Effects of Different Combinations of Gefitinib and Irinotecan in Lung Cancer Cell Lines Expressing Wild or Deletional EGFR

Lung Cancer. 2006 Jul;53(1):13-21. doi: 10.1016/j.lungcan.2006.03.014. Epub 2006 May 19.

Abstract

EGFR mutations are a major determinant of lung tumor response to gefitinib, an EGFR-specific tyrosine kinase inhibitor. Obtaining a response from lung tumors expressing wild-type EGFR is a major obstacle. The combination of gefitinib and cytotoxic drugs is one strategy against lung cancers expressing wild-type EGFR. The DNA topoisomerase inhibitor irinotecan sulfate (CPT-11) is active against lung cancer. We examined the sensitivity of lung cancers expressing wild- or mutant-type EGFR to the combination of gefitinib and CPT-11. The in vitro effect of gefitinib and SN-38 (the active metabolite of CPT-11) was examined in seven lung cancer cell lines using the dye formation assay with a combination index. When administered concurrently, gefitinib and SN-38 had a synergistic effect in five of the seven cell lines expressing wild-type EGFR, whereas the combination was antagonistic in PC-9 cells and a PC-9 subline resistant to gefitinib and expressing deletional mutant EGFR (PC-9/ZD). When administered sequentially, treatment with SN-38 followed by gefitinib had remarkable synergistic effects in the PC-9 and PC-9/ZD cells. In an in vivo tumor-bearing model, this combination had a schedule-dependent synergistic effect in the PC-9 and PC-9/ZD cells. An immunohistochemical analysis of the tumors in mice treated with CPT-11 and gefitinib demonstrated that the number of Ki-67 positive tumor cells induced by CPT-11 treatment was decreased when CPT-11 was administered in combination with gefitinib. In conclusion, the sequential combination of CPT-11 and gefitinib is considered to be active against lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Blotting, Western
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Cell Line, Tumor
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism
  • Gefitinib
  • Humans
  • Immunohistochemistry
  • Irinotecan
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics*
  • Mice
  • Quinazolines / administration & dosage
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Deletion
  • Survival Rate
  • Tumor Cells, Cultured

Substances

  • Quinazolines
  • Irinotecan
  • ErbB Receptors
  • Gefitinib
  • Camptothecin