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Effect of homoharringtonine on the viability of murine leukemia P388 cells resistant to either adriamycin, vincristine, or 1-β-D-arabinofuranosylcytosine

  • Original Articles
  • Homoharringtonine, Viability, Murine Leukemia, P388, Adriamycin
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Summary

Cultured murine leukemia P388 cell populations were derived from P388 cells resistant to vincristine (P388/VCR), adriamycin (P388/ADR), and 1-β-D-arabinofuranosylcytosine (P388/ARA-C) that were developed in vivo and to the parental drug-sensitive cells (P388/O) that were passaged in vivo. The doubling times of the cultured cell populations (mean±SD) between cell densities of 5×104 and 1×106 cells/ml were 14.2±2 h (P388/O), 16.5±1.9 h (P388/VCR), 16.9±1.2 h (P388/ADR), and 15.0±1.4 h (P388/ARA-C). Exponentially proliferating cultured cell populations were exposed to selected homoharringtonine (HHT) concentrations for 24 h and the surviving cell fractions were determined by colony formation in semisolid medium. The results, based on differential sensitivity of the cell populations to HHT, indicated that cultured P388/VCR cells were cross-resistant to 0.018–1.8 μg/ml HHT, P388/ADR cells were cross-resistant to 0.058–1.8 μg/ml HHT, and P388/ARA-C cells were collaterally sensitive to 0.09–0.36 μg/ml HHT. The results with the cultured P388/VCR, P388/ADR, P388/ARA-C, and P388/O cell populations were confirmed in animal experiments. CD2F1 mice bearing intraperitoneal (i.p.) implants of 1×106 P388/VCR, P388/ADR, P388/ARA-C, or P388/O leukemia cells were given HHT i.p. qd on days 1–9 postimplantation. Optimal treatment (≤LD10) produced in vivo cell kills of 2 to 3 log10 units in P388/O and about 7 log10 units in P388/ARA-C, whereas P388/VCR and P388/ADR cells actually increased by 1–2 log10 units during treatment. The results of this study indicate that cross-resistance (P388/VCR and P388/ADR) or collateral sensitivity to HHT (P388/ARA-C) is a function of the cellular properties of the target tumor cell populations that is independent of host factors.

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References

  1. Bachur NR (1975) Adriamycin (NSC 123127) pharmacology. Cancer Chemother Rep 6: 153

    Google Scholar 

  2. Bachur NR, Hildebraud RC, Jaenke RS (1940) Adriamycin and daunorubicin disposition in the rabbit. J Pharmacol Exp Ther 191: 331

    Google Scholar 

  3. Benjamin RS, Riggs CE Jr, Bachur NR (1973) Pharmacokinetics and metabolism of adriamycin in man. Clin Pharmacol Ther 14: 592

    Google Scholar 

  4. Biedler J, Peterson RHF (1981) Altered plasma membrane glycoconjugates of Chinese hamster cells with acquired resistance to actinomycin D, daunorubicin, and vincristine. In: Sartorelli AC, Bertino JR, Lazo JS (eds) Molecular actions and targets for cancer chemotherapeutic agents. Academic Press, New York, p 453

    Google Scholar 

  5. Boyed AW, Sullivan JR (1984) Leukemic cell differentiation in vivo and in vitro: arrest of proliferation parallels the differentiation induced by the antileukemic drug harringtonine. Blood 63: 384

    Google Scholar 

  6. Chou TC, Schmid FA, Feinberg A, Philips FS, Han J (1983) Uptake, initial effects, and chemotherapeutic efficacy of harringtonine in murine leukemic cells sensitive and resistant to vincristine and other chemotherapeutic agents. Cancer Res 43: 3074

    Google Scholar 

  7. Coonley CJ, Warrell RP Jr, Young CW (1983) Phase I trial of homoharringtonine administered as a five day continuous infusion. Cancer Treat Rep 67: 693

