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The range of optimal concentration and mechanisms of paclitaxel in radio-enhancement in gastrointestinal cancer cell lines

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Abstract

Aim

This study was performed to investigate the range of optimal concentration and mechanisms of paclitaxel (PXL) radio-enhancement in gastrointestinal cancer cell lines HT29 and MKN45.

Methods

Cell growth inhibition by PXL pretreatment at various concentrations (0–10 μM) followed by irradiation was investigated using a modified MTT assay. To investigate the mechanisms of the observed radio-enhancement, flow cytometry was conducted to define the cell cycle distributions. Furthermore, the alterations in expression of a DNA repair molecule [excision repair cross-complementation group1 (ERCC1)] and an angiogenesis factor [vascular endothelial growth factor (VEGF)] induced by PXL were investigated.

Results

Cytotoxic concentrations of PXL (0.1–10 μM) that cause accumulation of cells in the G2/M phase have strong radio-enhancing effects and inhibit total cell growth. The maximal non-cytotoxic concentration of PXL (0.01 μM) also had a radio-enhancing effect. The expression of the genes of ERCC1 and VEGF induced by radiation was suppressed by PXL pretreatment. The protein secretion of VEGF induced by radiation was suppressed at cytotoxic doses of PXL, and the induced protein secretion of ERCC1 was also suppressed even at maximal non-cytotoxic doses of PXL.

Conclusion

The range of optimal concentration for PXL pretreatment was 0.01–0.1 μM in these cells. Two major mechanisms of radio-enhancement are suggested: (1) PXL induces G2/M arrest leading to increased DNA damage after radiation, which results in mitotic death, and (2) PXL suppresses the expression of radiation-induced DNA repair molecules and angiogenesis factors, resulting in inhibition of cell growth and cell death.

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Authors and Affiliations

  1. Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Yuji Toiyama, Yasuhiro Inoue, Junichiro Hiro, Eiki Ojima, Hideki Watanabe, Youhei Narita, Atuko Hosono, Chikao Miki & Masato Kusunoki

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  1. Yuji Toiyama
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  2. Yasuhiro Inoue
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  3. Junichiro Hiro
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  4. Eiki Ojima
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  5. Hideki Watanabe
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  6. Youhei Narita
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  7. Atuko Hosono
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  9. Masato Kusunoki
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Correspondence to Masato Kusunoki.

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Toiyama, Y., Inoue, Y., Hiro, J. et al. The range of optimal concentration and mechanisms of paclitaxel in radio-enhancement in gastrointestinal cancer cell lines. Cancer Chemother Pharmacol 59, 733–742 (2007). https://doi.org/10.1007/s00280-006-0327-1

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  • DOI: https://doi.org/10.1007/s00280-006-0327-1

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