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Effects of Quinidine and Related Compounds on Cytotoxicity and Cellular Accumulation of Vincristine and Adriamycin in Drug- Resistant Tumor Cells1

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Effects of Quinidine and Related Compounds on Cytotoxicity and Cellular Accumulation of Vincristine and Adriamycin in Drug- Resistant Tumor Cells1 [CANCER RESEARCH 44, 4303-4307, October 1984] Effects of Quinidine and Related Compounds on Cytotoxicity and Cellular Accumulation of Vincristine and Adriamycin in Drug- resistant Tumor Cells1 Takashi Tsuruo,2 Harumi lida, Yoshiko Kitatani, Keiko Yokota, Shigeru Tsukagoshi, and Yoshio Sakurai Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Kami-lkebukuro, Toshima-ku, Tokyo 170, Japan ABSTRACT characteristics of tumor cells. We have reported that calcium channel blockers and calmod- Quinidine, which has antiarrhythmic activity, greatly enhanced ulin inhibitors increase cellular accumulation of VCR3 and ADM the cytotoxicity of vincristine (VCR) in tumor cells and especially in induced drug-resistant or inherently drug-resistant tumor cells in VCR-resistant sublines of P388 leukemia (P388/VCR) and (24,25,29-32) by inhibiting outward transport of these antitumor human myelogenous leukemia. A nontoxic concentration of quin- agents (24, 25, 29, 30), thereby causing reversal of drug resist idine increased VCR cytotoxicity in these resistant tumor cells ance in the tumor cells (24-27, 29-32). These observations, about 50 to 80 times, and the drug in combination with VCR together with previous findings, suggest that the drug efflux could completely reverse VCR resistance of these cell lines. mechanism in the plasma membrane of the resistant tumor cells Quinidine also enhanced the cytotoxicity of Adriamycin, espe cially in the Adriamycin-resistant subline of P388 leukemia; this might be related to the function of cellular calcium, as well as to enhancement (8-fold) was less than that of VCR toxicity in the changes in the plasma membrane (4, 14, 19). In further studies VCR-resistant tumor line. When administered daily for 10 days on this mechanism, we examined the effects on cellular accu mulation of VCR and ADM of various drugs that interact with with VCR, quinidine at doses of 50 to 125 mg/kg significantly enhanced the chemotherapeutic effect of VCR in P388/VCR- the membrane but do not block calcium channels. We found that antiarrhythmic agents, especially quinidine, have potent effects bearing mice. Some other antiarrhythmic agents also showed on the cytotoxicities and cellular accumulations of VCR and similar effects in vitro, but these effects were considerably lower ADM. than that of quinidine. Quinidine increased the cellular levels of VCR and daunomycin in VCR-resistant sublines of mouse and human tumors and the MATERIALS AND METHODS ADM-resistant mouse tumor line in vitro, respectively. Quinidine Drugs. VCR and ADM for clinical use were obtained from Shionogi also enhanced the cellular accumulation of VCR in P388/VCR and Co., Osaka, Japan, and Kyowa Hakko Kogyo Co., Tokyo, Japan, cells in vivo. Thus, the therapeutic effect observed in P388/VCR- respectively. [G-3H]VCR sulfate (5.8 Ci/mmol) and [G-3H]DAU (4.34 Ci/ bearing mice might be due to the enhanced accumulation of mmol) were purchased from the Radiochemical Center, Amersham, VCR in P388/VCR cells by quinidine. The increase of cellular England. Quinidine sulfate, propranolol hydrochloride, 5,5-diphenylhy- accumulation of VCR was partly explained by inhibition of efflux dantoin sodium salt, lidocaine, and ajimalin were purchased from Nakarai of VCR and daunomycin from the resistant tumor cells. The Chemical Co., Kyoto, Japan. Procainamide was a product of Sigma mechanism of this phenomenon is discussed in relation to pre Chemical Co., St. Louis, MO. Animals and Tumor Cells. Adult female BALB/c x DBA/2Cr F, vious findings on calcium channel blockers. (hereafter called CD2F,) mice weighing 20 to 23 g were obtained from Charles River Japan, Inc., Tokyo, Japan. P388, P388/VCR, and P388/ INTRODUCTION ADM cells lines were supplied by the National Cancer Institute, NIH, Bethesda, MD (26). The human myelogenous leukemia K562 cell line In experimental systems, it is known that anthracycline-resist- (17) was provided by Dr. Ezaki, and the K562/VCR cell line was estab ant tumor cells are also resistant to other DNA intercalating lished in this laboratory (28). drugs and to mitotic spindle poisons, including Vinca alkaloids, Cell Culture and Drug Treatment. Tumor cells were maintained in inhibitors of protein synthesis, and other structurally unrelated suspension in plastic dishes (Coming Glass Works, Coming, NY) in compounds (3, 5-7, 13, 16, 21, 33). The molecular mechanism Roswell Park Memorial Institute Medium 1640 supplemented with 10% of this pleiotropic phenotype of drug resistance remains far from fetal bovine serum (Flow Laboratories, Stanmore, New South Wales, Australia) and kanamycin (100 /¿g/ml)(growth medium) (26,29). Cultures clear; however, these