Shimoyama Tatsu, Koizumi Fumiaki, Fukumoto Hisao, Kiura Katsuyuki, Tanimoto Mitsune, Saijo Nagahiro, Nishio Kazuto
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.
Lung Cancer. 2006 Jul;53(1):13-21. doi: 10.1016/j.lungcan.2006.03.014. Epub 2006 May 19.
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.
表皮生长因子受体（EGFR）突变是肺肿瘤对吉非替尼（一种EGFR特异性酪氨酸激酶抑制剂）反应的主要决定因素。使表达野生型EGFR的肺肿瘤产生反应是一个主要障碍。吉非替尼与细胞毒性药物联合使用是针对表达野生型EGFR肺癌的一种策略。DNA拓扑异构酶抑制剂硫酸伊立替康（CPT-11）对肺癌有活性。我们研究了表达野生型或突变型EGFR的肺癌对吉非替尼和CPT-11联合用药的敏感性。使用染料形成试验和联合指数，在7种肺癌细胞系中检测了吉非替尼和SN-38（CPT-11的活性代谢物）的体外作用。同时给药时，吉非替尼和SN-38在7种表达野生型EGFR的细胞系中的5种中具有协同作用，而在PC-9细胞和对吉非替尼耐药且表达缺失突变型EGFR的PC-9亚系（PC-9/ZD）中，联合用药具有拮抗作用。序贯给药时，先用SN-38治疗再用吉非替尼在PC-9和PC-9/ZD细胞中具有显著的协同作用。在体内荷瘤模型中，这种联合用药在PC-9和PC-9/ZD细胞中具有时间依赖性协同作用。对接受CPT-11和吉非替尼治疗的小鼠肿瘤进行免疫组化分析表明，当CPT-11与吉非替尼联合给药时，CPT-11治疗诱导的Ki-67阳性肿瘤细胞数量减少。总之，CPT-11和吉非替尼序贯联合用药被认为对肺癌有活性。
