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Messenger RNA Levels of XPAC and ERCC1 in Ovarian Cancer Tissue Correlate with Response to Platinum-Based Chemotherapy

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Messenger RNA Levels of XPAC and ERCC1 in Ovarian Cancer Tissue Correlate with Response to Platinum-Based Chemotherapy Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. M Dabholkar, … , J J Yu, E Reed J Clin Invest. 1994;94(2):703-708. https://doi.org/10.1172/JCI117388. Research Article Nucleotide excision repair is a DNA repair pathway that is highly conserved in nature, with analogous repair systems described in Escherichia coli, yeast, and mammalian cells. The rate-limiting step, DNA damage recognition and excision, is effected by the protein products of the genes ERCC1 and XPAC. We therefore assessed mRNA levels of ERCC1 and XPAC in malignant ovarian cancer tissues from 28 patients that were harvested before the administration of platinum- based chemotherapy. Cancer tissues from patients whose tumors were clinically resistant to therapy (n = 13) showed greater levels of total ERCC1 mRNA (P = 0.059), full length transcript of ERCC1 mRNA (P = 0.026), and XPAC mRNA (P = 0.011), as compared with tumor tissues from those individuals clinically sensitive to therapy (n = 15). In 19 of these tissues, the percentage of alternative splicing of ERCC1 mRNA was assessed. ERCC1 splicing was highly variable, with no difference observed between responders and nonresponders. The alternatively spliced species constituted 2-58% of the total ERCC1 mRNA in responders (median = 18%) and 4-71% in nonresponders (median = 13%). These data suggest greater activity of the DNA excision repair genes ERCC1 and XPAC in ovarian cancer tissues of patients clinically resistant to platinum compounds. These data also indicate highly variable splicing of ERCC1 mRNA in ovarian cancer tissues in vivo, whether or […] Find the latest version: https://jci.me/117388/pdf Messenger RNA Levels of XPAC and ERCC1 in Ovarian Cancer Tissue Correlate with Response to Platinum-based Chemotherapy Meenakshi Dabholkar, Justine Vionnet, Frieda Bostick-Bruton, Jing Jie Yu, and Eddie Reed Medical Ovarian Cancer Section, Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892 Abstract Chinese hamster ovary [CHO] mutant cell lines of complemen- tation group 1) and XPAC (the human excision repair gene that Nucleotide excision repair is a DNA repair pathway that is corrects the defect in xeroderma pigmentosum group A cells) highly conserved in nature, with analogous repair systems have been cloned (4, 5). Several studies using mutant human described in Escherichia coli, yeast, and mammalian cells. and hamster cell lines that are defective in either of these genes, The rate-limiting step, DNA damage recognition and exci- and their transfected derivatives, and studies in human tumor sion, is effected by the protein products of the genes ERCC1 tissues indicate that the products encoded by these genes are and XPAC. We therefore assessed mRNA levels of ERCC1 involved in the excision repair of platinum-DNA adducts and XPAC in malignant ovarian cancer tissues from 28 (6-9). patients that were harvested before the administration of We have been interested in ascertaining the relative levels platinum-based chemotherapy. Cancer tissues from patients of expression of excision repair genes in malignant cells from whose tumors were clinically resistant to therapy (n = 13) cancer patients receiving platinum-based therapy (6). Currently showed greater levels of total ERCC1 mRNA (P = 0.059), accepted models of excision repair suggest that the damage full length transcript of ERCC1 mRNA (P = 0.026), and recognition/excision step is rate-limiting to the excision repair XPAC mRNA (P = 0.011), as compared with tumor tissues process (3). Studies on the homology of human excision repair from those individuals clinically sensitive to therapy (n genes with bacterial and yeast excision repair genes suggest = 15). In 19 of these tissues, the percentage of alternative that ERCC1 and XPAC may be the genes primarily involved splicing of ERCC1 mRNA was assessed. ERCC1 splicing in the recognition and excision of bulky DNA adducts (5, 10- was highly variable, with no difference observed between 12). This occurs with the help of putative helicases encoded by responders and nonresponders. The alternatively spliced ERCC2, ERCC3, and ERCC6 (2, 13). species constituted 2-58% of the total ERCC1 mRNA in The present study examines relative mRNA levels of expres- responders (median = 18%) and 4-71% in nonresponders sion of ERCC1 and XPAC in ovarian cancer tissues. We also (median = 13%). These data suggest greater activity of the assess the levels of an alternatively spliced species of ERCC1 DNA excision repair genes ERCC1 and XPAC in ovarian mRNA which does not contain exon VIII and is presumed to cancer tissues of patients clinically resistant to platinum be nonfunctional. These studies have been done in tumor tissues compounds. These data also indicate highly variable splicing taken from a cohort of 28 patients with ovarian cancer, before of ERCC1 mRNA in ovarian cancer tissues in vivo, whether the initiation of platinum-based therapy. We believe that as- or not such tissues are sensitive to platinum-based therapy. sessing patterns of mRNA expression of ERCC and XP genes (J. Clin. Invest. 1994. 94:703-708.) Key words: XPAC may assist in understanding the molecular control of cellular ERCC1 * ovarian cancer * platinum compounds resistance to DNA-damaging agents. Introduction Methods Excision repair of bulky DNA adducts, such as those formed Tissues studied. Fresh tumor tissues were obtained from 28 patients by cisplatin, appears to be mediated by an aggregate of genes, with ovarian cancer. These tissues were obtained before treatment with with ERCC and XP proteins being involved in DNA damage cisplatin- or carboplatin-based chemotherapy. Patients from whom tis- recognition and excision (1-3). The human DNA repair genes sues were obtained participated in either of three approved experimental treatment protocols for advanced stage ovarian cancer that have been ERCC ' (the human excision repair gene cross-complementing reported previously by the Medicine Branch of the National Cancer Institute (unpublished observations2, 14-16). Disease was followed by physical exam and by radiographic means, including abdominopelvic Address correspondence to Eddie Reed, Clinical Pharmacology Branch, CT scan and/or ultrasound examination. National Cancer Institute, National Institutes of Health, 9000 Rockville Complete response was defined as complete eradication of all evalu- Pike, Bldg. 10, Rm. 12N226, Bethesda, MD 20892. able disease, confirmed by peritoneoscopy. Partial response was defined Received for publication 15 October 1993 and in revised form 9 as a > 50% reduction in the sum of the products of the perpendicular February 1994. diameters of all measurable lesions lasting at least 1 mo. Progressive disease was a > 25% increase in the sum of the products of the perpen- 1. Abbreviations used in this paper: CHO, Chinese hamster ovary; dicular diameters of all measurable lesions or the appearance of new ERCC1, human DNA excision repair gene, cross-complementing CHO mutant cell lines of complementation group 1; RT/PCR, reverse tran- scription PCR; XPAC, human xeroderma pigmentosum group A correct- 2. Reed, E., M. L. Rothenberg, and E. Kohn, unpublished data from ing gene. approved experimental treatment protocol. "High dose carboplatin, cis- platin, and cyclophosphamide in the initial therapy of advanced stage The Journal of Clinical Investigation, Inc. epithelial ovarian cancer." Medicine Branch, National Cancer Institutes. Volume 94, August 1994, 703-708 Trial completed in 1992. ERCCI and XPAC in Ovarian Cancer Tissue 703 BLOT #1 RESPONDERS PATIENT# 1 2 3 4 5 6 7 8 9 10 11 ERCC 1 : :: :> . XPAC 13-ACTIN e*l gI BLOT #2 NON-RESPONDERS PATIENT# 12 13 14 15 16 17 18 ERCC1 ......._ XPAC -ACTIN BLOT #3 (RESPONDERS) AND NON-RESPONDERS Figure 1. Autoradiographs generated by RT/ PATI ENT#(1 9) 20 21 22 (23)(24)(25)26 27 28 PCR-amplified RNA from ovarian cancer tis- sues, after hybridization of Southern blots with radiolabeled probes for ERCC1, XPAC, ERCC1 * ^ and ,B-actin. Samples 1-11, 19, and 23-25 (blots I and 3) represent 15 tumor tissues patients responding platinum-based XPAC therapy; samples 12-18, 20-22, and 26-28 /:IiA.*EE____0_](blots 2 and 3) represent 13 tumor tissues /3-ACTIN 22_'f-'-_ ~~~~~~~~~~~~~therapy.from patients resistant to platinum-based lesions. Stable disease included those clinical circumstances which did and for 40 cycles for XPAC. The GeneAmp PCR reagent kit with not fit the definitions of objective response nor progression. Progressive AmpliTaq DNA polymerase (Perkin-Elmer Cetus Instruments, Norwalk, disease and stable disease patients are included in the nonresponder CT) was used for each gene. Aliquots of amplified DNA were electro- category. Complete response and partial response are included in the phoresed through a 1.5% agarose gel. Amplified DNA was visualized responder category. By these criteria, there are 15 patients who were by ethidium bromide staining, photographed over an ultraviolet (UV) responders and 13 nonresponders in the cohort. transilluminater (Hoefer Scientific Instruments, San Francisco, CA), and In vitro studies were performed using the ovarian cancer cell line transferred to Hybond N+ membrane (Amersham International, Buck- A2780/CP70, which has been described previously by our labora- inghamshire, UK). Oligonucleotides (26-mers) from the central region of tory (17). each amplified sequence were end-labeled with [32P]rATP (Amersham PCR analyses. A reverse transcription/polymerase chain reaction International) using
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