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Main Drug-Metabolizing Enzyme Systems in Human Breast Tumors and Peritumoral Tissues1

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Main Drug-Metabolizing Enzyme Systems in Human Breast Tumors and Peritumoral Tissues1 ICANÅ’R RKSKARCH 53. 3541-3546. August 1. 1993] Main Drug-metabolizing Enzyme Systems in Human Breast Tumors and Peritumoral Tissues1 Nicolas Albin, Liliane Massaad, Caroline Toussaint, Marie-Christine Mathieu, Jackie Morizet, Orlando Parise, Alain Gouyette, and Guy G. Chabot2 Département Je Pharmaca-ttmcologie el Pharmamgénétiiiue(INSERM U 140 and CNRS URA 147} ¡N.A.. L. M., C. T.. J. M.. O. P.. A. G.. G. C. C.¡.and Département d'Anatimui-Patholiixie ¡M-C.M.l Institut Gustavt-Roussy, V4805 Villejiiif Cedex. France ABSTRACT thus a very important health problem because of its considerable economic and social implications ( 1). In an attempt to better understand breast tumors sensitivity or resis The most active anticancer drugs used in breast cancer include tance to anticancer drugs, the main drug-metabolizing enzyme systems cyclophosphamide, methotrexate, 5-fluorouracil. doxorubicin, and were evaluated in both breast tumors and their corresponding peritu- vincristine (2). Cisplatin has also shown activity in the treatment of moral tissues in 12 patients. The following enzymes were assayed by Western blot: cytochromes P-4SO (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4); advanced disease, especially in nonpretreated patients (3). Although glutathione .S'-transferases (GST-a, -u, and -TI); and epoxide hydrolase. the most frequently used drug combinations CMF or CMFP (cyclo The activity of the following enzymes or cofactor were determined by phosphamide, methotrexate, 5-fluorouracil, prednisone) can reduce spectrophotometric or fluorometric assays: GST; total glutathione; I 1)1'- mortality in women under 50 years old (4), women who relapse during glucuronosyltransferase; ß-glucuronidase; sulfotransferase; and sulfa or soon after adjuvant systemic therapy (within 6-12 months after its tase. Results showed the absence of all probed cytochromes P-450 in both cessation) have a poor prognosis. These patients do not respond to the tumoral and peritumoral tissues. GST activity was significantly (P < 0.05) same systemic therapy used as adjuvant (5). In contrast, patients who higher in tumors (mean ±SD, 399 ±362 nmol/min/mg) than in corre develop métastasesafter a long cessation of adjuvant treatment appear sponding peritumoral tissues (86 ±67). The GST isoenzymes GST-u and to respond to the same therapy, especially if the sites of recurrent GST-IT (determined by immunoblotting) were also higher in tumors than in corresponding peritumoral tissues (3- and 5-fold, respectively). Both disease are local, regional, or in soft tissue (6). GST-u and GST-m levels were significantly correlated with GST activity. To better understand the biological characteristics of breast tumors GST-a was not detected in either tumoral or peritumoral tissues. Glu and also the response or resistance to chemotherapy in this disease, we tathione levels in tumors (22 ±23 nmol/mg protein) were not statistically have explored the main drug-metabolizing enzyme systems in breast different from peritumoral tissues (11 ±12). Epoxide hydrolase was ex tumors and peritumoral tissues. These drug-metabolizing systems are pressed at similar levels in tumors and peritumoral tissues. The glucu- known to play an important role in the susceptibility of organs or ronide-forming enzyme UDP-glucuronosyltransferase was 5-fold lower in tissues to toxic effects of drugs or other xenobiotics and could also tumors (0.1 ±0.2nmol/h/mg) than in peritumoral tissues (0.5 ±I), whereas influence tumor response to anticancer agents in vivo (7, 8). Although the opposite was observed for the hydrolytic enzyme ß-glucuronidase, recent progress has been made in human breast cancer concerning which was 6-fold higher in tumors (736 ±1392 nmol/h/mg) compared to some enzymes involved in drug metabolism (9, 10), no information is peritumoral tissues (125 ±75). No difference was noted between tumoral presently available concerning many other important enzymatic sys and peritumoral tissues for sulfotransferase ( I ±2 nmol/h/mg), but the corresponding hydrolytic enzyme (sulfatase) was 2-fold higher in tumoral tems in this tumor type. It was therefore of interest to assess breast tumors main phase I P-450s' and phase II enzyme systems involved tissues (14 ±15 nmol/h/mg) than in peritumoral tissues (6 ±2). In con clusion, several differences were observed between human breast tumors in drug metabolism (GST isoenzymes, LJDP-GT. and sulfotrans and peritumoral tissues for many conjugating enzymes (GST-u, GST-m, ferase), which are involved in functionalization and conjugation re and UDP-glucuronosyltransferase) and