Summary
To predict the clinical effect on leukemic disease of a combination regimen developed to circumvent multidrug resistance (MDR), we tested various antitumor agents in the presence and absence of AHC-52, a sensitizing agent for multidrug-resistant cells, in the i. v.-i. v. model of murine leukemia. In this model system, sensitive and resistant P388 murine leukemia cells are inoculated i. v. into mice, and each antitumor agent is injected via the i. v. route. Vincristine (VCR) had no effect on the survival of mice bearing VCR-resistant P388, a relatively poorly resistant subline, when given either as a single agent or in combination with AHC-52. In contrast, adriamycin (ADR) alone had no effect on these mice, but its combination with AHC-52 resulted in significant survival, the maximal value achieved being 196% (treated mice/control animals, T/C). Etoposide (VP-16) strongly enhanced survival, even when used alone, and this effect was markedly potentiated by AHC-52. Combination of any antitumor drug with AHC-52 was ineffective in mice bearing ADR-resistant P388, a highly resistant subline. On the other hand, AHC-52 strongly augmented the therapeutic efficacy of these antitumor agents in mice bearing the sensitive parent P388 leukemia, producing some curative effects. On the basis of these results, the feasibility of this type of combination therapy is discussed.
Similar content being viewed by others
References
Baer MR, Bloomfield CD (1991) Multidrug resistance in acute myeloid leukemia. J Natl Cancer Inst 83: 663
Endicott JA, Ling V (1989) The biochemistry of p-glycoprotein-mediated multidrug resistance. Annu Rev Biochem 58: 137
Ford JM, Hait WN (1990) Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacol Rev 42: 155
Holmes J, Jacobs A, Carter G, Janowska-Wieczorek A, Padua RA (1989) Multidrug resistance in haemopoietic cell lines, myelodysplastic dromes and acute myeloblastic leukemia. Br J Haematol 72: 40
Inaba M, Kobayashi H, Sakurai Y, Johnson RK (1979) Active efflux of daunorubicin and Adriamycin in sensitive and resistant sublines of P388 leukemia. Cancer Res 39: 2200
Inaba M, Fujikura R, Sakurai Y (1981) Active efflux common to vincristine and daunorubicin in vincristine-resistant P388 leukemia. Biochem Pharmacol 30: 1863
Inaba M, Shinoda H, Iinuma F (1988) Promoting agents of the activity of some antitumor agents against various kinds of tumor cell, including multiple drug resistant tumor cells and their synthetic methods. Japanese patent 63-135381, Kokai; European patent 0270926. European Patent Office, Munich
Ito Y, Tanimoto M, Kumazawa T, Okumura M, Morishima Y, Ohno R, Saito H (1989) Increased P-glycoprotein expression and multidrug-resistant gene (mdr1) amplification are infrequently found in fresh acute leukemia cells: sequential analysis of 15 cases at initial presentation and relapsed stage. Cancer 63: 1534
Johnson RK, Chitnis MP, Embrey WM, Gregory EB (1978) In vivo characteristics of resistance and cross-resistance of an Adriamycinresistant subline of P388 leukemia. Cancer Treat Rep 62: 1535
Kuwazuru Y, Yoshimura A, Hanada S, Utsunomiya A, Makino T, Ishibashi K, Kodama M, Iwahashi M, Arima T, Akiyama S (1990) Expression of the multidrug transporter, P-glycoprotein, in acute leukemia cells and correlation to clinical drug resistance. Cancer 66: 868
Ma DDF, Scurr RD, Davey RA, Mackertich SM, Harman DH, Dowden G, Isbiser JP, Bell DR (1987) Detection of a multidrug resistant phenotype in acute non-lymphoblastic leukemia. Lancet I: 135
Moscow JA, Cowan KH (1988) Multidrug resistance. J Natl Cancer Inst 80: 14
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65: 55
Pirker R, Goldstein LJ, Ludwig H, Linkesch W, Lechner C, Gottesman MM, Pastan I (1989) Expression of a multidrug gene in blast crisis of chronic myelogenous leukemia. Cancer Commun 1: 141
Pirker R, Wallner J, Geissler K, Linkesch W, Haas OA, Bettelheim P, Hopfner M, Scherrer R, Valent P, Havelec L, Ludwig H, Lechner K (1991) MDR1 gene expression and treatment outcome in acute myeloid leukemia. J Natl Cancer Inst 83: 708
Radel S, Fredericks W, Mayhew E, Baker R (1990) P-glycoprotein expression and modulation of cell-membrane morphology in Adriamycin-resistant P388 leukemia cells. Cancer Chemother Pharmacol 25: 241
Raymond M, Rose E, Housman DE, Gros P (1990) Physical mapping, amplification, and overexpression of the mouse mdr gene family in multidrug-resistant cells. Mol Cell Biol 10: 1642
Sato H, Preisler H, Day R, Raza A, Larson R, Browman G, Goldberg J, Vogler R, Grunwald H, Gottlieb A (1990) MDR1 transcript levels as an indication of resistant disease in acute myelogenous leukemia. Br J Haematol 75: 340
Shinoda H, Inaba M Tsuruo T (1989) In vivo circumvention of vincristine resistance in mice with P388 leukemia using a novel compound, AHC-52. Cancer Res 49: 1722
Tsuruo T (1988) Mechanisms of multidrug resistance and implications for therapy. Jpn J Cancer Res 79: 285
Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1981) Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 41: 1967
Tsuruo T, Iida H, Nojiri M, Tsukagoshi S, Sakurai Y (1983) Circumvention of vincristine and Adriamycin resistance in vitro and in vivo by calcium influx blockers. 43: 2905
Van der Bliek AM, Borst P (1989) Multidrug resistance. Adv Cancer Res 52: 165
Wilkoff LJ, Dulmadge EA (1978) Resistance and cross-resistance of cultured leukemia P388 cells to vincristine, Adriamycin analogs and actinomycin D. J Natl Cancer Inst 61: 1521
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Shinoda, H., Ebisu, H., Mitsuhashi, J. et al. Therapeutic efficacy of combination of antitumor agent with AHC-52 against multidrug-resistant cells in the intravenously inoculated P388 leukemia model. Cancer Chemother. Pharmacol. 30, 335–340 (1992). https://doi.org/10.1007/BF00689959
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00689959