pleiotropic drug-resistant tumor cells pos were incubated at 37°in a humidified atmosphere of 5% CO2 in air. For sess an enhanced drug efflux function common to various anti- experiments on the effects of drugs, tumor cells (P388, 2 x 104; P388/ tumor agents described above (7, 12, 18, 20, 21, 29). Recent VCR, 3 x 104; P388/ADM, 2 x 104; and K562 and K562/VCR, 4 x 104) findings (4, 14, 19) have suggested that the mechanism of were cultured at 37°for 5 hr in Falcon No. 2054 culture tubes containing pleiotropic drug resistance is closely related to the expression of 2 ml of growth medium in a humidified atmosphere of 5% CO2 in air. a glycoprotein with a molecular weight of about 170,000 on the Then, the cells were treated with graded concentrations of VCR (0.1 to cell surface. Development of pleiotropic drug resistance of tumor 100 nw) or ADM (0.01 to 10 /¿M)inthe absence or presence of antiar cells is now believed to be related to changes in membrane rhythmic drugs (1.0 to 100 MM,depending on the drug), reincubated for 72 hr in the presence of drugs, and counted in a Model ZBI Coulter 1This work was supported by grants-in-akJ for cancer research from the Ministry of Education, Science, and Culture (57010075) and from the Ministry of Health and 3The abbreviations used are: VCR, vincristine; ADM, Adriamycin; DAU,dauno Welfare (57-3), Japan. mycin; P388/VCR, P388 leukemia cells resistant to vincristine; P388/ADM, P388 2 Recipient of an award from the Society for Promotion of Cancer Research, leukemiacells resistant to Adriamycin; K562/VCR, human myelogenous leukemia Japan. To whom requests for reprints should be addressed. K562 cells resistant to vincristine; 1C»,concentrationof drug required for 50% Received September 19, 1983; accepted June 25,1984. inhibitionof cell growth. OCTOBER 1984 4303 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1984 American Association for Cancer Research. T. Tsuruo et al. Counter (29). Three tubes were used for each drug concentration. In the of 10 fiM, it inhibited the growth of mouse cell lines only slightly control experiment, tumor cells grew exponentially during the incubation (<5%) and had no effect on growth of human-derived cell lines, period; their final cell numbers are given in each chart and table. Drugs while at a concentration of 30 /UM,it caused about 10% growth were dissolved in dimethyl sulfoxide at a final concentration of 100 ITIM and diluted with phosphate-buffered saline (0.2 M sodium phosphate:0.15 inhibition. The sensitivities of P388 and P388/VCR cells to VCR and the M NaCI, pH 7.4). The final concentration of dimethyl sulfoxide in the culture was less than 0.1% (v/v), which had no detectable effect on cell effect of quinidine on these sensitivities are illustrated in Chart growth. 1. P388/VCR cells were resistant to VCR, and the index of The ICsoSin the presence or absence of drugs were determined by resistance was approximately 16, as determined by comparison plotting the logarithm of the drug concentration versus the growth rate of the ICsovalues for the 2 cell lines (Chart 1). Quinidine enhanced (percentage of control) of the treated cells (26, 29). the cytotoxicity of VCR in P388 cells; at 10 MM,it increased the Evaluation of Antitumor Activity. A sample of 0.1 ml of diluted ascites cytotoxicity 2-fold as compared with the IC50value. It also greatly fluid containing 106 P388/VCR cells was transplanted i.p. into CD2F, increased the cytotoxicity of VCR against P388/VCR cells, the mice. VCR was dissolved in 0.9% NaCI solution. Quinidine was sus increase being 82-fold at 10 UM quinidine. As quinidine shifted pended in a small volume of 2% (w/v) methyl cellulose (No. 25; Nakarai the IC50value of VCR for P388/VCR cells to smaller values than Chemicals, Kyoto, Japan) and diluted with 0.9% NaCI solution. The final that (1.78 nM) of P388 cells, it completely overcame the VCR concentration of methyl cellulose was less than 0.1%. This vehicle had no effect on the antitumor activity of VCR. The 2 drugs were mixed, and resistance of these cells. the mixture was administered at a dose of 0.02 ml/g body weight i.p. The effects of quinidine on the sensitivities of K562 and K562/ daily for 10 days starting from the day after tumor inoculation (26, 29). VCR cells to VCR and of P388 and P388/ADM cells to ADM The doses of quinidine and VCR were 50 to 125 mg/kg and 100 to 200 were also examined in the same manner, as illustrated in Chart /ig/kg. respectively. Groups of 10 mice were used in the experiments. 1. The ICsovalues of VCR and ADM in absence and presence of As described previously (26, 29), quinidine are summarized in Table 1. Quinidine enhanced VCR Mean survival time of treated mice cytotoxicity against human K562 cells and especially VCR-re- Antitumor activity (%) = x 100. Mean survival time of control mice sistant lines (Table 1). It caused a 2-fold increase in VCR cyto Cellular Uptake of [3H]VCR and [3H]DAU in the Presence of Quini toxicity in K562 cells as determined from ICso values.
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