Skip to main content
SpringerLink
Log in

Identification of anthracyclines and related agents that retain preferential activity over Adriamycin in multidrug-resistant cell lines, and further resistance modification by verapamil and cyclosporin A

  • Original Articles
  • Anthracyclines, Adriamycin, Multidrug Resistance, Verapamil, Cyclosporin A
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

An Erratum to this article was published on 01 September 1990

Summary

A range of anthracyclines and related compounds were evaluated for activity against murine and human cell lines exhibiting multidrug resistance (MDR). Cell lines used were the NCI-H69 human small-cell lung cancer line and the EMT6 murine mammary tumour line, together with their multidrug-resistant counterparts produced by in vitro exposure to Adriamycin (ADM). Chemosensitivity testing was carried out using the tetrazolium (MTT) dye assay. Results were expressed as the ratio of the ID50 for the resistant line to that obtained in the parent, i.e. the resistance factor (RF). Compounds exhibiting much lower RF values than ADM in both resistant cell lines were identified as those anthracyclines with 9-alkyl substituents and those with certain changes to the amino sugar residue at position 3′ and 4′, together with the anthracenedione mitoxantrone (MIT). In a further attempt to overcome resistance, we used four of these compounds, Ro 31-1215, 4′-deoxy-4′-iodo-ADM (iodo-ADM), aclacinomycin A (ACL) and MIT (all yielding low RF values), in combination with the resistance modifiers verapamil (VRP) and cyclosporin A (CYA). Additional enhancement of chemosensitivity was achieved in the ADM-resistant sublines, as shown by the further decrease in RF values. At the concentrations used, the largest effects were generally seen with CYA, and the combination of this modifier with ACL and MIT was particularly effective. For the H69/LX4 resistant line, the latter combinations gave RF values approaching unity. These findings point to the use of analogues with the 9-alkyl substituent and/or specific changes to the sugar residue in combination with resistance modifiers as a therapeutic strategy for circumvention of the MDR phenotype.

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

References

  1. Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbot BJ, Shoemaker RH, Boyd MR (1988) Feasibility of drug screening with panels of human tumour cell lines using a microculture tetrazolium assay. Cancer Res 48: 589–601

    Google Scholar 

  2. Arcamone F (1985) Properties of antitumour anthracyclines and new developments in their application: Cain Memorial Award Lecture. Cancer Res 45: 5995–5999

    Google Scholar 

  3. Barbieri B, Suarto A, Penco S, Geroni C, Bellini O, Fumagli A, Casazza AM, Guiliana FC (1984) Biologic activity of 4'-haloanthracyclines. Proc Am Assoc Cancer Res 25: 305

    Google Scholar 

  4. Biedler JL, Riehm H (1970) Cellular resistance to actinomycin D in Chinese hamster cells in vitro: cross-resistance, radioautographic and cytogenetic studies. Cancer Res 30: 1174–1184

    Google Scholar 

  5. Carmichael J, De Graff WG, Gazdar AF, Minna JD, Mitchell JB (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 47: 936–942

    Google Scholar 

  6. Chabner B (1986) The oncologic end game (Karnofsky Memorial Lecture). J Clin Oncol 4: 625–638

    Google Scholar 

  7. Chandrasekaran B, Dimling J, Capizzi RL (1987) Cross-resistance to menogaril and mitoxantrone in a subline of P388 leukaemia resistant to doxorubicin. Cancer Treat Rep 71: 195–196

    Google Scholar 

  8. Chen CJ, Chin JE, Ueda K, Clark DP, Pastan I, Gottesman MM, Roninson IB (1986) Internal duplication and homology with bacterial transport proteins in the MDR 1 (P-glycoprotein) gene from multidrug resistant cells. Cell 47: 381–389

    Google Scholar 

  9. Cole SP (1986) Rapid chemosensitivity testing of human lung tumour cells using the MTT assay. Cancer Chemother Pharmacol 7: 259–263

    Google Scholar 

  10. Gibby EM, Boyse O, Hill BT (1987) Selective interactions of verapamil with anthraquinones in Adriamycin-sensitive and-resistant murine and human tumour cell lines. Cancer Chemother Pharmacol 20: 5–7

