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The effect of gefitinib (Iressa, ZD1839) in combination with oxaliplatin is schedule-dependent in colon cancer cell lines

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Abstract

Background

Clinical trials of gefitinib (Iressa, ZD1839) in combination with cytotoxic agents have been carried out or are ongoing in several varieties of tumor. To provide a rationale for future clinical trials, the effects of combining gefitinib with oxaliplatin in different sequences of administration and different dose ratios in two colon cancer cell lines were evaluated.

Materials and methods

The colon cancer cell lines HT-29 and LoVo were used. The methods consisted of median effect and combination index analysis, Western blot, mass spectrometry, and a cell death ELISA.

Results

In vitro analysis demonstrated that the combination effects of the two agents were sequence-dependent. Changing the sequence of administration from gefitinib first to gefitinib last changed the combination effect from antagonism to synergy. The dose ratio between the two agents affected the combination effects. When equiactive doses of the two agents were used with the sequence gefitinib following oxaliplatin, the greatest level of synergism was obtained (CI=0.6±0.2, P=0.032). Further evaluation revealed that gefitinib significantly inhibited removal of Pt-DNA adducts (P<0.05), providing a potential explanation for the sequence-dependent synergy observed with gefitinib following oxaliplatin. However, this effect was not dose-dependent. Additional studies demonstrated that gefitinib enhanced the effects of oxaliplatin by maintaining oxaliplatin-induced apoptosis, and equiactive dose of gefitinib following oxaliplatin induced prominent enhancement of apoptosis.

Conclusions

Oxaliplatin followed by an equiactive relative dose of gefitinib is an appropriate combination for evaluation in colon cancer.

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Acknowledgements

We thank AstraZeneca Pharmaceuticals (Macclesfield, UK) for supplies of gefitinib. Iressa is a trademark of the AstraZeneca group of companies. This work was partially supported by grants from the Italian Association for Cancer Research (AIRC) (funds 2002 - C.R. 1363).

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Authors and Affiliations

  1. Beijing 307 Hospital Cancer Center, No 2. North Taiping Road, 100039, Beijing, China

    Jian-Ming Xu

  2. Clinical Experimental Oncology Laboratory, National Cancer Institute, Via Amendola 209, 70126, Bari, Italy

    Amalia Azzariti & Angelo Paradiso

  3. Medical and Experimental Oncology Unit, National Cancer Institute, Via Amendola 209, 70126, Bari, Italy

    Giuseppe Colucci

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  1. Jian-Ming Xu
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  2. Amalia Azzariti
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  3. Giuseppe Colucci
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  4. Angelo Paradiso
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Correspondence to Angelo Paradiso.

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Xu, JM., Azzariti, A., Colucci, G. et al. The effect of gefitinib (Iressa, ZD1839) in combination with oxaliplatin is schedule-dependent in colon cancer cell lines. Cancer Chemother Pharmacol 52, 442–448 (2003). https://doi.org/10.1007/s00280-003-0687-8

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  • DOI: https://doi.org/10.1007/s00280-003-0687-8

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