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Experimental study of combination therapy with S-1 against pancreatic cancer

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Abstract

Purpose

To determine the most effective combination chemotherapy with S-1 against pancreatic cancer and to clarify the mechanism of synergy between S-1 and the partner drug.

Methods

We tested a combination of S-1 with the following antitumor drugs in an in vitro MTT assay against pancreatic cancer cell line MIA PaCa-2: gemcitabine (GEM), cisplatin (CDDP), irinotecan (CPT-11), mitomycin C, adriamycin, and paclitaxel. The efficacy of S-1, GEM, and a combination of S-1 and GEM was also tested in vivo by administering S-1 (10 mg/kg) orally to nude mice five times a week for 3 weeks, and GEM (100 mg/kg) intravenously every 2–3 days for a total of six times. A treated-to-control ratio (T/C) of relative mean tumor weight values less than 50% was determined to be effective. Furthermore, we investigated the mechanism of the synergistic effect of S-1 and GEM on the cell cycle by flow cytometry, because both S-1 and GEM are known as antimetabolic drugs. To verify cell death induced by a change in the distribution of the cell cycle phases, we investigated apoptosis by sub-G1 analysis and a TUNEL assay.

Results

From classical isobolography analysis of the in vitro MTT assay, the combination of S-1 plus GEM was found to be the most effective of the combinations tested. In vivo, T/C (percentage) with the combination of S-1 plus GEM was 48.2%, which was lower than that of S-1 or GEM alone, and the combination enhanced antitumor activity. Cell cycle analysis showed greater cell cycle delay with the combination treatment (S-1 plus GEM) than for each single drug treatment, and apoptotic cells were detected only in treatments including GEM.

Conclusion

The combination chemotherapy of S-1 and GEM appears to be useful for pancreatic cancer. Both cycle delay by S-1 plus GEM and apoptosis induced by GEM are involved in this synergistic mechanism.

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Authors and Affiliations

  1. Department of Pharmacy, Yokohama Rosai Hospital, Yokohama, Japan

    Jun Yoshizawa

  2. Division of Research, BioMedical Laboratory, Kitasato Institute Hospital, Tokyo, Japan

    Asako Takizawa, Osamu Takeuchi & Yukio Suzuki

  3. Laboratory Animal Center, Center for Basic Research, Kitasato Institute, Tokyo, Japan

    Osamu Hiraku & Ken Sasaki

  4. Department of Pharmacy, Center for Clinical Pharmacy and Clinical Sciences, Kitasato University, Tokyo, Japan

    Yoshihito Morimoto, Koichiro Atsuda & Gaku Inoue

  5. Department of Bioregulation, Center for Clinical Pharmacy and Clinical Sciences, Kitasato University, Tokyo, Japan

    Yukio Suzuki

  6. Department of Surgery, Kitasato Institute Hospital, Shirokane 5-9-1, Minato-ku, Tokyo, Japan

    Fumiki Asanuma & Yoshinori Yamada

Authors
  1. Jun Yoshizawa
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  2. Asako Takizawa
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  3. Osamu Takeuchi
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  4. Osamu Hiraku
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  5. Ken Sasaki
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  6. Yoshihito Morimoto
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  7. Koichiro Atsuda
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  8. Gaku Inoue
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  9. Yukio Suzuki
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  10. Fumiki Asanuma
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  11. Yoshinori Yamada
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Correspondence to Yoshinori Yamada.

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Yoshizawa, J., Takizawa, A., Takeuchi, O. et al. Experimental study of combination therapy with S-1 against pancreatic cancer. Cancer Chemother Pharmacol 64, 1211–1219 (2009). https://doi.org/10.1007/s00280-009-0990-0

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  • DOI: https://doi.org/10.1007/s00280-009-0990-0

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