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¹ Department of Surgery and Clinical Oncology, Graduate School of Medicine and ² Department of Pathology, School of Allied Health Science, Faculty of Medicine, Osaka University, Osaka, Japan; ³ Brunel Institute of Cancer Genetics and Pharmacogenomics, Department of Biological Sciences, Brunel University, Uxbridge, Middlesex, United Kingdom; ⁴ Yakult Central Institute for Microbiological Research, Yaho, Kunitachi; and ⁵ Department of Molecular Biology, Toho University Faculty of Medicine, Ohmori-Nishi, Ohta, Tokyo, Japan

Requests for reprints: Hirofumi Yamamoto, Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita City, Osaka 565-0871, Japan. Phone: 81-6-6879-3251; Fax: 81-6-6879-3259. E-mail: kobunyam{at}surg2.med.osaka-u.ac.jp

Clinical studies have shown that oxaliplatin, a novel platinum derivative, is a potent chemotherapeutic agent for colorectal cancer when combined with 5-fluorouracil and leucovorin. Although the toxic activity is based on covalent adducts between platinum and DNA, its actual biological behavior is mostly unknown. In an effort to explore the mechanism of tumor susceptibility to oxaliplatin, we examined the cytotoxic effects of oxaliplatin in colorectal cancer cell lines in reference to p53 gene status. Although p53 gene status did not clearly predict sensitivity to oxaliplatin, p53 wild-type cells including HCT116 were sensitive but HCT116 p53^–/– were found to be resistant to oxaliplatin. Oxaliplatin caused strong p21^waf1/cip1 induction and G₀-G₁ arrest in p53 wild-type cells, whereas cisplatin did not induce G₀-G₁ arrest. Assays using p53 wild but p21^waf1/cip1 null HCT116 cells revealed that oxaliplatin did not show G₀-G₁ arrest and reduced growth-inhibitory effects, suggesting that p21^waf1/cip1 may be a key element in oxaliplatin-treated p53 wild-type cells. Although HCT116 is DNA mismatch repair–deficient, a mismatch repair–proficient HCT116+ch3 cell line displayed similar responses with regard to p21^waf1/cip1-mediated growth inhibition and G₀-G₁ arrest. In p53 mutant cells, on the other hand, oxaliplatin caused an abrupt transition from G₁ to S phase and eventually resulted in G₂-M arrest. This abrupt entry into S phase was associated with loss of the p21^waf1/cip1 protein via proteasome-mediated degradation. These findings suggest that p21^waf1/cip1 plays a role in oxaliplatin-mediated cell cycle and growth control in p53-dependent and -independent pathways.

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⁶ H. Yamamoto, Y. Fujie, et al., unpublished data.

Received 1/11/05; revised 7/16/05; accepted 8/10/05.