title: Effects of different combinations of gefitinib and irinotecan in lung cancer cell lines expressing wild or deletional EGFR.
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.
authors.affiliation: Shien-Lab and Medical Oncology, National Cancer Center Hospital, Pharmacology Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Tatsu
authors.initials: T
authors.lastname: Shimoyama
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Koizumi
authors.forename: Hisao
authors.initials: H
authors.lastname: Fukumoto
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D051379:Mice; D011799:Quinazolines / Q000008:administration & dosage; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D011799:Quinazolines; D000077146:Irinotecan; D066246:ErbB Receptors; D000077156:Gefitinib; D002166:Camptothecin