y. O., Y. S.], 5-1-1 Tsukiji, Chuo-ku, Tokyo 104, Japan, and First Department of Internal Medicine, Kagawa Medical School, 1750-1 Ikenobe, Miki-cho, Kagawa 761-07, Japan [M. B., S. I.]

The mechanism of resistance to cis-diamminedichloroplatinum(II) (CDDP) is still controversial, although several kinds of processes have been proposed. For elucidation of the mechanism of CDDP resistance in CDDP-resistant human non-small cell lung cancer cells (PC-9/0.5, 7.1-fold resistant), we examined the formation of DNA interstrand cross-links (ICL), one kind of DNA damage induced by CDDP, its repair, and intracellular accumulation of CDDP. We measured the frequency of CDDP-induced ICL by means of the alkaline elution technique and the amount of intracellular platinum for intracellular accumulation of CDDP by means of atomic absorption spectrophotometry in PC-9 (parental cell) and PC-9/0.5 cells.

Formation of ICL in PC-9 cells exposed to 5 µg of CDDP per ml for 6 h was 5.85 times that in PC-9/0.5 cells. On the other hand, the ability to repair CDDP-induced ICL was identical in both cell lines. Intracellular accumulation studies revealed that PC-9 retained 5.07 times as much platinum as that in PC-9/0.5 after 3-h exposure to CDDP.

It was conjectured that the decrease in the intracellular accumulation of CDDP might be the main cause of CDDP resistance in PC-9 cells, since the decreased accumulation was paralleled by the decreased level of ICL.

¹ This research was supported in part by Grants-in-Aid from the Ministry of Health and Welfare for the Comprehensive 10-Year Strategy for Cancer Control and from the Ministry of Education, Science, and Culture, Japan. The data were presented, in part, at the 80th Annual Meeting of the American Association for Cancer Research, San Francisco, CA (1).

² Recipient of a research resident fellowship from the Foundation for Promotion of Cancer Research.

³ To whom requests for reprints should be addressed.

Received 7/25/89. Revised 1/15/90.

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