Abstract
Multidrug resistance (MDR) and more specifically the expression of P-glycoprotein (Pgp) have been studied extensively in vitro. Unfortunately, it appears that the predictive value of MDR recognized in vitro is mostly an incorrect measure to determine the responsiveness of a particular tumour in the clinic. This misunderstood or overvalued role of MDR might explain the failure of strategies to reverse Pgp function by the use of modulators in solid tumours. To obtain more insight in in vivo drug resistance we investigated a panel of 15 human ovarian cancer xenografts consisting of the most common histological subtypes known in ovarian cancer patients. The response rate to cisplatin, cyclophosphamide and doxorubicin in the xenografts resembled the results of phase II trials with these agents in ovarian cancer patients. This resemblance justifies drug resistance studies in this experimental in vivo human tumour system. We determined the expression levels of MDR 1, MRP 1, LRP and topoisomerase IIα mRNA by the RNase protection assay and the presence of MRP1 and LRP proteins by immunohistochemistry. The S-phase fraction was investigated as a separate parameter by flow cytometry. In none of the 15 ovarian cancer xenografts was MDR 1 expression detectable. The expression levels of MRP 1 and LRP were low to moderate and resembled the presence of the MRP1 and LRP proteins. There was a weak, inverse relationship between the expression levels of LRP and sensitivity to cisplatin and cyclophosphamide (r = –0.44 and –0.45), but not to doxorubicin. The levels of topoisomerase IIα varied among the xenografts (0.73–2.66) and failed to correlate with doxorubicin resistance (r = 0.14). The S-phase fraction, however, showed a relation with the sensitivity to cisplatin (r = 0.66). Among the determinants studied in ovarian cancer in vivo, LRP mRNA and the S-phase fraction were the best predictive factors for drug response and most specifically for the activity of cisplatin. © 2000 Cancer Research Campaign
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References
Arts HJG, Katsaros D, De Vries EGE, Massobrio M, Genta F, Danese S, Arisio R, Scheper RJ, Kool M, Scheffer GL, Willemse PHB, Van der Zee AGJ and Suurmeijer AJH (1999) Drug resistance-associated markers P-glycoprotein, multidrug resistance- associated protein 1, multidrug resistance-associated protein 2, and lung resistance protein as prognostic factors in ovarian carcinoma. Clin Cancer Res 5: 2798–2805
Baas F, Jongsma APM, Broxterman HJ, Arceci RJ, Housman D, Scheffer GL, Riethorst A, Van Groenigen M, Nieuwint AWM and Joenje H (1990) Non-P-glycoprotein mediated mechanism for multidrug resistance precedes P-glycoprotein expression during in vitro selection for doxorubicin resistance in a human lung cancer cell line. Cancer Res 50: 5392–5398
Bourhis J, Goldstein LJ, Riou G, Pastan I, Gottesman MM and Benard J (1989) Expression of a human multidrug resistance gene in ovarian carcinomas. Cancer Res 49: 5062–5065
Boven E, Winograd B, Berger DP, Dumont MP, Braakhuis BJM, Fodstad O, Langdon SP and Fiebig HH (1992) Phase II preclinical drug screening in human tumour xenografts: a first European multicenter collaborative study. Cancer Res 52: 5940–5947
Chevillard S, Pouillart P, Beldjord C, Asselain B, Beuzeboc P, Magdelenat H and Vielh P (1996) Sequential assessment of multidrug resistance phenotype and measurement of S-phase fraction as predictive markers of breast cancer response to neoadjuvant chemotherapy. Cancer 77: 292–300
Cole SPC, Sparks KE, Fraser K, Loe DW, Grant CE, Wilson GM and Deeley RG (1994) Pharmacological characterization of multidrug resistant MRP-transfected human tumour cells. Cancer Res 54: 5902–5910
Cornarotti M, Capranico G, Bohm S, Oriana S, Spatti GB, Mariani L, Ballabio G and Zunino F (1996) Gene expression of DNA topoisomerases I, II alpha and II beta and response to cisplatin-based chemotherapy in advanced ovarian carcinoma. Int J Cancer 67: 479–484
