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Cancer Chemotherapy and Pharmacology
Erschienen in: Cancer Chemotherapy and Pharmacology 6/2003

01.12.2003 | Original Article

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

verfasst von: Jian-Ming Xu, Amalia Azzariti, Giuseppe Colucci, Angelo Paradiso

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 6/2003

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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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Metadaten
Titel
The effect of gefitinib (Iressa, ZD1839) in combination with oxaliplatin is schedule-dependent in colon cancer cell lines
verfasst von
Jian-Ming Xu
Amalia Azzariti
Giuseppe Colucci
Angelo Paradiso
Publikationsdatum
01.12.2003
Verlag
Springer-Verlag
Erschienen in
Cancer Chemotherapy and Pharmacology / Ausgabe 6/2003
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-003-0687-8

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