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.
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.
Bungo
M
M
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Fujiwara
Y
Y
Kasahara
K
K
Nakagawa
K
K
Ohe
Y
Y
Sasaki
Y
Y
Irino
S
S
Saijo
N
N
D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004351:Drug Resistance; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004247:DNA; D002945:Cisplatin