Determinants of Drug Response in a Cisplatin‐resistant Human Lung Cancer Cell Line

Yasuhiro Fujiwara, Yoshikazu Sugimoto, Kazuo Kasahara, Masami Bungo, Michio Yamakido, Kenneth D. Tew, Nagahiro Saijo

研究成果: Article査読

89 被引用数 (Scopus)

抄録

To elucidate the mechanism(s) of cisplatin resistance, we have characterized a human non‐small cell lung cancer cell line (PC‐9/CDDP) selected from the wild type (PC‐9) for acquired resistance to cisplatin. PC‐9/CDDP demonstrated 28‐fold resistance to cisplatin, with cross resistance to other chemotherapeutic drugs including chlorambucil (× 6.3), melphalan (× 3.7) and 3‐[(4‐amino‐2‐methyl‐5‐pyrimidinyl)]methyl‐1‐(2‐chloroethyl)‐1‐nitrosourea (ACNU) (× 3.9). There was no expression of mdr‐1 mRNA in either wild‐type or resistant cells. The mRNA and protein levels of glutathione S‐transferase (GST) × were similar in the two lines. A GST‐μ isozyme was present in equal amounts and the activities of selenium‐dependent and independent glutathione peroxidase and glutathione reductase were unchanged. The mRNA level of human metallothionein IIA and the total intracellular metallothionein levels were reduced in the resistant cells. Significantly increased intracellular glutathione (GSH) levels were found in the resistant cells (20.0 vs. 63.5 nmol/mg protein) and manipulation of these levels with buthionine sulfoximine produced a partial sensitization to either cisplatin or chlorambucil. Increased GSH probably also played a role in determining cadmium chloride resistance of the PC‐9/CDDP, even though this cell line had a reduced metallothionein level. Also contributing to the cisplatin resistance phenotype was a reduced intracellular level of platinum in the PC‐9/CDDP. Thus, at least two distinct mechanisms have been selected in the resistant cells which confer the phenotype and allow degrees of cross resistance to other electrophilic drugs.

本文言語English
ページ(範囲)527-535
ページ数9
ジャーナルJapanese Journal of Cancer Research
81
5
DOI
出版ステータスPublished - 1990 5
外部発表はい

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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