title: Topoisomerase IIalpha and other drug resistance markers in advanced non-small cell lung cancer.
abstract: Resistance to chemotherapy is common in non-small cell lung cancer. The aim of this study was to investigate the prognostic impact of in vitro established drug resistance markers on the response to chemotherapy in patients with advanced non-small cell lung cancer. Samples of 38 patients were analyzed by immunohistochemical staining, for topoisomerase IIalpha and IIbeta, Ki-67, MRP and LRP. In addition, mutation analysis of the topoisomerase IIalpha gene, the B/DNBS and the Tyr804 region, was performed. Lung tumor biopsies were taken prior for treatment with one of the following regimens; cisplatin/paclitaxel, cisplatin/VM26 or VP16, or carboplatin/VP16/ifosfamide. Seventeen patients obtained a partial response, 12 had stable disease and nine patients had progressive disease. None of the investigated markers was related with overall response rate. In one sample a point mutation in the B/DNBS region of the topo IIalpha gene was detected which substitutes IIe(510) with Val. This tumor had a partial response to four courses of cisplatin/VP16 treatment. The survival analysis showed that the patients with high topo IIalpha expressing tumors had a significantly worse survival compared with the patients with low or intermediate topo IIalpha expressing tumors. In conclusion, no relation was observed between expression of topoisomerase IIalpha, IIbeta, Ki-67, MRP or LRP and response rate. Furthermore, worse survival was seen in patients with high topoisomerase IIalpha expressing tumors. In one tumor sample, a newly described mutation in the B/DNBS region of the topo IIalpha gene was detected, which does not appear to be related to drug resistance.
authors.affiliation: Department of Medical Oncology, University Hospital, Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: A C
authors.initials: AC
authors.lastname: Dingemans
authors.forename: J
authors.initials: J
authors.lastname: van Ark-Otte
authors.forename: S
authors.initials: S
authors.lastname: Span
authors.forename: G V
authors.initials: GV
authors.lastname: Scagliotti
authors.forename: P
authors.initials: P
authors.lastname: van der Valk
authors.forename: P E
authors.initials: PE
authors.lastname: Postmus
authors.forename: G
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000032:analysis; D019943:Amino Acid Substitution; D000951:Antigens, Neoplasm; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D015415:Biomarkers; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D002945:Cisplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D004252:DNA Mutational Analysis; D004250:DNA Topoisomerases, Type II / Q000032:analysis* / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D007527:Isoenzymes / Q000032:analysis* / Q000235:genetics; D019394:Ki-67 Antigen / Q000032:analysis; D015993:Life Tables; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000032:analysis* / Q000235:genetics; D017239:Paclitaxel / Q000008:administration & dosage; D017354:Point Mutation; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D013713:Teniposide / Q000008:administration & dosage; D019772:Topotecan / Q000008:administration & dosage; D016896:Treatment Outcome; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein
chemical_list: D018528:ATP-Binding Cassette Transporters; D000951:Antigens, Neoplasm; D015415:Biomarkers; D002945:Cisplatin; D003520:Cyclophosphamide; D004250:DNA Topoisomerases, Type II; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D004317:Doxorubicin; D005047:Etoposide; D007069:Ifosfamide; D007527:Isoenzymes; D019394:Ki-67 Antigen; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D017239:Paclitaxel; D013713:Teniposide; D019772:Topotecan; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein