1. Effects of different combinations of gefitinib and irinotecan in lung cancer cell lines expressing wild or deletional EGFR.
- Author
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Shimoyama T, Koizumi F, Fukumoto H, Kiura K, Tanimoto M, Saijo N, and Nishio K
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma genetics, Animals, 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 metabolism, Gefitinib, Humans, Immunohistochemistry, Irinotecan, Mice, Quinazolines administration & dosage, Reverse Transcriptase Polymerase Chain Reaction, Sequence Deletion, Survival Rate, Tumor Cells, Cultured, Antineoplastic Combined Chemotherapy Protocols therapeutic use, ErbB Receptors genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics
- 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.
- Published
- 2006
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