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Factors affecting sensitivity to antitumor platinum derivatives of human colorectal tumor cell lines

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Abstract

Purpose

The aim of this study is to examine the factors affecting sensitivity to cisplatin, carboplatin, and oxaliplatin in human colorectal tumor cell lines.

Methods

Caco-2, DLD-1, HCT-15, HCT116, LS180, SW620, and WiDr cells were used. Their growth inhibition by platinum derivatives was evaluated with a WST-1 assay utilizing succinate dehydrogenase activity. Cellular accumulation and DNA-binding of platinum were measured with an inductively coupled plasma mass spectrometer. The mRNA levels of copper transporters (hCtr1, ATP7A, and ATP7B) and organic cation transporters (hOCT1, hOCT2, and hOCT3) were evaluated by the real-time reverse transcription-PCR method using SYBR® green.

Results

The cytotoxicity of platinum derivatives ranked oxaliplatin > cisplatin > carboplatin in almost all cells used. Cellular accumulation and DNA-binding of platinum varied among the types of cells, but levels were similar on treatment with cisplatin and oxaliplatin, and lower in response to carboplatin. The levels of copper and organic cation transporter mRNAs also differed with cell type. A correlation analysis revealed that sensitivity to platinum derivatives was dependent in part on the amount of platinum bound to DNA. In addition, the cellular accumulation of platinum and level of ATP7A mRNA may be factors affecting the cytotoxicity of cisplatin, while the cytotoxicity of oxaliplatin was suggested to be affected by the levels of ATP7A and hOCT1 mRNAs.

Conclusion

Some factors affecting the sensitivity of tumor cells to platinum derivatives were proposed, and will provide useful information for cancer chemotherapy with platinum derivatives.

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Acknowledgments

The authors are grateful to Associate Professor Kazuki Nagasawa, Ph.D. (Department of Environmental Biochemistry, Kyoto Pharmaceutical University) for technical advice. This work was supported in part by a Matching Fund Subsidy for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Department of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan

    Noriaki Kitada, Kohji Takara, Tetsuya Minegaki, Chihiro Itoh, Masayuki Tsujimoto & Teruyoshi Yokoyama

  2. Frontier Education Center, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshidashimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Toshiyuki Sakaeda

Authors
  1. Noriaki Kitada
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  2. Kohji Takara
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  3. Tetsuya Minegaki
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  4. Chihiro Itoh
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  5. Masayuki Tsujimoto
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  6. Toshiyuki Sakaeda
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  7. Teruyoshi Yokoyama
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Correspondence to Kohji Takara.

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Kitada, N., Takara, K., Minegaki, T. et al. Factors affecting sensitivity to antitumor platinum derivatives of human colorectal tumor cell lines. Cancer Chemother Pharmacol 62, 577–584 (2008). https://doi.org/10.1007/s00280-007-0640-3

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  • DOI: https://doi.org/10.1007/s00280-007-0640-3

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