    Google Scholar 

  8. Delfel NE (1980) Alkaloid distribution and catabolism in Cephalotaxus harringtonia. Phytochemistry 19: 403

    Google Scholar 

  9. Delfel NE, Rothfus JA (1977) Antitumor alkaloids in callus cultures of Cephalotaxus harringtonia. Phytochemistry 16: 1595

    Google Scholar 

  10. Fresno M, Jimenez A, Vazquez D (1977) Inhibition of translation in eukaryotic systems by harringtonine. Eur J Biochem 72: 323

    Google Scholar 

  11. Gros P, Croop J, Roninson I, Varshavsky A, Housman D (1986) Isolation and characterization of DNA sequences amplified im multidrug-resistant hamster cells. Proc Natl Acad Sci USA 83: 337

    Google Scholar 

  12. Huang MT (1975) Harringtonine, an inhibitor of protein synthesis. Mol Pharmacol 11: 511

    Google Scholar 

  13. Kartner N, Riordan JR, Ling V (1983) Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science 221: 1285

    Google Scholar 

  14. Kendall MG, Stuart A (1963) The advanced theory of statistics, vol 1. Griffin, London, p 232

    Google Scholar 

  15. Legha SS, Keating M, Picket S, Ajani JA, Ever M, Bodey GP (1984) Phase I clinical investigation of homoharringtonine. Cancer Treat Rep 68: 1085

    Google Scholar 

  16. Ling V (1985) Multidrug-resistant mutants. In: Gottesman MM (ed) Molecular cell genetics. John Wiley and Sons, New York, p 773

    Google Scholar 

  17. Ling V, Thompson LH (1974) Reduced permeability in CHO cells as a mechanism of resistance to colchicine. J Cell Physiol 83: 103

    Google Scholar 

  18. Malamud SC, Ohnuma T, Coffey V (1984) Phase I study of homoharringtonine in 10 day schedule: 6 hr infusion daily vs continuous infusion. Proc Am Assoc Cancer Res 25: 179

    Google Scholar 

  19. Morton HJ (1970) A survey of commercially available tissue culture media. In Vitro 6: 89

    Google Scholar 

  20. Neidhart JA, Young DC, Derocher D, Metz EN (1983) Phase I trial of homoharringtonine. Cancer Treat Rep 67: 801

    Google Scholar 

  21. Neidhart JA, Young DC, Kraut E, Howinstein B, Metz EN (1986) Phase I trial of homoharringtonine administered by prolonged continuous infusion. Cancer Res 46: 967

    Google Scholar 

  22. Ohnuma T, Holland JF (1985) Homoharringtonine as a new antileukemic agent. J Clin Oncol 3: 604

    Google Scholar 

  23. Pastan I, Gottesman M (1987) Multiple-drug resistance in human cancer. New Engl J Med 316: 1388

    Google Scholar 

  24. Protocols for screening chemical agents and natural products against animal tumors and other biological systems, 3rd ed (1972) National Cancer Institute, Cancer Chemother Rep, vol 3, part 3, no 2

  25. Roninson IB, Chin JE, Choi K, Gros P, Housman DE, Fojo A, Shen D-W, Gottesman MM, Pastan I (1986) Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcinoma cells. Proc Natl Acad Sci USA 83: 4538

    Google Scholar 

  26. Sartorelli AC, Creasey WA (1969) Cancer chemotherapy. Ann Rev Pharmacol 9: 51

    Google Scholar 

  27. Schabel FM Jr, Skipper HE, Trader MW (1965) Experimental evaluation of potential anticancer agents: XIX. Sensitivity of nondividing leukemia cell populations to certain classes of drug in vitro. Cancer Chemother Rep 48: 17

    Google Scholar 

  28. Schabel FM Jr, Griswold DP Jr, Laster WR Jr, Corbett Th, Lloyd HH (1977) Quantitative evaluation of anticancer agent activity in experimental animals. Pharmacol Ther [A] 1: 411

    Google Scholar 

  29. Schabel FM Jr, Skipper HE, Trader MW, Laster WR Jr, Corbett TH, Griswold DP Jr (1980) Concepts for controlling drug-resistant tumor cells. In: Mouridsen HT, Palshof T (eds) Breast cancer. Experimental and clinical aspects. Pergamon Press, Oxford, p 199

    Google Scholar 

  30. Shoemaker R, Wolpert-DeFilippes M, Plowman J, Abbott B, Venditti J, Trader M, Griswold D, Gerlach J, Ling V (1986) Pleotropic resistance and drug development. In: Hall TC (ed) Progress in clinical and biological research, vol 223, Cancer drug resistance. Alan R. Liss, New York, p 143

    Google Scholar 

  31. Smith CR, Powell RG, Mikolajczak KL (1976) The genus Cephalotaxus: source of homoharringtonine and related anticancer alkaloids. Cancer Treat Rep 60: 1157

    Google Scholar 

  32. Takemura Y, Ohnuma T, Chou T-C, Okano T, Holland JF (1985) Biologic and pharmacologic effects of harringtonine on human leukemia-lymphoma cells. Cancer Chemother Pharmacol 14: 206

    Google Scholar 

  33. Tscherne JS, Pestka S (1975) Inhibition of protein synthesis in intact HeLa cells. Antimicrob Agents Chemother 8: 479

    Google Scholar 

  34. Warrell RP Jr, Coonley CJ, Gee TS (1985) Homoharringtonine: an effective new drug for remission induction in refractory nonlymphoblastic leukemia. J Clin Oncol 3: 617

    Google Scholar 

  35. Wilkoff LJ, Dulmadge EA (1978) Resistance and cross-resistance of cultured leukemia P388 cells to vincristine, adriamycin, adriamycin analogs, and actinomycin D. J Natl Cancer Inst 61: 1521

    Google Scholar 

  36. Wilkoff LJ, Dulmadge EA (1980) Partial cross-resistance of cultured murine leukemia vincristine-resistant P388 cells to 4′-demethylepipodophyllotoxin ethylidene-β-D-glucoside. Proc Soc Exp Biol Med 164: 51

    Google Scholar 

  37. Wilkoff LJ, Dulmadge EA (1982) Cross-resistance of cultured murine leukemia vincristine-resistant P388 cells to vinblastine, vindesine, and bis-(N-ethylidene vindesine)disulfide, disulfate. J Natl Cancer Inst 68: 1023

    Google Scholar 

  38. Wilkoff LJ, Dixon GJ, Dulmadge EA, Schabel FM Jr (1967) Effect of 1,3-bis(2-chloroethyl)-l-nitrosourea (NSC-409962) and nitrogen mustard (NSC-762) on kinetic behavior of cultured L1210 leukemia cells. Cancer Chemother Rep 51: 7

    Google Scholar 

  39. Wilkoff LJ, Dulmadge EA, Lloyd HH (1978) Effect of adriamycin on the reproductive integrity of cultured leukemia L1210 and P388 cells. J Natl Cancer Inst 60: 1117

    Google Scholar 

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Authors and Affiliations

  1. Kettering-Meyer Laboratory, Southern Research Institute, P.O. Box 55305, 35255-5305, Birmingham, AL, USA

    Lee J. Wilkoff, Elizabeth A. Dulmadge, W. R. Laster Jr. & Daniel P. Griswold Jr.

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  1. Lee J. Wilkoff
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  2. Elizabeth A. Dulmadge
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  3. W. R. Laster Jr.
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  4. Daniel P. Griswold Jr.
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Additional information

This work was supported by Contract NO1-CM-97309 with the Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Md 20892

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Wilkoff, L.J., Dulmadge, E.A., Laster, W.R. et al. Effect of homoharringtonine on the viability of murine leukemia P388 cells resistant to either adriamycin, vincristine, or 1-β-D-arabinofuranosylcytosine. Cancer Chemother. Pharmacol. 23, 145–150 (1989). https://doi.org/10.1007/BF00267945

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