Summary
S 9788 is a novel triazinoaminopiperidine derivative which does not belong to any of the classes of compounds known to reverse multidrug resistance (MDR). S 9788 was far more potent than verapamil (VRP) in reversing resistance to adriamycin (ADR) in the ADR-selected murine leukaemia cell lines P388/ADR-1 and P388/ADR-10, and the human chronic myelogenous leukaemia K562/R. Fold reversion with S 9788 (5μM was, respectively, 3.5, 5.4 and 11.3 times greater than that with VRP (5μM). S 9788 was also a more potent reversant of ADR resistance in the intrinsically resistant human colon adenocarcinoma COLO 320DM (2.3 fold), and of vincristine (VCR) resistance in the human MDR1 gene-transfected squamous lung carcinoma line S1/tMDR1 (5.6 fold). The activity of S 9788 depended on both the MDR cell line and the cytotoxic agent. S 9788 (50–100 mg/kg/d) administered IP once a day on days 1–4 resulted in a dose-dependent increase in the chemotherapeutic effect of VCR (0.25 mg/kg/d) in P388/VCR-bearing mice and ADR (4 mg/kg/d) in P388/ADR-bearing mice. Increases in antitumor activity were (% T/C) of +20–34% in the P388/ADR model and +50–78% in the P388/VCR model with respect to cytotoxic agent treatment alone. S 9788 appeared to be devoid of toxicity at its effective doses. The mechanism of action of S 9788 is unknown but S 9788 (0.5–10μM) induced a dose-dependent increase in ADR accumulation in KB-Al cells and compared to verapamil its effect was twice as active and approximately seven times more potent. We conclude that S 9788 is a novel agent capable of reversing MDRin vitro andin vivo, and whose pharmacological profile warrants its selection as a candidate drug for eventual assessment in the clinic.
Similar content being viewed by others
References
Goldstein LJ, Galski H, Fojo A, Willingham M, Lai SL, Gazdar A, Pirker R, Green A, Crist W, Brodeur GM, Lieber M, Cossman J, Gottesman MM, Pastan I: Expression of a multidrug resistance gene in human cancers, J Natl Cancer Inst 81:116–124, 1989
Wishart GC, Plumb JA, Going JJ, McNicol AM, McArdle CS, Tsuruo T, Kaye SB: P-glycoprotein expression in primary breast cancer detected by immunocytochemistry with two monoclonal antibodies. Br J Cancer 62:758–761, 1990
Noonan KE, Beck C, Holzmayer TA, Chin JE, Wunder JS, Andrulis IL, Gazdar AF, Willman CL, Griffith B, Von Hoff DD, Roninson IB: Quantitative analysis of MDR1 (multidrug resistance) gene expression in human tumors by polymerase chain reaction. Proc Natl Acad Sci USA 87:7160–7164, 1990
Salmon SE, Grogan TM, Miller T, Scheper R, Dalton WS: Prediction of doxorubicin resistancein vitro in myeloma, lymphoma, and breast cancer by P-glycoprotein staining. J Natl Cancer Inst 81:696–701, 1989
Kartner N, Riordan JR, Ling V: Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science 221:1285–1288, 1983
Ueda K, Clark DP, Chen C, Roninson IB, Gottesman MM, Pastan I: The human multidrug resistance (mdr1) gene. cDNA cloning and transcription initiation. J Biol Chem 262(2):505–508, 1987
Dano K: Active outward transport of daunomycin in resistant Ehrlich ascites tumor cells. Biochim Biophys Acta 323:466–483, 1973
Inaba M, Kobayashi H, Sakurai Y, Johnson RK: Active efflux of daunorubicin and adriamycin in sensitive and resistant sublines of P388 leukaemia. Cancer Res 39:2200–2203, 1979
Gros P, Neriah YB, Croop JM, Housman DE: Isolation and expression of a complementary DNA that confers multidrug resistance. Nature 323:728–731, 1986
Ueda K, Cardarelli C, Gottesman MM, Pastan I: Expression of a full-length cDNA for the human MDR1 gene confers resistance to colchicine, doxorubicin and vinblastine. Proc Natl Acad Sci USA 84:3004–3008, 1987
Choi K, Chen C, Kriegler M, Roninson IB: An altered pattern of cross-resistance in multidrug resistant cells results from spontaneous mutations in the mdr1 (P-glycoprotein) gene. Cell 53:519–529, 1988
Tsuruo T: Reversal of multidrug resistance by calcium channel blockers and other agents. In Roninson IB (ed.) Molecular and Cellular Biology of Multidrug Resistance in Tumor Cells, Plenum Publishing Corporation, New York, 1989, pp 349–365
Ford JM, Hait WN: Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacological Reviews 42(3):155–199, 1990
Tsuruo T, Iida H, Yamashiro M, Tsukagoshi S, Sakurai Y: Enhancement of vincristine and adriamycin induced cytotoxicity by verapamil in P388 leukaemia and its resistant sublines to vincristine and adriamycin. Biochem Pharmacol 31:3138–3140, 1982
Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y: Increased accumulation of vincristine and adriamycin in drug-resistant tumor cells following incubation with calcium antagonists and calmodulin inhibitors. Cancer Res 42:4730–4733, 1982
Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y: Overcoming of vincristine resistance in P388 leukaemiain vivo andin vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 41:1967–1972, 1981
Slater LM, Sweet P, Stupecky M, Wetzel MN, Gupta S: Cyclosporin A corrects daunorubicin resistance in Ehrlich ascites carcinoma. Br J Cancer 54:235–238, 1986
Sato W, Fukazawa N, Suzuki T, Yusa K, Tsuruo T: Circumvention of multidrug resistance by a newly synthesised quinoline derivative, MS-073. Cancer Res 51:2420–2424, 1991
Shinoda H, Inaba M, Tsuruo T:In vivo circumvention of vincristine resistance in mice with P388 leukaemia using a novel compound, AHC-52. Cancer Res 49:1722–1726, 1989
Presant CA, Kennedy PS, Wiseman C, Gala K, Bouzaglou A, Wyres M, Naessig V: Verapamil reversal of clinical doxorubicin resistance in human cancer. A Wiltshire Oncology Medical Group Pilot phase I–II Study. Am J Clin Oncol 9(4):355–357, 1986
Dalton WS, Grogan TM, Meltzer PS, Schaper RJ, Durie BGM, Taylor CW, Miller TP, Salmon SE: Drug resistance in multiple myeloma and non-Hodgkin's lymphoma: detection of P-glycoprotein and potential circumvention by addition of verapamil to chemotherapy. J Clin Oncol 7(4):415–424, 1989
Miller TP, Grogan TM, Dalton WS, Spier CM, Scheper RJ, Salmon SE: P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high dose-verapamil. J Clin Oncol 9(1): 17–24, 1991
Reizenstein P: Can verapamil induce second response in patients refractory to vincristine? Anticancer Res 10:955–958, 1990
Pennock GD, Dalton WS, Roeske WR, Appleton CP, Mosley K, Plezia P, Miller TP, Salmon SE: Systemic toxic effects associated with high-dose verapamil infusion and chemotherapy administration. J Natl Cancer Inst 83(2): 105–110, 1991
Cano-Gauci DF, Riordan JR: Action of calcium antagonists on multidrug resistant cells. Specific cytotoxicity independent of increased cancer drug accumulation. Biochem Pharmacol 36:2115–2123, 1987
Warr JR, Brewer F, Anderson M, Fergusson J: Verapamil hypersensitivity of vincristine resistant chinese hamster ovary cell lines. Cell Biol Int Rep 10:389–399, 1986
Twentyman PR, Fox NE, Bleehen NM: Drug resistance in human lung cancer cell lines: cross-resistance studies and effects of the calcium blocker verapamil. Int J Radiat Oncol Biol Phys 12:1355–1358, 1986
Weinstein RS, Jakate SM, Dominguez JM, Lebovitz MD, Koukoulis GK, Kuszak JR, Klusens LF, Grogan TM, Saclarides TJ, Roninson IB, Coon JS: Relationship of the expression of the multidrug resistance gene product (P-glycoprotein) in human colon carcinoma to local tumor aggressiveness and lymph node metastasis. Cancer Res 51:2720–2726, 1991
De Isabella P, Capranico G, Binaschi M, Tinelli S, Zunino F: Evidence of DNA topoisomerase II-dependent mechanisms of multidrug resistance in P388 leukaemia cells. Mol Pharmacol 37:11–16, 1990
Slovak ML, Hoeltge GA, Dalton WS, Trent JM: Pharmacological and biological evidence for differing mechanisms of doxorubicin resistance in two human tumor cell lines. Cancer Res 48:2793–2797, 1988
Slapak CA, Daniel JC, Levy SB: Sequential emergence of distinct resistance phenotypes in murine erythroleukemia cells under adriamycin selection: decreased anthracycline uptake precedes increased P-glycoprotein expression. Cancer Res 50:7895–7901, 1990
Cordon-Cardo C, O'Brien JP, Casals D, Rittman-Graver L, Biedler JL, Melamed MR, Bertino JR: Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 86:695–698, 1989
Arceci RJ, Croop JM, Horwitz SB, Housman D: The gene encoding multidrug resistance is induced and expressed at high levels during pregnancy in the secretory epithelium of the uterus. Proc Natl Acad Sci USA 85:4350–5354, 1988
Zamora JM, Pearce HL, Beck WT: Physical-chemical properties shared by compounds that modulate multidrug resistance in human leukaemia cells. Molecular Pharmacol 33:454–462, 1988
Keizer HG, Schuurhuis GJ, Broxterman HJ, Lankelma J, Schoonen W, Joenje H: Correlation of multidrug resistance with decreased drug accumulation, altered subcellular drug distribution and increased P-glycoprotein expression in cultured SW-1573 human lung tumor cells. Cancer Res 49:2988–2993, 1989
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Pierré, A., Dunn, T.A., Kraus-Berthier, L. et al. In vitro andin vivo circumvention of multidrug resistance by Servier 9788, a novel triazinoaminopiperidine derivative. Invest New Drugs 10, 137–148 (1992). https://doi.org/10.1007/BF00877238
Issue Date:
DOI: https://doi.org/10.1007/BF00877238