Duyndam MCA, Hilhorst MCGW, Verheul HMW, Pinedo HM and Boven E (2000) VEGF165expression differentially affects the growth inhibition induced by anticancer agents in human ovarian cancer xenografts. Keystone Symposium on angiogenesis. Salt Lake City, March 2000, abst
Flens MJ, Scheffer GL, Van der Valk P, Broxterman HJ, Eijdems EWHM, Huysmans ACLM, Izquierdo MA and Scheper RJ (1997) Identification of novel drug resistance-associated proteins by a panel of rat monoclonal antibodies. Int J Cancer 73: 249–257
Ghazal-Aswad S, Hogarth L, Hall AG, George M, Sinha DP, Lind M, Calvert AH, Sunter JP and Newell DR (1996) The relationship between tumour glutathione concentration, glutathione S-transferase isoenzyme expression and response to single agent carboplatin in epithelial ovarian cancer patients. Br J Cancer 74: 468–473
Giaccone G, Van Ark-Otte J, Scagliotti G, Capranico G, Van der Valk P, Rubio G, Dalesio O, Lopez R, Zunino F, Walboomers J and Pinedo HM (1995) Differential expression of DNA topoisomerases in non-small cell lung cancer and normal lung. Biochim Biophys Acta 1264: 337–346
Hamaguchi K, Godwin AK, Yakushiji M, O-Dwyer PJ, Ozols RF and Hamilton TC (1993) Cross-resistance to diverse drugs is associated with primary cisplatin resistance in ovarian cancer cell lines. Cancer Research 53: 5225–5232
Hamilton TC, Young RC and Ozols RF (1984) Experimental model systems of ovarian cancer: applications to the design and evaluation of new treatment approaches. Semin Oncol 11: 285–298
Ishikawa T and Ali-Osman F (1993) Glutathione-associated cis-diamminedichloroplatinum(II) metabolism and ATP-dependent efflux from leukemia cells. Molecular characterization of glutathione-platinum complex and its biological significance. J Biol Chem 268: 20116–20125
Ishikawa T, Akimaru K, Kuo MT, Priebe W and Suzuki M (1995) How does the MRP/GS-X pump export doxorubicin? [letter]. J Natl Cancer Inst 87: 1639–1640
Izquierdo MA, Van der Zee AGJ, Vermorken JB, Van der Valk P, Belien JAM, Giaccone G, Scheffer GL, Flens MJ, Pinedo HM, Kenemans P, Meijer CJLM, De Vries EGE and Scheper RJ (1995) Drug resistance-associated marker Lrp for prediction of response to chemotherapy and prognoses in advanced ovarian carcinoma. J Natl Cancer Inst 87: 1230–1232
Izquierdo MA, Shoemaker RH, Flens MJ, Scheffer GL, Wu L, Prather TR and Scheper RJ (1996) Overlapping phenotypes of multidrug resistance among panels of human cancer-cell lines. Int J Cancer 65: 230–237
Jansen WJM, Pinedo HM, Van der Wilt CL, Feller N, Bamberger U and Boven E (1995) The influence of BIBW22BS, a dipyridamole derivative, on the antiproliferative effects of 5-fluorouracil, methotrexate and gemcitabine in vitro and in human tumour xenografts. Eur J Cancer 31A: 2313–2319
Johnson SW, Ozols RF and Hamilton TC (1993) Mechanisms of drug resistance in ovarian cancer. Cancer 71: 644–649
Kavallaris M, Leary JA, Barrett JA and Friedlander ML (1996) MDR1 and multidrug resistance-associated protein (MRP) gene expression in epithelial ovarian tumours. Cancer Lett 102: 7–16
Kolfschoten GM, Pinedo HM, Scheffer PG, Schlüper HMM, Erkelens CAM and Boven E (2000) Development of a panel of 15 human ovarian cancer xenografts for drug screening and determination of the role of the glutathione detoxification system. Gynecol Oncol 76: 362–368
Kool M, De Haas M, Scheffer GL, Scheper RJ, Van Eijk MJT, Juijn JA, Baas F and Borst P (1997) Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res 57: 3537–3547
Langdon SP, Hendriks HR, Braakhuis BJM, Pratesi G, Berger DP, Fodstad O, Fiebig HH and Boven E (1994) Preclinical phase II studies in human tumour xenografts: a European multicenter follow-up study. Ann Oncol 5: 415–422
Lautier D, Canitrot Y, Deeley RG and Cole SP (1996) Multidrug resistance mediated by the multidrug resistance protein (MRP) gene. Biochem Pharmacol 52: 967–977
List AF, Spier CS, Grogan TM, Johnson C, Roe DJ, Greer JP, Wolff SN, Broxterman HJ, Scheffer GL, Scheper RJ and Dalton WS (1996) Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia. Blood 87: 2464–2469
Loe DW, Deeley RG and Cole SPC (1996) Biology of the multidrug resistance-associated protein, MRP. Eur J Cancer 32A: 945–957
