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Combination of highly purified human leukocyte interferon α and 13-cis-retinoic acid for the treatment of metastiatic melanoma

  • Original Article
  • Melanoma, 13-Cis-Retinoic Acid, Interferon α
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Abstract

The effect of 13-cis-retinoic acid and highly purified human leukocyte interferon α (Alphaferon) therapy for metastatic melanoma was studied. A group of 17 patients with disseminated malignant melanoma were treated over a 6-month period. They received 60 mg 13-cis-retinoic acid/day continuously and ten cycles of interferon α (IFNα). IFN was administered by subcutaneous injection, at a daily dose of 6×106 IU Alphaferon. The 5-day treament period was followed by an IFN-free interval of 2 weeks. We were able to observe an overall response rate of 30% with 12% complete responses (2 out of 17 patients). Sites of response included the skin, lung, liver and lymph nodes. All responses have now lasted over 6 months. Therapy was generally well tolerated and could be performed on an outpatient basis. Side-effects of this combination therapy did not exceed the established side-effects of the two substances. We also studied 2′-5′-oligoadenylate synthetase, β2-microglobulin and neopterin levels during the whole treatment course. All patients were within the normal range before treatment and a sharp rise occurred during each IFN cycle. The maximum being observed 24 h after the third injection. This indicates a high biological activity of IFNα administered cyclicly during the whole treatment course. This finding also corresponds well with the absence of neutralizing antibodies before and after the whole treatment period.

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References

  1. Ahmann DL, Creagan ET, Hahn RG, Edmonson JH, Bisel HF, Schaid DJ (1989) Complete responses and long term survival after systemic chemotherapy for patients with advanced malignant melanoma. Cancer 63: 224–227

    PubMed  Google Scholar 

  2. Ahren B, Engman K, Lindblom A (1992) Tolerance to long-term treatment of malignant carcinoid with a highly purified human leukocyte α-interforon. Anticancer Res 12: 881–884

    PubMed  Google Scholar 

  3. Berglund O, Engmann, K, Ehrnst A, Anderson J, Lidman K, Akerlund B, Sönnerberg A, Strannegard Ö (1991) Combined treatment of symptomatic human immuinodeficiency virus type I infection with native interforen-α and zidovudine. J Infect Dis 163: 710–715

    PubMed  Google Scholar 

  4. Breier S, Pensel R, Roffe C (1990) High dose DTIC with recombinant human interferon alpha-2b (rhifn2b) for the treatment of metastatic melanoma (MM). Proc Am Soc Clin Oncol 9: A1090

    Google Scholar 

  5. Bruchelt G, Fierbeck G, Schiebel U, Bogenschütz O, Rassner G, Niethammer D (1992) Determination of 2′-5′-oligoadenylate synthetase in serum and peripheral blood mononuclear cells before and after subcutaneous applications of recombinant interferon beta and gamma. Eur J Clin Chem Clin Biochem 30: 521–528

    PubMed  Google Scholar 

  6. Carbone PP, Castello W (1976) Eastern cooperative oncology group studies with DTIC (NSC 45388) Cancer Treat Rep 60: 193–198

    PubMed  Google Scholar 

  7. Castello G, Ruocco V, Satrino RA, Zarilli D (1991) Role of interferons in the therapy of melanoma. Melanoma Res 1: 311–325

    Google Scholar 

  8. Constanzi JJ (1976) DTIC (NSC 45388) studies in the Southwest Oncology Group. Cancer Treat Rep 60: 189–192

    PubMed  Google Scholar 

  9. Cuellar-Bravo A, Martin-Ruiz JL, Orbach-Arbouys S (1985) Decreased natural killer cell activity after prolonged administration of interferon in cancer patients. Immunol Lett 10: 137–139

    PubMed  Google Scholar 

  10. Dhingra K, Papadopoulos N, Lippmann S, Lotan R Legha SS (1993) Phase II study of alpha-interferon and 13-cis-retinoic acid in metastatic melanoma. Invest New Drugs 11: 39–43

    PubMed  Google Scholar 

  11. Dimitrovsky E, Bosl GJ (1992) Active cancer therapy combining 13-cis-retinoic acid with interferon-alpha. J Natl Cancer Inst 84: 218–219

    PubMed  Google Scholar 

  12. Elsässer-Beile U, Drees N, Neumann HA, Schöpf E (1987) Phase II trial of recombinant leukocyte A interferon in advanced malignant melanoma. J Cancer Res Clin Oncol 113: 273–278

    PubMed  Google Scholar 

  13. Ernstoff MS, Fusi S, Kirkwood JM (1983) Parameters of interferon action: immunological effects of whole leukocyte interferon (IFN-α) in phase I–II trials. J Biol Response Mod 2: 528–539

    PubMed  Google Scholar 

  14. Falkson CI, Falkson G, Falkson HC (1991) Improved results with the addition of interferon alhpa 2b to decarbazine in the treatment of patients with metastatic malignant melanoma. J Clin Oncol 8: 1403–1408

    Google Scholar 

  15. Fierlbeck G, d'Hoedt B, Stroebel W, Stutte H, Bogenschütz O, Rassner G (1992) Intraläsionale Therapie von Melanommetastasen mit rekombinantem Interferon-β. Hautarzt 43: 16–21

    PubMed  Google Scholar 

  16. Fierlbeck G, Schreiner T, Schaber B, Walser A, Rassner G (1994) Neutralizing interferon-beta antibodies in melanoma patients treated with recombinant and natural interferon-beta. Cancer Immunol Immunother 39: 263–268

    PubMed  Google Scholar 

  17. Frey JR, Peck R, Bollag W (1991) Antiproliferative activity of retinoids, interferon-alpha and their combination in five human transformed cell lines. Cancer Lett 57: 223–227

    PubMed  Google Scholar 

  18. Garbe C, Kreuser ED, Zouboulis CC, Stadler R, Orfanos CE (1992) Combined treatment of metastatic melanoma with interferons and cytotoxic drugs. Semin Oncol 19: 63–69

    Google Scholar 

  19. Goldberg RM, Ayoob M, Silgals R, Ahlgren JD, Neefe JR (1985) Phase II trial of lymphoblastoid interferon in metastatic malignant melanoma. Cancer Treat Rep 69: 813–816

    PubMed  Google Scholar 

  20. Helige C, Smolle J, Zellnig G, Hartmann E, Fink-Puches R, Kerl H, Tritthart HA (1993) Inhibition of K1735-M2 melanoma cell invasion in vitro by retinoic acid. Clin Exp Metastasis 11: 409–418

    PubMed  Google Scholar 

  21. Hendrix MJC, Wood WR, Seftor EA, Lotan D, Nakanima M, Misiorowski RL, Seftor REB, Stetler-Stevenson WG, Bevacqua SJ, Liotta LA, Sobel MF, Raz A, Lotan R (1990) Retionoic acid inhibition of human melanoma cell invasion through a reconstituted basement membrane and its relation to decreases in the expression of proteolytic enzymes and motility factor receptor. Cancer Res 50: 4121–4130

    PubMed  Google Scholar 

  22. Hersey P, Mac Donald M, Hall C (1986) Immunological effects of recombinant Interferon alpha 2a in patients with disseminated melanoma. Cancer 57: 1666–1674

    PubMed  Google Scholar 

  23. Hersey P, MeLeod RC, Thomson DB (1989) Phase I/II study of tolerability and efficacy of recombinant interferon (Roferon) with dacarbacin (DTIC) in advanced malignant melanoma. J Interferon Res 9 [Suppl 2]: 118

    Google Scholar 

  24. Hill GJ, Kremmtz ET, Hill HZ (1984) Dimethyl-triazan-imidazole carboxamide and combination therapy for melanoma IV late results after complete response to chemotherapy. Cancer 53: 1299–1305

    PubMed  Google Scholar 

  25. Hiscott J, Ryals J, Dierks P, Hofman V, Weissmann C (1984) The expression of human interferon alpha genes. Philos Trans R Soc Lond [Biol] 307: 217–226

    Google Scholar 

  26. Ishihara K, Hayasaka K, Yamamoto A, Hasegawa F (1983) Clinical responses of patients with malignant skin neoplasia to intralesional treatment with three types of interferons. In: Kishida T (ed) Interferons. ISIFN, Kyoto, pp 222–227

    Google Scholar 

  27. Kawade Y (1980) An analysis of neutralization reaction of interferon by antibody: a proposal on the expression of neutralization titer. J Interferon Res 1: 61–70

    PubMed  Google Scholar 

  28. Kirkwood JM, Ernstoff MS (1990) Role of interforons in the therapy of melanoma. J Invest Dermatol 95: 180–184

    Google Scholar 

  29. Kono T, Furukawa M, Tanii T, Taniguchie S, Mizuno N, Ishii M, Hamada T (1991) Effect of retinoic acid on the infiltration of murine melanoma cells into the type I collagen gel. Acta Derm Venereol (Stockh) 71: 41–87

    Google Scholar 

  30. Krown SE, Burk MW, Kirkwood JM (1984) Human leukocyte (alpha) interferon in metastatic malignant melanoma: the American Cancer Society phase II trial. Cancer Treat Rep 68: 723–726

    PubMed  Google Scholar 

  31. Legha SS (1986) Interferons in the treatment of malignant melanoma. Cancer 57: 1675–1677

    PubMed  Google Scholar 

  32. Legha SS, Papadoupoulos N, Pickett S Plager C, Dimery IW, Benjamin RS, Itri L (1984) Adjuvant therapy for high risk local and regional melanoma using 13-cis-retinoic acid: In: Jones SE, Salmon SE (eds) Adjuvant therapy of cancer IV. Grune & Stratton, Orlando, Fla, pp 577–582

    Google Scholar 

  33. Lippman SM, Shimm DS, Meyskens FI (1988) Nonsurgical treatments for skin cancer: Retinoids and α-interferon. J Dermatol Surg Oncol 14: 862–869

    PubMed  Google Scholar 

  34. Lippman SM, Parkinson DR, Itri L, Weber RS, Schantz SP, Ota DM, Schusterman MA, Krakoff AS, Gutterman JU, Hong WK (1992) 13-cis-Retinoic acid plus interferon-alpha: effective theapy for advanced squamous cell carcinoma of the skin. J Natl Cancer Inst 84: 235–241

    PubMed  Google Scholar 

  35. Lippman SM, Kavanagh JJ, Paredes-Espinoza M, Delgadillo-Madrueno F, Paredes-Casillas P, Hong WK, Massimini G, Holdener E, Krakoff IH (1993) 13-cis-Retinoic acid plus interferon α2a in locally advanced squamous cell carcinoma of the cervix. J Natl Cancer Inst 85: 499–500

    PubMed  Google Scholar 

  36. Lotan R (1985) Mechanism of inhibition of tumor cell proliferation by retinoids. In: Saurat (ed) Retinods: new trends in research and therapy. Karger, Basel, pp 97–105

    Google Scholar 

  37. Lotan R (1992) Inhibitory effects of retinoids on tumor cell invasion and metastasis. In: Rabes H, Peters PE, Munk K (eds) Metastasis: basic research and its clinical applications. Contrib Oncol 44: 154–175

  38. Lotan R (1986) Retinoids and melanoma cells. In: Sherman MI (ed) Retinoids and cell differentiation. CRC, Boca Raton, Fla, pp 61–78

    Google Scholar 

  39. Lotan R, Hendrix MJC, Lippman S (1991) Retinoids in the management of melanoma. In: Marks R (ed) Retinoids in cutaneous malignancy. Frontiers in pharmacology and therapeutics. Blackwell, Oxford, pp 133–149

    Google Scholar 

  40. Mayer P, Handgretinger R, Bruchelt G, Schaber B, Rassner G, Fierbeck G (1994) Activation of cellular cytotoxicity and complement-mediated lysis of melanoma and neuroblastoma cells in vitro by murine antiganglioside antibodies MB 3.6 and 14.G2a. Melanoma Res 4: 101–106

    PubMed  Google Scholar 

  41. McClay EF, Mastrangelo MJ (1988) Systemic chemotherapy for metastatic melanoma. Semin Oncol 15: 569–577

    PubMed  Google Scholar 

  42. Medenica RD, Slack N (1985) Immunomodulatory activity of human leukocyte interferon in cancer patients: results obtained during pulse therapy schedule. Cancer Drug Deliv 2: 91–118

    PubMed  Google Scholar 

  43. Medenica RD, Slack N (1985) Clinical results of leukocyte interferon induced tumor regression in resistant human metastatic cancer resistant to chemotherapy and/or radiotherapy-pulse therapy schedule. Cancer Drug Deliv 2: 53–76

    PubMed  Google Scholar 

  44. Meyskens Fljr, Gilmartin E, Alberts DS, Levine NS, Brooks R, Salmon SE, Surwatt EA (1982) Activity of isotretinoin against squamous cell cancers and preneoplastic lisions. Cancer Treat Rep 66: 1315–1319

    PubMed  Google Scholar 

  45. Redfern CP, Daly AK, Latham JA, Todd C (1990) The biological activity of retinoids in melanoma cells. Induction of expression of retinoic acid receptor-beta by retinoic acid in S91 melanoma cells. FEBS Lett 273: 19–22

    PubMed  Google Scholar 

  46. Retsas, S, Priestman TJ, Newton KA (1983) Evaluation of human lymphoblastoid interferon in advanced malignant melanoma. Cancer 51: 273–76

    PubMed  Google Scholar 

  47. Ron IG, Mordish Y, Eisenthal A, Skornick Y, Inbar MJ, Chaitchik S (1994) A phase II study of combined administration of dacarbazine and carboplatin with home therapy of recombinant interleukin-2 and interferon-α2a in patients with advanced malignant melanoma. Cancer Immunol Immunother 38: 379–384

    PubMed  Google Scholar 

  48. Rustin GJS, Dische S, De Garis SN, Nelstrop A (1988) Treatment of advanced malignant melanoma with interferon and etretinate. Eur J Cancer Clin Oncol 24: 783–784

    PubMed  Google Scholar 

  49. Schaber B, Mayer P, Schreiner T, Rassner G, Fierlbeck G (1994) Antiproliferative activity of natural interferon alpha, isotretinoin and their combination varies in different human melanoma cell lines. Melanoma Res 4: 321–326

    Google Scholar 

  50. Smith MA, Parkinson DR, Cheson BD, Friedman MA (1992) Retinoids in cancer therapy. J Clin Oncol 10: 839–864

    PubMed  Google Scholar 

  51. Sporn MB, Roberts AB, Goodman DS (1994) Cellular biology and biochemistry of retinoids. Raven, New York: 475–520

    Google Scholar 

  52. Thomson DB, Adena M, McLeod GRC, Hersey P, Gill PG, Coates AS, Olver IN, Defford RF, Lowenthal RM, Beadle GF, Walpole ET, Boland K, Kingston D (1993) Interferon alpha 2a does not improve response or survival when combined with dacarbazine in metastatic malignant melanoma: results of a multi-institutional Australian randomized trial. Melanoma Res 3: 133–138

    PubMed  Google Scholar 

  53. Wahlin A, Holm J, Engman K (1991) Leukocyte interferon in the treatment of chronic myelogenous leukemia in second chronic phase. Acta Oncol 5: 611–615

    Google Scholar 

  54. Wussov P v, Block B, Hartmann F, Deicher H (1988) Intralesional interferon alpha therapy in advanced malignant melanoma. Cancer 61: 1071–1074

    PubMed  Google Scholar 

  55. Wussow P v, Jakschies D, Freund M, Hehlmann R, Brockhaus F, Hochkeppel H, Horisberger M, Deicher H (1991) Treatment of anti-recombinant interferon-alpha 2 antibody positive CML patients with natural interferon-alpha. Br J Haematol 78: 210–216

    PubMed  Google Scholar 

  56. Wussow P, Pralle H, Hochkeppel HK, Jakschies D, Sannen S, Schmidt H, Hüller-Rosenau D, Franke M, Haferlach T, Zwingers T, Rapp U, Deicher H (1991) Effective natural interferon-alpha therapy in recombinant interferon-alpha-resistant patients with hairy cell leukemia. Blood 78: 38–43

    PubMed  Google Scholar 

  57. Zoon KC, Zur Nedden DL, Enterline JC, Mainschewitz JF, Dyer DR, Boykins RA, Bekisz J, Gerrard TL (1987) Chemical and biological characterisation of natural human lymphoblastoid interferon alphas. In: Cantell K, Schellekens H (eds) The biology of the interferon system. Nijhoff, Amsterdam, pp 567–569

    Google Scholar 

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  1. Department of Dermatology, University of Tübingen, Liebermeisterstr. 25, 72076, Tübingen, Germany

    Gerhard Fierlbeck, Tilmann Schreiner & Gernot Rassner

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  1. Gerhard Fierlbeck
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  2. Tilmann Schreiner
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  3. Gernot Rassner
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Fierlbeck, G., Schreiner, T. & Rassner, G. Combination of highly purified human leukocyte interferon α and 13-cis-retinoic acid for the treatment of metastiatic melanoma. Cancer Immunol Immunother 40, 157–164 (1995). https://doi.org/10.1007/BF01517347

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  • DOI: https://doi.org/10.1007/BF01517347

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