    Google Scholar 

  11. Gros P, Croop J, Houseman D (1986) Mammalian multidrug resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell 47: 371–380

    Google Scholar 

  12. Hess AD, Colombani PM (1986) Mechanism of action: in vitro studies. Prog Allergy 38: 198–221

    Google Scholar 

  13. Hill BT, Dennis LY, Li X, Whelan RDH (1985) Identification of anthracycline analogues with enhanced cytotoxicity and lack of cross-resistance to Adriamycin using a series of mammalian cell lines in-vitro. Cancer Chemother Pharmacol 14: 194–201

    Google Scholar 

  14. Inaba M, Johnson RK (1978) Uptake and retention of Adriamycin and daunomycin by sensitive and anthracycline resistant sublines of P388 leukemia. Biochem Pharmacol 27: 2123–2130

    Google Scholar 

  15. 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: 2200–2203

    Google Scholar 

  16. Kahan BD, Reid M, Newburger J (1983) Pharmacokinetics of cyclosporine in human renal transplantation. Transplant Proc 15: 446–451

    Google Scholar 

  17. Kaye S, Merry S (1985) Tumour cell resistance to anthracyclines — a review. Cancer Chemother Pharmacol 14: 96–103

    Google Scholar 

  18. Kraemer HP, Berscheid HG, Ronneberger H, Zilg H, Sedacek HH (1986) Preclinical evaluation of cytorhodin S, a new anthracycline, with activity in a human tumor based screening system. Proceedings of the 5th NCI EORTC symposium on new cancer therapy, Amsterdam

  19. Leopold WR, Nelson JM, Plowman J, Jackson RC (1985) Anthrapyrazoles, a new class of intercalating agents with highlevel, broad spectrum activity against murine tumours. Cancer Res 45: 5532–5539

    Google Scholar 

  20. Meador J, Sweet P, Stupecky M, Wetzel M (1987) Cyclosporin A enhances daunorubicin efficacy in Ehrlich ascites carcinoma and murine hepatoma 129. Cancer Res 47: 6216–6219

    Google Scholar 

  21. Merry S, Courtney ER, McCormick C, Kaye SB, Freshney I (1986) In vitro cross-resistance patterns of anthracyclines in human non-small cell lung cancer lines with differing inherent resistance to Adriamycin. Br J Cancer 55: 336–337

    Google Scholar 

  22. Merry S, Courtney ER, Fetherson CA, Kaye SB, Freshney I (1987) Circumvention of drug resistance in human non-small cell lung cancer in vitro by verapamil. Br J Cancer 56: 401–405

    Google Scholar 

  23. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival. Application to proliferation and cytotoxicity assays. J Immunol Methods 65: 55

    Google Scholar 

  24. Riordan JR, Ling V (1985) Genetic and biochemical characterisation of multidrug resistance. Pharmacol Ther 28: 51–75

    Google Scholar 

  25. Rogan AM, Hamilton TC, Young RC, Klecker RW Jr, Ozols RF (1984) Reversal of Adriamycin resistance by verapamil in human ovarian cancer. Science 224: 994–996

    Google Scholar 

  26. Safa AR, Glover CI, Meyers MB (1986) Vinblastine photoaffinity labelling of a high molecular weight surface membrane glycoprotein specific for multidrug-resistant cells. J Biol Chem 261: 6137–6140

    Google Scholar 

  27. Scott CA, Westmacott D, Broadhurst MJ, Thomas GJ, Hall MJ (1986) 9-Alkyl anthracyclines. Absence of cross-resistance to Adriamycin in human and murine cell cultures. Br J Cancer 53: 595–600

    Google Scholar 

  28. Sehested M, Skovsgaard T, Deurs B van, Winther-Nielsen H (1987) Increase in nonspecific adsorptive endocytosis in anthracycline and vinca alkaloid-resistant Ehrlich ascites tumor cell lines. J Natl Cancer Inst 78: 171–177

    Google Scholar 

  29. Sehested M, Skovsgaard T, Deurs B van, Winther-Nielsen H (1987) Increased plasma membrane traffic in daunorubicin resistant P388 leukaemia cells. Effect of daunorubicin and verapamil. Br J Cancer 56: 747–751

    Google Scholar 

  30. Selby P (1984) Acquired resistance to cancer chemotherapy. Br Med J 288: 1252–1253

    Google Scholar 

  31. Skovsgaard T (1978) Carrier mediated transport of daunomycin, Adriamycin and rubidazone in Ehrlich ascites tumour cells. Biochem Pharmacol 27: 1221–1227

    Google Scholar 

  32. Slater LM, Sweet P, Stupecky M, Wetzel MW, Gupta S (1986) Cyclosporin A corrects daunorubicin resistance in Ehrlich ascites carcinoma. Br J Cancer 54 235–238

    Google Scholar 

  33. Slater TF, Sawyer B, Stauli U (1963) Studies on succinatetetrazolium reductase systems. Biochim Biophys Acta 77: 383

    Google Scholar 

  34. Streeter DG, Johl JS, Gordon GR, Peters JH (1986) Uptake and retention of morpholinyl anthracyclines by Adriamycinsensitive and-resistant P388 cells. Cancer Chemother Pharmacol 16: 247–252

    Google Scholar 

  35. Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1982) Increased accumulation of vincristine and Adriamycin in drug resistant P388 tumour cells following incubation with calcium antagonists and calmodulin inhibitors. Cancer Res 42: 4730–4733

    Google Scholar 

  36. Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1983) Potentiation of vincristine and Adriamycin effects in human haemopoietic cell lines by calcium antagonists and calmodulin inhibitors. Cancer Res 43: 2267–2272

    Google Scholar 

  37. Tsuruo T, Kawabata H, Nagumo N, Iida H, Kitatani Y, Tsukagoshi S, Sakurai Y (1985) Potentiation of antitumor agents by calcium channel blockers with special reference to crossresistance patterns. Cancer Chemother Phrmacol 15: 16–19

    Google Scholar 

  38. Twentyman PR (1988) Modification of cytotoxic drug resistance by non-immunosuppressive cyclosporins. Br J Cancer 57: 254–258

    Google Scholar 

  39. Twentyman PR, Luscombe M (1987) A study of some variables in a tetrazolium dye (MTT) based assay for cell growth and chemosensitivity. Br J Cancer 56: 279–285

    Google Scholar 

  40. Twentyman PR, Fox NE, Wright K, Bleehen NM (1986) Derivation and preliminary characterisation of Adriamycin resistant lines of human lung cancer cells. Br J Cancer 53: 529–537

    Google Scholar 

  41. Twentyman PR, Fox NE, Wright KA, Workman P, Broadhurst MJ, Martin JA, Bleehen NM (1986) The in-vitro effects and cross-resistance patterns of some novel anthracyclines. Br J Cancer 53: 585–594

    Google Scholar 

  42. Twentyman PR, Fox NE, White DJG (1987) Cyclosporin A and its analogues as modifiers of Adriamycin and vincristine resistance in a multi-drug resistant human lung cancer cellline. Br J Cancer 56: 55–57

    Google Scholar 

  43. Weiss RB, Saosy G, Clagett-Carr K, Russo M, Leyland-Jones B (1986) Anthracycline analogs: the past, present and future. Cancer Chemother Pharmacol 18: 185–197

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. MRC Clinical Oncology and Radiotherapeutics Unit, Hills Road, CB2, 2QH, Cambridge, UK

    Helen M. Coley, Peter R. Twentyman & Paul Workman

Authors
  1. Helen M. Coley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter R. Twentyman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul Workman
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/BF02897301.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Coley, H.M., Twentyman, P.R. & Workman, P. Identification of anthracyclines and related agents that retain preferential activity over Adriamycin in multidrug-resistant cell lines, and further resistance modification by verapamil and cyclosporin A. Cancer Chemother. Pharmacol. 24, 284–290 (1989). https://doi.org/10.1007/BF00304759

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00304759

Keywords

Search

Navigation