Molthoff CFM, Calame JJ, Pinedo HM and Boven E (1991) Human ovarian cancer xenografts in nude mice: characterization and analysis of antigen expression. Int J Cancer 47: 72–79
Neijt JP, Ten Bokkel Huinink WW, Van der Burg MEL, Van Oosterom AT, Vriesendorp R and Pinedo HM (1984) Current status of systemic chemotherapy in the treatment of advanced ovarian cancer with emphasis on CHAP-5. Radiother Oncol 2: 19–29
Nielsen D, Maare C and Skovsgaard T (1996) Cellular resistance to anthracyclines. Gen Pharmacol 27: 251–255
Noonan KE, Beck C, Holzmayer TA, Chin JE, Wunder JS, Andrulis IL, Gazdar AF, Willman CL, Griffith B, Von Hoff DD and Roninson IB (1990) Quantitative analysis of MDR1 (multidrug resistance) gene expression in human tumours by polymerase chain reaction. Proc Natl Acad Sci USA 87: 7160–7164
Pinedo HM and Giaccone G (1995) P-glycoprotein – a marker of cancer-cell behavior [editorial; comment]. N Engl J Med 333: 1417–1419
Raaijmakers HG, Izqueirdo MA, Lokhorst HM, De Leeuw C, Belien JA, Bloem AC, Dekker AW, Scheper RJ and Sonneveld P (1998) Lung-resistance-related protein expression is a negative predictive factor for response to conventional low but not to intensified dose alkylating chemotherapy in multiple myeloma. Blood 91: 1029–1036
Remvikos Y, Beuzeboc P, Zajdela A, Voillemot N, Magdelenat H and Pouillart P (1989) Correlation of pretreatment proliferative activity of breast cancer with the response to cytotoxic chemotherapy. J Natl Cancer Inst 81: 1383–1387
Roninson IB (1992) The role of the MDR1 (P-glycoprotein) gene in multidrug resistance in vitro and in vivo. Biochem Pharmacol 43: 95–102
Rubin SC, Finstad CL, Hoskins WJ, Saigo PE, Provencher DM, Federici MG, Hakes TB, Markman M, Reichman BS, Lloyd KO and Lewis JL (1990) Expression of P-glycoprotein in epithelial ovarian cancer: evaluation as a marker of multidrug resistance. Am J Obstet Gynecol 163: 69–73
Scheffer GL, Wijngaard PLJ, Flens MJ, Izquierdo MA, Slovak ML, Pinedo HM, Meijer CJLM, Clevers HC and Scheper RJ (1995) The drug resistance-related protein LRP is the human major vault protein. Nat Med 1: 578–582
Schmidt RA, Conrad EU, Collins C, Rabinovitch P and Finney A (1993) Measurement and prediction of the short-term response of soft tissue sarcomas to chemotherapy. Cancer 72: 2593–2601
Schröder CP, Godwin AK, O'Dwyer PJ, Tew KD, Hamilton TC and Ozols RF (1996) Glutathione and drug resistance. Cancer Invest 14: 158–168
Spyratos F, Briffod M, Tubiana-Hulin M, Andrieu C, Mayras C, Pallud C, Lasry S and Rouesse J (1992) Sequential cytopunctures during preoperative chemotherapy for primary breast carcinoma. II. DNA flow cytometry changes during chemotherapy, tumor regression, and short-term follow-up. Cancer 69: 470–475
Van der Zee AGJ, Hollema H, De Jong S, Boonstra H, Gouw A, Willemse PHB, Zijlstra JG and De Vries EGE (1991) P-glycoprotein expression and DNA topoisomerase I and II activity in benign tumors of the ovary and in malignant tumors of the ovary, before and after platinum/cyclophosphamide chemotherapy. Cancer Res 51: 5915–5920
Zaman GJR, Versantvoort CHM, Smit JJM, Eijdems EWHM, De Haas M, Smith AJ, Broxterman HJ, Mulder NH, De Vries EGE, Baas F and Borst P (1993) Analysis of the expression of MRP, the gene for a new putative transmembrane drug transporter, in human multidrug resistant lung cancer cell lines. Cancer Res 53: 1747–1750
Zijlstra JG, De Vries EGE and Mulder NH (1987) Multifactorial drug resistance in an adriamycin-resistant human small cell lung carcinoma cell line. Cancer Res 47: 1780–1784
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Kolfschoten, G., Hulscher, T., Pinedo, H. et al. Drug resistance features and S-phase fraction as possible determinants for drug response in a panel of human ovarian cancer xenografts. Br J Cancer 83, 921–927 (2000). https://doi.org/10.1054/bjoc.2000.1373
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DOI: https://doi.org/10.1054/bjoc.2000.1373
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