hydrolytic enzymes (sulfatase and actions, respectively. We also assessed GSH content and the hydro ß-glucuronidase). These noteworthy differences between tumoral and per lytic enzymes EH, ß-glucuronidase. and sulfatase. itumoral tissues with regard to their main drug-metabolizing enzymes In this report, we present the comparison of the main drug-metab could play a role in the relative drug sensitivity or insensitivity of human olizing enzyme systems in human breast tumors and their correspond breast cancer tissues to chemotherapeutic agents and could be potential ing peritumoral tissues. Our results showed significant qualitative and targets for chemotherapeutic interventions. quantitative differences between tumoral and peritumoral tissues, for many enzymatic pathways. These differences between breast tumors INTRODUCTION and peritumoral tissues with regard to drug-metabolizing enzyme systems could play a role in the relative drug sensitivity or insensi Breast cancer is the leading cause of death in women aged between tivity of breast cancer tissues to chemotherapeutic agents. 35 and 55 years and. after cardiovascular disease, it is the second most common cause of death in women older than 55 years. During the past 20 years, both earlier diagnosis and adjuvant systemic treatment have MATERIALS AND METHODS been able to increase disease free and overall survival of most pa Chemicals and Enzymes tients. The next progress in this disease could be expected from new 5.5'-dithiobis(2-nitrobenzoic acid), NADPH, 4-methylumbelliferone, 4-m- active agents or alternative modalities of treatment. Breast cancer is ethylumbelliferone sulfate. 4-methylumbelliferone glucuronide. reduced GSH. l-chloro-2.4-dinitrobenzene. ß-glucuronidase, and sulfatase were purchased from Sigma Chemical Co. (St. Louis, MO). Phénobarbitaland 3-methylcholan- Received 2/4/93; accepted 5/24/93. threne were purchased from Specia (Rhône-Poulenc, Paris, France) and from The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with Aldrich (Milwaukee, WI), respectively. All other chemicals were of the highest 18 U.S.C. Section 1734 solely to indicate this fact. purity available from standard commercial sources. 1This work was supported by the Fondation pour la Recherche Médicale,the Institut National de la Santéetde la Recherche Médicale(INSERM). and théCentreNational de la Recherche Scientifique (CNRS). 1The abbreviations used are: P-450. cytochrome P-450; CDNB. l-chloro-2,4-dinitro- 2 To whom requests for reprints should be addressed, at Institut Gustave-Roussy. benzene; GST, glutathione ¿'-transl'erase;GSH, glutathione; EH. epoxide hydrolase; UDP- Départementde Pharmaco-toxicologie et Pharmacogénétique.Pavillonde Recherche 2. GT. UDP-glucuronosyltransI'erase; GST-a. basic GST; GST-ir, acidic GST; GST-u., neu 94X05 Villejuif Cedex. France. tral GST. 3541 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1993 American Association for Cancer Research. DRUG-METABOLIZING ENZYMES IN BREAST TUMORS AND PERITUMORAl. TISSUES Human Tissues Antigens and Antibodies Liver samples were provided from the Necker hospital tissue bank (Paris, In a previous study it was demonstrated that antibodies directed against rat France). Breast tissues were kindly provided by Dr. M-C. Mathieu (Gustave- or human antigens could recognize the corresponding mouse liver proteins Roussy Institute. Micropathology Laboratory, Villejuif, France). Breast tumors (15). and their corresponding peritumoral tissues were obtained from 12 different P-450. In this study we used the P-450 gene nomenclature based on the patients. All tissues were obtained during surgical excision of the tumor done updated list published by Nebert et al. (16). Polyclonal antirat P-450 1A1/1A2 and antirat 2B1/B2 were prepared in Dr. Beaune's laboratory (INSERM U 75, before chemotherapy. Peritumoral specimens were taken in a macroscopically Paris, France) and checked against Dr. F. P. Guengerich's preparations of P-450 noncancerous region of the resected tumor pieces (tumorectomy or mastecto my). Specimens were fro/en within 30 min and stored at -80°C to allow (Vanderbilt University, Nashville, TN). The polyclonal anti-rat P-450 2E1 was preservation of cellular enzymes. Part of each tissue sample was reserved for kindly provided by Dr. C. S. Yang (17). Monoclonal anlihuman P-450 3A4 was prepared as previously described (18). Polyclonal antihuman P-450 2C8-10 histopathological examination and the remainder was used for this investiga tion. was described by Shimada et al. (19). EH. Human epoxide hydrolase and their corresponding polyclonal antibod ies were previously described by Beaune et al. (20) and checked against Dr. Mouse Tissues Guengerich's preparations. GST. The polyclonal antihuman GST-a. -fi. and -n were purchased from In some experiments, we used
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