Experimental study of effect of epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in combination with irinotecan

Jian ming Xu, Yue min Li, Yan Wang, Chuan hua Zhao, Shou jun Yuan, Wu wei Yang, Zhi qiang Li, Y. Han, Amalia Azzariti, Angelo Paradiso

Research output: Contribution to journalArticlepeer-review

Abstract

OBJECTIVE: To assess the optimal regimen and its mechanism of ZD1839 in combination with SN38, the active metabolite of irinotecan (CPT-11), in the colon cancer cell lines HT-29 and LoVo. METHODS: Chou and Talalay method was used to analyze the combination effects of sequencing of ZD1839 and SN38. Western blotting and immunoprecipitation were used to determine the effects of ZD1839 and/or SN38 on their targeted enzymes and downstream markers. Apoptosis was assayed by analyzing histone-associated DNA fragment. RESULTS: Sequential SN38 followed by ZD1839 produced a synergistic effect. In contrast, SN38 following ZD1839 exhibited an antagonist effect. SN38 markedly inhibited topoisomerase I (Topo-I) activity. ZD1839 did not alter epidermal growth factor receptor (EGFR) expression, but resulted in a complete inhibition of EGFR phosphorylation. Sequential ZD1839 followed by SN38 did not show any enhanced inhibition effect on Topo-I activity, phosphorylation of EGFR and one of its downstream markers MAPK. However, simultaneous SN38 plus ZD1839, and sequential SN38 followed by ZD1839 administrations showed modest inhibition effect on EGFR's another downstream marker AKT. The combination schedules also showed prominent influence on cell cycle distribution. ZD1839 maintained SN38-induced DNA damage and apoptosis. CONCLUSION: Sequential SN38 followed by ZD1839 may be a favorable combination schedule.

Original languageEnglish
Pages (from-to)578-582
Number of pages5
JournalZhonghua zhong liu za zhi [Chinese journal of oncology]
Volume28
Issue number8
Publication statusPublished - Aug 2006

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Fingerprint

Dive into the research topics of 'Experimental study of effect of epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in combination with irinotecan'. Together they form a unique fingerprint.

Cite this