Characterization of sequence-dependent synergy between ZD1839 ('Iressa') and oxaliplatin

Jian Ming Xu, Amalia Azzariti, Montemuro Severino, Bing Lu, Giuseppe Colucci, Angelo Paradiso

Research output: Contribution to journalArticle

Abstract

ZD1839 ('Iressa'), a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is currently undergoing preclinical and clinical evaluation in several solid tumors. The present study aimed to assess the effect of ZD1839 in combination with oxaliplatin in the colon cancer cell lines HT-29 and LoVo. For in vitro chemosensitivity testing, cells were treated with serial dilutions of each drug sequentially at a fixed ratio of doses that corresponded to 1/20, 1/10, 1/5, 1/2, 1, 1.5 and 2 times the individual IC 50 values. Oxaliplatin followed by ZD1839 produced a synergistic effect. In contrast, oxaliplatin following ZD1839 exhibited an additive effect at best. Mass spectrometry examination revealed that ZD1839 modestly enhanced cellular oxaliplatin accumulation and platinum-DNA (Pt-DNA) adducts (P>0.05). In additional studies, high-performance liquid chromatography revealed that oxaliplatin had no effect on ZD1839 accumulation. In contrast, ZD1839 markedly inhibited removal of Pt-DNA adducts (P

Original languageEnglish
Pages (from-to)551-563
Number of pages13
JournalBiochemical Pharmacology
Volume66
Issue number4
DOIs
Publication statusPublished - Aug 15 2003

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Keywords

  • Colon cancer
  • EGFR-TKI
  • HT-29
  • LoVo
  • Sequence-dependent
  • ZD1839 ('Iressa')

ASJC Scopus subject areas

  • Pharmacology

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