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 repair

• Published in: Cancer research (Chicago, Ill.) Vol. 50; no. 9; pp. 2549 - 2553
• Main Authors: Bungo, M, Fujiwara, Y, Kasahara, K, Nakagawa, K, Ohe, Y, Sasaki, Y, Irino, S, Saijo, N
• Format: Journal Article
• Language: English
• Published: United States 01.05.1990
• Subjects: Carcinoma, Non-Small-Cell Lung - metabolism; Cisplatin - pharmacokinetics; Cisplatin - pharmacology; DNA - drug effects; DNA - metabolism; DNA Damage; DNA Repair; Drug Resistance; Humans; Lung Neoplasms - metabolism; Tumor Cells, Cultured - drug effects
• ISSN: 0008-5472

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 micrograms 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.