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Melphalan, and Etoposide

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Melphalan, and Etoposide [CANCER RESEARCH56, 3577—3582,August1, 19961 Transfection of Glutathione S-Transferase (GST)-n' Antisense Complementary DNA Increases the Sensitivity of a Colon Cancer Cell Line to Adriamycin, Cisplatin, Melphalan, and Etoposide Noriyoshi Ban, Yasuo Takahashi, Tetsuji Takayama, Toshiro Kura, Tatsuro Katahira, Sumio Sakamaki, and Yoshiro Nlitsu' Department oflnternal Medicine (Section 4), Sapporo Medical University, South-i, West-16, Chuo-ku, Sapporo 060, Japan ABSTRACT cancer agents before treatment, which suggests that GST-ir is in volved in intrinsic resistance as well (12). However, these studies The goal ofthis study was to demonstrate that glutathione S-transferase have not shed light directly on the question of whether the expression (GST)-ii' is directly involved in the Intrinsic and acquired resistance of of GST-ir is in fact a cause of drug resistance or merely a reactive cancer cells to anticancer drugs. To this end, GST.i@ antisense eDNA was transfected Into the cultured human colon cancer cell line M7609, which change that accompanies the development of resistance. expresses an Innately high level of GST.ir and shows intrinsic drug Accordingly, various investigators have attempted to obtain direct resistance, and Into an M7609 strain with acquired resistance to Adria proof of the involvement of GST-'rr in anticancer drug resistance by mycin (ADRLe., M7609/ADR cells). The changes in the sensitivity of these the transfection of GST-ii@expression vectors to cultured cancer cells. transfectants to various anticancer drugs were investigated. The intracel For example, Moscow et a!. (13) transfected a GST-ir expression lular concentrations of GST.ir in M7609/anti.1 cells and M7609/anti-2 vector to MCF-7 cells (a cultured human breast cancer cell line) and cells, two clones that were established by transfection of GST-i@antisense showed that the cells acquired resistance to etoposide and ethacrynic eDNA Into M7609 cells, were decreased to approximately half of those acid, but there was no change in the cells' sensitivity to CDDP or detected in the parent cells (M7609) and in the control cells transfected melphalan. Another group, Miyazaki et a!. (14), transfected a GST-ir with vector alone (M7609/pLJ). The sensitivities of the antisense transfec expression vector to Chinese hamster ovarian cells and found that the tents In relation to ADR, cisplatin, melphalan, and etoposide were in cells were resistant to CDDP but not to ADR. Nakagawa et a!. (15) creased —3.3-fold, 2.3-fold, 2.2-fold, and 2.1-fold, respectively, compared with those of M7609 and M7609/pLJ. On the other hand, the sensitivities transfected a GST-ir expression vector to NIH3T3 cells that had been of the antisense transfectants to Taxol, vincristine, S-fluorouradll, and transformed with H-ras and found that although the resistance to ADR mitomycin C were not significanfly changed. Similarly, the transfection of had been increased, the cells did not acquire resistance to alkylating antisense cDNA Into M7609/ADR cells resulted in the reduction of intra. agents. In yet another study, Black et al. (16) transfected a GST-ir cellular GST-ir concentration (by about half) and an Increased sensitivity expression vector to Saccharomyces cerevisiae and reported that to ADR (4.4-fold), but no increase In 5-fluorouradil sensitivity. Thus, resistance was acquired to ADR and chlorambucil. However, the GST-@risconsidered to be a multidrug resistance factor that Is responsible results of these experiments involving the transfection of GST-ir gene for both the intrinsic and acquired resistance of cancer cells to anticancer are not entirely unambiguous. drugs such as ADR, cisplatin, melphalan, and etoposide. In an attempt to explain these various findings, Tew (17) proposed a number of hypotheses, including: (a) the possibility that the level of INTRODUCTION reduced GSH in the target cells was below that necessary for the activation of the GSHJGST detoxification system; (b) the possibility GST-ir 2 expression is increased in various human cancer tissues, that the level of the cell membrane-bound GSH-conjugate export including gastric cancer, colon cancer, lung cancer, oral cavity cancer, pump was insufficient; (c) the possibility that the level of native GST and uterine cancer; thus it is employed in cancer research as a tumor expression by the cells used was already at a maximum; (d) the marker (1—5).There have also been numerous reports showing that the possibility that the transcription efficiency of the transfected GST-'rr expression of GST-ir is elevated in various cultured cells lines pos gene was insufficient or that the turnover was accelerated; and (e) the sessing resistance to anticancer drugs such as ADR (6), melphalan (7), possibility that the importance of the GSH/GST detoxification system CDDP (8), cyclophosphamide (9), and chiorambucil (10) as well as in in the overall anticancer drug resistance mechanism was low. Tew in vivo cancer tissues that have become resistant to therapy after thus suggested that the approach of transferring the GST-ir gene to administration of anticancer agents (11). We have recently estab target cells and thereby causing an increase in GST-ir activity had not lished, from a human colon cancer cell line (M7609), an ADR been adequate. resistant cell line (M7609/ADR) that showed increased expression of In consideration of this background, we designed the present study GST-ir but not of p-glycoprotein, multidrug-resistance associated on the basis of the reverse supposition that if the expression of GST-ir protein (MRP), and topoisomerase ll.