Clofibrate (CPIB), an antihyperlipidemic agent, was utilized as a drug response modulator to modify the cytotoxicity of adriamycin (ADR) in vitro in P388 murine lymphocytic leukemia cells sensitive (P388/S) and resistant (P388/ADR) to ADR. CPIB elicited concentration and time dependent DNA biosynthesis inhibition which was completely reversible up to the concentration of 0.0025 % in P388/S. However, only a partial reversibility of DNA biosynthesis inhibition was observed in P388/ADR cells treated with 0.0025 % of CPIB. In both P388/S and P388/ADR there was complete and irreversible DNA biosynthesis inhibition at CPIB concentration of 0.005%. These findings were further confirmed by tumorigenicity anaysis. CPIB was ineffective in altering ADR cytotoxicity in P388/S ceils. However, in P388/ADR, CPIB enhanced ADR cytotoxicity at the lower concentrations of ADR and decreased the cytotoxicity upon increase in ADR concentrations. The enhancement in ADR cytotoxicity by CPIB in P388/ADR was due to increased ADR accumulation which was absent in P388/S cells. The present findings suggest the utility of CPIB as a selective agent to circumvent ADR resistance and to reduce host toxicity due to the drug.
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References
1.
BachurN.R., MooreA.L., BernsteinJ.G., LuiA.: Tissue distribution and disposition of daunomycin (NSC 82151) in mice: fluorometric and isotopic methods. Cancer Chemother. Rep., 54: 89–94, 1970.
2.
BonadonnaG., BerettaG., TanichiG.: Adriamycin in combination and in combined treatment modalities. Tumori, 60: 394–416, 1974.
3.
BrownF.U., KleinM., KandaswamyT.S., MandelH.G.: Rapid membrane filtration technics for studying action of 6-thioguanine on tumor cells in vitro. Cancer Res., 23: 254–259, 1963.
4.
ChitnisM.P., PradhanS.G., SatyamoorthyK., BasrurV.S.: Restoration of drug sensitivity by nitroxazepine hydrochloride in P388 murine leukemia cells resistant to adriamycin. Cancer Drug Delivery, 4: 1–9, 1987.
5.
CornwellM.M., PastanI., GottessmanM.M.: Certain calcium channel blockers bind specifically to multidrug resistant human KB carcinoma membrane vesicles and inhibit drug binding to P-glycoprotein. J. Biol. Chem., 262: 2162–2170, 1987.
6.
DanoK.: Cross resistance between vinca alkaloids and anthracyclines in Ehrlich ascites tumor in vivo. Cancer Chemother. Rep., 56: 701–708, 1972.
7.
Di MarcoA.: Adriamycin: mode and mechanisms of action. Cancer Chemother. Rep., 6: 91–106, 1975.
8.
DoroshowJ.H.: Anthracycline antibiotic stimulated superoxide hydrogen peroxide and hydroxyl radical production by NADH. Cancer Res., 43: 4543–4551, 1983.
9.
GanapathiR., GrabowskiD.: Enhancement of sensitivity of adriamycin in resistant P388 leukemia by calmodulin inhibitor trifluoroperazine. Cancer Res., 43: 3696–3699, 1983.
10.
GarmanD., CenterM.S.: Alterations in cell surface membranes in Chinese hamster lung cells resistant to adriamycin. Biochem. Biophys. Res. Commun, 105: 157–163, 1982.
11.
GeranR.I., GreenbergN.H., MacdonaldM.M., SchumacherA.M., AbottB.J.: Protocols for screening chemical agents and natural products against animal tumors and other biological systems. Cancer Chemother. Rep., 3: 3, 1972.
12.
GerlachJ.H., EndicottJ.A., JurankaP.F., HundersonG., SarangiF., DeucharsK.L., LingV.: Homology between p-glycoprotein and a bacterial hemolysin transport protein suggest a model for multidrug resistance. Nature, 324: 485–489, 1986.
13.
GuffyM.M., NorthJ.A., BurnsC.P.: Effect of cellular fatty acid alteration on adriamycin sensitivity in cultured L1210 murine leukemia cells. Cancer Res., 44: 1863–1866, 1984.
14.
GustafsonA.: Clofibrate and related compounds in hyper lipoproteinaemia - R review. Postgrad. Med. J., 51(Suppl. 8): 66–71, 1975.
15.
HollermanW.M., DegregorioM.W., GanapathiR., WilburJ.R., MacherB.A.: Characterization of cellular lipids in doxorubicin sensitive and resistant P388 mouse leukemia cells. Cancer Chemother. Pharmacol., 17: 11–15, 1986.
16.
InabaM., KobayashiH., SakuraiY., JohnsonR.K.: Active efflux of daunorubicin and adriamycin in sensitive and resistant sublines of P388 leukemia. Cancer Res., 39: 2200–2203, 1979.
17.
InabaM., FujikuraR., TsukagoshiS., SakuraiY.: Restored in vitro sensitivity of adriamycin and vincristine resistant P388 leukemia with reserpine. Biochem. Pharmacol., 30: 2191–2194, 1981.
18.
JohnsonR.K., ChitnisM.P., EmbreyW.M., GregoryE.B.: In vivo characteristics of resistance and cross resistance of adriamycin resistant subline of P388 leukemia. Cancer Treat. Rep., 62: 1535–1547, 1978.
19.
KayeS., MerryS.: Tumor cell resistance to anthracyclines - a review. Cancer Chemother. Pharmacol., 14: 96–103, 1985.
20.
KrishnakanthaT.P., KurupC.K.R.: Increase in hepatic catalase and glycerol dehydrogenase activities on administration of clofibrate and clofenate to the rat. Biochem. J., 130: 167–175, 1972.
21.
MizunoS., IshidaA.: Selective enhancement of the cytotoxicity of the bleomycin derivative, pepleomycin by local anaesthetics alone and combined with hyperthermia. Cancer Res., 42: 4726–4729, 1982.
22.
NakagawaM., IshiharaN., ShimokavaT., KojimaS.: Effect of clofibrate on lipid peroxidation in rats treated with aspirin and 4-pentenoic acid. J. Biochem., 101: 81–88, 1987.
23.
PavlikE.J., KendaD.E., Van NagellJ.R., KeatonK., HansonM.B., DonaldsonE.S.: Properties of anticancer agents relevant to in vitro determination of human tumor cell sensitivity. Cancer Chemother. Pharmacol., 11: 8–15, 1983.
24.
PetersonR.H.F., MyersB.A., SpenglerB.A., BiedlerJ.L.: Alteration of plasma membrane glycopeptides and gangliosides of Chinese hamster cells accompanying development of resistance to daunomycin and vincristine. Cancer Res., 43: 222–228, 1983.
25.
PradhanS.G., ChitnisM.P., BasrurV., SatyamoorthyK.T.: Modulation of in vitro response to adriamycin by verapamil in murine P388 leukemia, Ehrlich ascites carcinoma and sarcoma 180. Eur. J. Cancer Clin. Oncol., 23: 437–442, 1987.
26.
RamuA., GlaubigerD., MagrathI.T., JoshiA.: Plasma membrane lipid structural order in doxorubicin-sensitive and resistant P388 cells. Cancer Res., 43: 5533–5537, 1983.
27.
RamuA., GlaubigerD., WeintraubH.: Differences in lipid composition of doxorubicin-sensitive and -resistant P388 cells. Cancer Treat. Rep., 68: 637–641, 1984a.
28.
RamuA., FuksZ., GattS., GlaubigerD.: Reversal of acquired resistance to doxorubicin in P388 murine leukemia cells by perhexiline maleate. Cancer Res., 44: 144–148, 1984b.
29.
SeigfriedJ.M., BurkeT.G., TrittonT.R.: Cellular transport of anthracyclines by passive diffusion - implication for drug resistance. Biochem. Pharmacol., 34: 593–598, 1985.
30.
SinhaB.K., GregoryJ.L.: Role of one electron and two electron reaction products of adriamycin and daunomycin in deoxyribonucleotide acid binding. Biochem. Pharmacol., 30: 2626–2629, 1981.
31.
TsuruoT., IidaH., TamashiroM., TsukagoshiS., SakuraiY.: Enhancement of vincristine and adriamycin induced cytotoxicity by verapamil in P388 leukemia and its resistant sublines to vincristine and adriamycin. Biochem, Pharmacol., 31: 3138–3140, 1982.
32.
TsuruoT., IidaH., KitataniY., KeikoY., TsukagoshiS., SakuraiY.: Effects of quinidine and related compounds on cytotoxicity and cellular accumulation of vincristine and adriamycin in drug-resistant tumor cells. Cancer Res., 44: 4303–4307, 1984.
33.
YoungR.C., OzolsR.F., MyersC.E.: The anthracycline anti-neoplastic drugs. N. Engl. J. Med., 305: 139–153, 1981.
