Increased mRNA levels of xeroderma pigmentosum complementation group B (XPB) and Cockayne's syndrome complementation group B (CSB) without increased mRNA levels of multidrug-resistance gene (MDR1) or metallothionein-II (MT-II) in platinum-resistant human ovarian cancer tissues.
Tumor tissue specimens from human ovarian cancer patients were assessed for relative mRNA abundance levels of several genes thought to be involved in the development of in vitro drug resistance in this disease. Higher mRNA levels of Xeroderma pigmentosum group B (XPB), which links DNA repair with DNA transcription, and of Cockayne's syndrome group B (CSB), which is essential for gene-specific repair, were observed in tumor tissues that were clinically resistant to platinum-based chemotherapy, as compared with tissues from patients responding to therapy. In a cohort of 27 patients, mRNA levels of XPB averaged 5-fold higher in platinum-resistant tumors (P = 0.001); and for CSB, mRNA levels averaged 6-fold higher but with greater variability (P = 0.033). Concurrently, these platinum-resistant tumor tissues did not exhibit significantly higher mRNA levels for the MDR1 (multidrug-resistance) gene (P = 0.134) or of the metallothionein-II (MT-II) gene (P = 0.598). Since these platinum-resistant tumors also show higher mRNA levels of ERCC1 and XPA, platinum resistance appears to be associated with concurrent up-regulation of four genes (XPA, ERCC1, XPB, and CSB). These four genes participate in DNA damage excision activity, gene-specific repair, and linkage of DNA repair with DNA transcription. These data suggest that concurrent up-regulation of genes involved in nucleotide excision repair may be important in clinical resistance to platinum-based chemotherapy in this disease.
Dabholkar
M
M
Medical Ovarian Cancer Section, Medicine Branch, National Cancer Institute, National Institutes of Health, 20892, USA, Bethesda, MD, USA.
Thornton
K
K
Vionnet
J
J
Bostick-Bruton
F
F
Yu
J J
JJ
Reed
E
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D010984:Platinum / Q000494:pharmacology; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger; C072022:XPBC-ERCC-3 protein; D010984:Platinum; D008668:Metallothionein; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes