Skip to main content
SpringerLink
Log in

Synergistic cytotoxic actions of cisplatin and liposomal valinomycin on human ovarian carcinoma cells

  • Original Articles
  • Cisplatin, Liposomal Valinomycin, Ovarian Carcinoma
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Summary

We have previously shown that the toxicity of valinomycin (VM), a membrane-active agent with antineo-plastic activity, can be dramatically reduced with no loss of the antitumor efficacy of the drug by incorporating it into liposomes. In the present study, we investigated the interaction betweencis-diamminedichloroplatinum(II) (CDDP) and VM in terms of in vitro cytotoxicity to human ovarian tumor cells. Using the MTT assay and analyzing the data using the median-effect principle, we showed that synergistic cytotoxic interactions exist between CDDP and VM in their liposomal form. The degree of cytotoxic synergism was influenced by the duration of drug exposure and the dose ratio. The cellular accumulation of platinum by ovarian cells at 37°C was slightly higher after exposure to VM as compared with controls; however, it is not clear that this accounts for the cytotoxic synergism. These results suggest that the combination of liposomal VM and CDDP may have merit as a form of localized drug delivery for the treatment of ovarian cancer disseminated within the peritoneal space.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CDDP:

cisplatin,cis-diamminedichloroplatinum(II)

VM:

valinomycin

MLV-VM:

liposomal valinomycin

MTT:

3-(4,5-dimethyl thiazol-2-yl)-2,5 diphenyl-tetrazolium bromide (thiazolyl blue)

alpha-MEM:

alpha minimal essential medium

CHO:

Chinese hamster ovary

IC50 :

concentration causing 50% inhibition of cell growth

IC10 :

concentration causing 10% inhibition of cell growth

SF:

surviving fraction

fa:

fraction affected

CI:

combination index

References

  1. Alley MC, Scudiero DA, Monks A, Hunsey ML, Czerwinski MJ, Pine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR (1989) Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res 48: 589

    Google Scholar 

  2. Berenbaum MC (1978) A method for testing for synergy with a number of agents. J Infect Dis 137 (2): 122

    Google Scholar 

  3. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248

    Google Scholar 

  4. Burns CP (1988) Membranes and cancer chemotherapy. Cancer Invest 6 (4), 439

    Google Scholar 

  5. Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 47: 936

    Google Scholar 

  6. Carter SK (1984) Cisplatin-past, present and future. In: Haker MP, Douple EB, Krakoff IH (eds) Platinum coordination complexes in cancer chemotherapy. Martinus Nijhoff, Boston, pp 295

    Google Scholar 

  7. Chabot GG, Valeriote FA (1986) Modification of cell sensitivity to anticancer agents by polyenes. In: Valeriole FA, Baker LH (eds) Biochemical modulation of anitcancer agents: experimental and clinical approaches. Martinus Nijhoff, Boston, p 295

    Google Scholar 

  8. Chou J, Chou T-C (1987) Dose-effect analysis with microcomputers. Biosoft, Cambridge

    Google Scholar 

  9. Chou T-C, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22: 27

    Google Scholar 

  10. Chou T-C, Talalay P (1987) Application of the median-effect principle for the assessment of low-dose risk of carcinogens and for the quantitation of synergism and antagonism of chemotherapeutic agents. In: Harrap KR, Connors TA (eds) New avenues in developmental cancer chemotherapy. Academic Press, New York, p 37

    Google Scholar 

  11. Daoud SS, Juliano RL (1986) Enhancement of the therapeutic index of valinomycin by incorporation in liposomes. Proc Am Assoc Cancer Res 27: 409

    Google Scholar 

  12. Daoud SS, Juliano RL (1986) Reduced toxicity and enhanced antitumor effects in mice of the ionophoric drug valinomycin when incorporated in liposomes. Cancer Res 46: 5518

    Google Scholar 

  13. Daoud SS, Juliano RL (1989) In vitro effect of liposome-incorporated valinomycin on growth and macromolecular synthesis of normal and ras-transformed 3T3 cells. Cancer Chemother Pharmacol 23: 151

    Google Scholar 

  14. Daoud SS, Juliano RL (1989) Modulation of doxorubicin resistance by valinomycin (NSC-122023) and liposomal valinomycin in Chinese hamster ovary cells. Cancer Res 49: 2661

    Google Scholar 

  15. Daoud SS, Hume LE, Juliano RL (1989) Liposomes in cancer therapy. Adv Drug Rev 3: 405

    Google Scholar 

  16. Durand RE, Goldie JH (1987) Interaction of etoposide and cisplatin in an in vitro tumor model. Cancer Treat Rep 72: 673

    Google Scholar 

  17. Eastman A (1984) Characterization of the interaction of cis-diamminedichloroplatinum(II) with DNA. In: Haker MP, Douple EB, Krakoff IH (eds) Platinum coordination complexes in cancer chemotherapy. Martinus Nijhoff, Boston, p 56

    Google Scholar 

  18. Einhorn LH, Donohue J (1977) cis-diamminedichloroplatinum(II), vinblastine and bleomycin combination therapy in disseminated testicular cancer. Ann Intern Med 87: 293

    Google Scholar 

  19. Erickson LC, Zwelling LA, Ducore JM, Sharkey NA, Kohn KW (1981) Differential cytotoxicity and DNA crosslinking in normal and transformed human fibrobasts treated with cis-diamminedichloroplatinum(II) in vitro. Cancer Res 41: 2791

    Google Scholar 

  20. Forde NH, Daoud SS (1990) Cisplatinum and liposomal valinomycin in ovarian cancer: cytoxicity synergism in vitro. Proc Am Assoc Cancer Res 31: 2298

    Google Scholar 

  21. Friedman SJ, Skehan P (1984) Cell membranes: targets of selective antitumor chemotherapy. In: Prased SS (ed) Novel approaches to cancer chemotherapy. Academic Press, New York, p 329

    Google Scholar 

  22. Grinstein S, Cohen S, Rothstein A (1984) Cytoplasmic pH regulation in thymic lymphocytes by an amiloride-sensitive Na+/H+ antiport. J Gen Physiol 83: 341

    Google Scholar 

  23. Grinstein S, Rotin D, Mason MJ (1989) Na+/H+ exchange and growth factor-induced cytosolic pH changes. Role in cellular proliferation. Biochim Biophys Acta 988: 73

    Google Scholar 

  24. Hoelzl-Wallach DF, Mikkelsen RB, Kwock L (1981) Plasma membrane as targets and mediators. In: Sartorelli AC, Lazo JS, Bertino JR (eds) Tumor chemotherapeutic agents. Academic Press, New York, p 433

    Google Scholar 

  25. Jackson MJ (1986) Weak electrolyte transport across biological membranes: general principles. In: Andreoli TE, Hoffman JF, Fanestil DD, Schultz SG (eds) Physiology of membrane disorders. Plenum Press, New York London, p 235

    Google Scholar 

  26. Jacobs C (1980) The role of cisplatin in the treatment of recurrent head and neck cancer. In: Prestayko AW, Crooke ST, Carter SK (eds) Cisplatin F current status and new developments. Academic Press, New York, p 423

    Google Scholar 

  27. Kikuchi Y, Oomori K, Kizawa I, Hirata J, Kita T, Miyauchi M (1987) Enhancement of antineoplastic effects of cisplatin by calmodulin antagonists in nude mice bearing human ovarian carcinoma. Cancer Res 47: 6459

    Google Scholar 

  28. Kitagawa S, Awai M, Kametani F (1987) Relationship of the effects of nigericin on the aggregation and cytoplasmic pH of bovine platelets in the presence of different cations. Biochim Biophys Acta 930: 48

    Google Scholar 

  29. Kleuser B, Rieter H, Adam G (1985) Selective effects by valinomycin on cytotoxicity and cell cycle arrest of transformed versus non-transformed rodent fibroblasts in vitro. Cancer Res 45: 3022

    Google Scholar 

  30. Krakoff IH (1979) Nephrotoxicity of cis-dichlorodiammineplatinum(II). Cancer Treat Rep 63: 1523

    Google Scholar 

  31. Loehrer PJ, Einhorn LH (1984) Diagnosis and treatment. Drugs five years later: cisplatin. Ann Intern Med 100: 704

    Google Scholar 

  32. Markman M (1985) Melphalan and cytarabine administered intraperitoneally as single agents and combination intraperitoneal chemotherapy with cisplatin and cytarabine. Semin Oncol 12 (3): 33

    Google Scholar 

  33. Mauldin SK, Gibbons G, Wyrick SD, Chaney SG (1988) Intracellular biotransformation of platinum with the 1,2-diaminocyclohexane carrier ligand in the L1210 cell line. Cancer Res 48: 5136

    Google Scholar 

  34. Medias NE, Harrington JT (1978) Platinum nephrotoxicity. Am J Med 65: 307

    Google Scholar 

  35. Moolenar WH (1986) Effects of growth factors on intracellular pH regulation. Annu Rev Physiol 48: 363

    Google Scholar 

  36. Onoda JM, Nelson KK, Taylor JD, Honn KV (1989) In vivo characterization of combination antitumor chemotherapy with calcium channel blockers and cis-diamminedichloroplatinum(II). Cancer Res 49: 2844

    Google Scholar 

  37. Ozols RF, Young RC (1984) Chemotherapy of ovarian cancer. Semin Oncol 11: 251

    Google Scholar 

  38. Park J-G, Kramer BS, Steinberg SM, Carmichael J, Collins JM, Minna JD, Gazdar AF (1987) Chemosensitivity testing of human colorectal carcinoma cell lines using a tetrazolium-based assay. Cancer Res 47: 5875

    Google Scholar 

  39. Plumb JA, Milroy R, Kaye SB (1989) Effects of pH dependence of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide formazan absorption on chemosensitivity determined by a novel tetrazolium-based assay. Cancer Res 49: 4435

    Google Scholar 

  40. Pouyssegur J, Sardet C, Franchi A, L'Allemain G, Paris S (1984) A specific mutation abolishing Na+/H+ antiport activity in hamster fibroblasts precludes growth at neutral and acidic pH. Proc Natl Acad Sci USA 81: 4833

    Google Scholar 

  41. Randoloph VL, Vallejo A, Spiro RH, Shah J, Strong E, HuVos A, Wittes R (1978) Combination therapy of advanced head and neck cancer. Cancer 41: 460

    Google Scholar 

  42. Roberts JJ, Thomson AJ (1979) The mechanism of action of antitumor platinum compounds. Prog Nucleic Acid Res Mol Biol 22: 71

    Google Scholar 

  43. Rossof AH, Slayton RE, Perlia CP (1972) Preliminary clinical experience with cis-diamminedichloroplatinum(II) (NSC-119 875, CACP). Cancer 30: 1415

    Google Scholar 

  44. Rotin D, Wan P, Grinstein S, Tannock I (1987) Cytotoxicity of compounds that interfere with the regulation of intracellular pH: a potential new class of anticancer drugs. Cancer Res 47: 1497

    Google Scholar 

  45. Sorenson CM, Eastman A (1988) Mechanism of cis-diamminedi-chloroplatinum(II)-induced cytotoxicity: role of G2 arrest and DNA double-strand breaks. Cancer Res 48: 4484

    Google Scholar 

  46. Swinnen LJ, Barnes DM, Fisher SG, Albain KS, Fisher RI, Eickerson LC (1989) 1-β-d-Arabinofuranosylcytosine and hydroxyurea production of cytotoxic synergy with cis-diamminedichloroplatinum(II) and modification of platinum-induced DNA interstrand cross-linking. Cancer Res 49: 1383

    Google Scholar 

  47. Tritton TR, Hickman JA (1985) Cell membranes as a chemotherapeutic target. In: Experimental and Clinical Progress in Cancer Chemotherapy. Muggia FM (ed) Martinus Nijoff, Boston, pp 81–131

    Google Scholar 

  48. Tritton TR, Grace Y, Ehrlich YH (1985) Mechanisms of membrane-mediated cytotoxicity by Adriamycin. In: Chandra P (ed) New experimental modalities in the control of neoplasia. Plenum Press, New York London, p 195

    Google Scholar 

  49. Tycko B, Maxfield FR (1982) Rapid acidification of endocytic vesicles containing α2-macroglobulin. Cell 28: 643

    Google Scholar 

  50. Von Hoff DD, Schilsky R, Reichert CM, Reddick RL, Rozencweig M, Young RC, Muggia EM (1979) Toxic effects of cis-dichlorodiammineplatinum in man. Cancer Treat Rep 63: 1527

    Google Scholar 

  51. Zwelling LA, Khon RW (1980) Effects of cisplatin on DNA and the possible relationships to cytotoxicity and mutagenicity in mammalian cells. In: Prestayko AW, Crooke ST, Carter SK (eds) Cisplatin F current status and new developments. Academic Press, New York, p 21

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, 27 599-7365, Chapel Hill, NC, USA

    Sayed S. Daoud & Nicholas H. Forde

Authors
  1. Sayed S. Daoud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicholas H. Forde
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Daoud, S.S., Forde, N.H. Synergistic cytotoxic actions of cisplatin and liposomal valinomycin on human ovarian carcinoma cells. Cancer Chemother. Pharmacol. 28, 370–376 (1991). https://doi.org/10.1007/BF00685692

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00685692

Keywords

Search

Navigation