Point mutations in the topoisomerase I gene in patients with non-small cell lung cancer treated with irinotecan.
Reverse transcription polymerase chain reaction (RT-PCR) single-strand conformation polymorphism analysis was used to detect topoisomerase I (top1) mutations in total RNA from 16 specimens that were excised during surgery from eight patients with non-small cell lung cancer (NSCLC) who had received preoperative chemotherapy consisting of irinotecan (CPT-11) and cisplatin. PCR single-strand conformation polymorphism and subsequent DNA sequencing analysis showed two nucleotide substitutions resulting in Trp736stop (TGG to TGA) and Gly737Ser (GGT to AGT) in one tumor specimen. The mutations were located near a site in top1 that was previously reported to harbor a mutation in the human lung cancer cell line PC7/CPT, which was selected for CPT resistance. These results demonstrate that mutations in top1 occur after chemotherapy with CPT-11 in NSCLC patients and suggest that development of resistance to CPT-11 in some patients may involve mutation of top1. However, the significance of top1 mutations to CPT resistance needs to be further investigated.
Tsurutani
Junji
J
Fourth Department of Internal Medicine, Kinki University School of Medicine, Ohonohigashi 377-2, Osakasayama, Osaka 589-8511, Japan.
Nitta
Takashi
T
Hirashima
Tomonori
T
Komiya
Takefumi
T
Uejima
Hisao
H
Tada
Hirohito
H
Syunichi
Negoro
N
Tohda
Aritomo
A
Fukuoka
Masahiro
M
Nakagawa
Kazuhiko
K
D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D003131:Combined Modality Therapy; D004264:DNA Topoisomerases, Type I / Q000235:genetics*; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016296:Mutagenesis / Q000187:drug effects; D017354:Point Mutation / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D004273:DNA, Neoplasm; D012333:RNA, Messenger; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin