Abstract
Several authors have demonstrated that coumarin (1,2-benzopyrone) in combination with cimetidine can produce objective antitumor responses in some patients with advanced renal cell carcinoma. The purpose of this report is to review the clinical development of coumarin, with or without cimetidine, with special reference to renal cell carcinoma (RCC). Previously unpublished data concerning the survival of a population of patients with RCC, who were treated on a phase I trial of coumarin and cimetidine, are presented. The rationale and study design of an active randomized, double-blinded, placebo-controlled trial of coumarin for RCC are discussed. A progress report is given for an ongoing phase I trial of oral 7-hydroxycoumarin, the major human metabolite of coumarin.
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References
Berkarda B, Bouffard-Eyoboglu H, Derman U (1983) The effect of coumarin derivatives on the immunological system of man. Agents Actions 13:50–52
Dexeus FH, Logothetis CJ, Sella A, Fitz K, Amato R, Reuben JM, Dozier N (1990) Phase II study of coumarin and cimetidine in patients with metastatic renal-cell carcinoma. J Clin Oncol 8:325–329
Friedman H (1981) Immunomodulating effects of cimetidine. In: Hersh EM, et al (eds) Augmenting agents in cancer therapy. Raven Press, New York, pp 417–425
Kokron O, Maca S, Gasser G, Schmidt PR (1991) Cimetidine and coumarin therapy of renal-cell carcinoma. Oncology 48:102–106
Kokron O, Baumgartner G, Theyer G, et al (1993) Randomised study in metastatic renal-cell cancer: coumarin versus coumarin+cimetidine. J Ir Coll Physicians Surg 22 [Suppl 1] 10–11
Marshall ME, Mendelsohn L, Butler K, Riley LK, Cantrell J, Har-vey J, Wiseman C, Taylor T, Macdonald JS (1987) Treatment of metastatic renal-cell carcinoma with coumarin (1,2-benzopyrone) and cimetidine: a pilot study. J Clin Oncol 5:862–866
Marshall ME, Butler K, Cantrell J, Wiseman C, Mendelsohn L (1989a) Treatment of advanced malignant melanoma with coumarin (1,2-benzopyrone) and cimetidine: a pilot study. Cancer Chemother Pharmacol 24:65–66
Marshall ME, Conley D, Hollingsworth P, Brown S Thompson JS (1989b) Effects of coumarin (1,2-benzopyrone) on lymphocyte, natural killer cell and monocyte functions in vitro. J Biol Response Mod 8:70–85
Marshall ME, Riley LK, Rhoades J, Eicchorn T, Jennings CD, Ci bull M, Thompson J (1989c) Effects of coumarin (1,2-benzopyrone) and cimetidine on peripheral blood lymphocytes, natural killer cells and monocytes in patients with advanced malignancies. J Biol Resp Mod 8:62–69
Marshall ME, Butler K, Fried A (1991a) Phase I evaluation of coumarin (1,2-benzopyrone) and cimetidine in patients with advanced malignancies. Mol Biother 3:170–178
Marshall ME, Rhoades JL, Mattingly C, Jennings CD (1991b) Coumarin (1,2-benzopyrone) enhances DR and DQ antigen expressions by peripheral blood mononuclear cells in vitro. Molec Biother 3:204–206
Marshall ME, Kervin K, Benefield C, Umerani A, Albainy-Jenei S, Zhao Q, Khazeili MB (1993) Growth inhibitory effects of coumarin (1,2-benzopyrone) and 7-hydroxycoumarin on human malignant cell lines in vitro. J Cancer Res Clin Oncol 120 [Suppl]
Moran E, Prosser E, O'Kennedy R, Thornes RD (1993) The effect of coumarin and 7-hydroxycoumarin on the growth of human tumor cell lines. Proc Internat Soc Coumarin Invest, Dublin, Ireland. J Ir Coll Physicians Surg 22 (Suppl 1]:41–43
Murray RDH, Mendez J, Brown SA (1982) The natural coumarins: Occurrence, chemistry and biochemistry. Wiley, New York
Osbard ME, Shin YJ, Shlesinger M (1981) Successful tumor immunotherapy with cimetidine in mice. Lancet I:636–639
Sakasrabudke DM, McCune CS, O'Donnell RW, Henshaw EC (1986) Inhibition of suppressor T-lymphocytes (Ts) by cimetidine. Proc Am Assoc Cancer Res 27:328
Seliger B, Pettersson H (1993) Mechanisms of action of 7-OH-coumarin on human malignant glioblastoma cell lines. (in press)
Sharifi S, Lotterer E, Michaelis HC, Bircher J (1992) Pharmaco-kinetics of coumarin and its metabolites. Preliminary results in three healthy volunteers. J Ir Coll Physicians Surg 22 [Suppl 1]:29–32
Siegers CP, Bostelmann HC (1993) Effect of coumarin on cell proliferation in human tumor cell lines. Proc Internat Soc Coumarin Invest, Dublin, Ireland. J Ir Coll Physicians Surg 22 [Suppl 1]:47–48
Stuhlmeier K, Theyer G, Baumgartner G, Zlabinger GJ (1991) Synergistic effect of coumarin (1,2-benzopyrone) and endotoxin in the induction of human interleukin-1. Clin Exp Immunol 84:317
Thornes RD, Lynch G (1983) Combination of cimetidine with other drugs for treatment of cancer. N Engl J Med 308:591–592
Thornes RD, Edlow DW, Wood S Jr (1968) Inhibition of locomotion of cancer cells in vivo by anticoagulant therapy. Effects of sodium warfarin on V2 cancer cells, granulocytes and macrophages in rabbits. Johns Hopkins Med J 123:305–316
Thornes RD, Lynch G, Sheehan MW, (1982) Cimetidine and coumarin therapy of melanoma. Lancet II:328
Zänker KS (1993) Coumarin(s) interface between cell growth inhibition, expression of oncogenes, tumour cell locomotion and cell-tocell communication. J Ir Coll Physicians Surg 22 [Suppl 1] 51–55
Zänker KS, Blumel G, Lange J, Stewart JR (1984) Coumarin in melanoma patients: an experimental and clinical study. Drugs Exp Clin Res 10:767–774
Zlabinger GJ, Bohmig G, Rosenkranz AR, Stuhlmeier KM, (1993) Intracellular signalling in coumarin-enhanced IL-1 production induced by LPS. Proceedings of the International Society for Coumarin Investigators, Dublin, Ireland. J Ir Coll Physicians Surg 22 [Suppl 1]:38–40
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Marshall, M.E., Mohler, J.L., Edmonds, K. et al. An updated review of the clinical development of coumarin (1,2-benzopyrone) and 7-hydroxycoumarin. J Cancer Res Clin Oncol 120 (Suppl 1), S39–S42 (1994). https://doi.org/10.1007/BF01377124
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DOI: https://doi.org/10.1007/BF01377124