@ These observations suggest by cells was inhibited, then the activity of GST-ir should decrease that the expression of GST-ii@is involved in the acquisition of resist without any dependence on the level of GSH in the cells or the ance to anticancer drugs. Furthermore, elevated expression of GST-ir GSH-conjugate export pump. We tested the validity of this approach has been demonstrated even in cancers that show resistance to anti by transfection of GST-ir antisense cDNA to the M7609 human colon cancer cell line and to its ADR-resistant subline, M7609/ADR, and Received 2/5/96; accepted 5124/96. The costs of publication of this article were defrayed in part by the payment of page then testing these cell lines for multidrug sensitivity. charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom inquests for reprints should be addressed, at Department of Internal MATERIALS AND METHODS Medicine (Section 4), Sapporo Medical University School of Medicine, South-l, West-l6, Chuo-ku, Sapporo 060, Japan. Phone: 81-I 1-611-2111, extension 3260; Fax: 81-11-612- Cell Linesand Cell CUltUre.Humancoloncancercell lineM7609(18) 7987. was kindly provided by Dr. S. Machida (Hirosaki University, Hirosaki, Japan). 2 Abbreviations used are: GST-ir, glutathione S-transferase ir, ADR, Adriamycin; This cell line was established from a colon cancer patient who had not been CDDP, cisplatin; OSH, glutathione; 5-Ri, 5-fluorouracil; VCR, vincristine; MMC, mit omycin C. treated with anticancer drugs. M7609/ADR, an ADR-resistant cell line, was 3 Unpublished data. established from M7609 cells in our laboratory according to the method of 3577 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1996 American Association for Cancer Research. INCREASE OF DRUG SENSITIVITY BY GST-ir ANTISENSE cDNA Whelan et a!. (19). M7609/ADR shows a resistance to ADR approximately six labeled with 32P, using the random primer method (25) and were used as times greater than that of M7609. M7609/ADR also shows cross-resistance to probes. Hybridization and washings were performed according to the proce CDDP, etoposide, and melphalan but not to 5-FU, VCR, and MMC. In dures described in “SouthernBlotting.― addition, M7609/ADR shows two times greater expression of GST-ir than the GST-ii Quantitation by ELISA. Afterwashingeach cell preparationtwo parent cell line but shows no increases of p-glycoprotein, MRP, and topoi times in cold PBS (10 mMsodium phosphate buffer containing 0.9% NaCl), somerase II.@ Both of these cell lines were cultured in RPM! 1640 (Life the cells were adjusted to a concentration of 1 X l0@/miinthe same buffer and Technologies, Inc., Grand Island, NY) containing 10% FCS (Flow Laborato were homogenized with a Dounce homogenizer. The lysates were then cen lies, North Ryde, Australia) in tissue-culture flasks; incubation was performed trifuged at 12,000 rpm for 15 mm, and the concentration of GST-ir in each at 37°Cinan atmosphere of air containing 5% CO2. supernatant was measured by the sandwich ELISA established in our labora Construction of a GST-i@ Antisense Vector. The plasmid pGpi2 (20), tory as described previously (27, 28). containing GST-ir cDNA, was obtained from the Japanese Cancer Research Sensitivities to Various Anticancer Drugs. ADR, 5-FU, and MMC were Resources Bank (Tokyo, Japan), and the p11 vector (21) was kindly provided purchased from Kyowa Hakko Kogyo Co., Ltd. (Tokyo, Japan), whereas by Dr. G. Wu (University of Connecticut, Farmington, Cl'). pGpi2 was etoposide and CDDP were obtained from Nippon Kayaku Co., Ltti (Tokyo, digested with EcoRI, and a 0.7-kb EcoRI-EcoRI fragment containing the Japan), and VCR was purchased from Shionogi Co., Ltd. (Tokyo, Japan). whole coding region for GST-ir was recovered. Both ends of this fragment Melphalan and ethacrynic acid were obtained from Sigma Chemical Co. (St. were then blunted with the Klenow fragment (Takara Shuzo Co., Ltd., Kyoto, Louis, MO), and Taxol was supplied by Bristol-Myers (Tokyo, Japan). The Japan). The pll vector was linearized with BamHI, the blunting of both sensitivities of each cultured cell line to these various anticancer drugs were terminals was similarly performed using the Kienow fragment, and was de determined by the dye-uptake method (29).
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