Paper| Volume 30, ISSUE 11, P1670-1674, 1994

Download started.


In vitro sequence-dependent synergistic effect of suramin and camptothecin

      This paper is only available as a PDF. To read, Please Download here.


      Suramin, a hexasulphonated naphthylurea with activity in prostatic cancer, possesses a wide variety of antitumour mechanisms of action, one of which is the inhibition of topoisomerase II. In this in vitro study, suramin was combined with the topoisomerase I inhibitor, camptothecin. Several suramin concentrations (0.2–3000 μM) were combined with camptothecin (0.4 pM-20 μM) in MCF-7 and PC3 human cancer cell line cultures. In addition, we studied the topoisomerase II and I gene expression by northern blot analysis, and the cell cycle distribution by flow cytometry, after exposure to suramin. While there was only an additive effect when suramin and camptothecin were added simultaneously, a remarkable synergism was obtained when camptothecin was added after a 3-day exposure to suramin. Topoisomerase II and I gene expression and the number of cells in S phase were significantly reduced after exposure to suramin. In conclusion, interaction of suramin with camptothecin is schedule-dependent can be synergistic. These findings might help in identifying optimal combinations of suramin or other topoisomerase II inhibitors, with topoisomerase I inhibitors.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Berenbaum M.C.
        What is synergy?.
        Pharmacol Rev. 1989; 41: 93-141
        • LaRocca R.V.
        • Stein C.A.
        • Myers C.E.
        Suramin: prototype of a new generation of antitumor compounds.
        Cancer Cells. 1990; 2: 106-115
        • Taylor C.W.
        • Lui R.
        • Fanta P.
        • Salmon S.E.
        Effects of suramin on in vitro growth of fresh human tumors.
        J Natl Cancer Inst. 1992; 84: 489-494
        • Vignon F.
        • Prebois C.
        • Rochefort H.
        Inhibition of breast cancer growth by suramin.
        J Natl Cancer Inst. 1992; 84: 38-42
        • Bojanowski K.
        • Lelievre S.
        • Markovits J.
        • Couprie J.
        • Jacquemin-Sablon A.
        • Kragh Larsen A.
        Suramin is an inhibitor of DNA topoisomerase II in vitro in Chinese hamster fibrosarcoma cells.
        in: Proc Natl Acad USA. 89. 1992: 3025-3029
        • Liu L.F.
        DNA topoisomerase poisons as antitumor drugs.
        Annu Rev Biochem. 1989; 58: 351-375
        • Stein C.A.
        • LaRocca R.V.
        • Thomas R.
        • McAtee N.
        • Myers C.E.
        Suramin: an anticancer drug with a unique mechanism of action.
        J Clin Oncol. 1989; 7: 499-508
        • Motzer R.J.
        • Nanus D.M.
        • O'Moore P.
        • et al.
        Phase II trial of suramin in patients with advanced renal cell carcinoma: treatment results, pharmacokinetics, and tumor growth factor expression.
        Cancer Res. 1992; 52: 5775-5779
        • van Rijswijk R.E.N.
        • van Loenen A.C.
        • Wagstaff J.
        • et al.
        Suramin: rapid loading and weekly maintenance regimens for cancer patients.
        J Clin Oncol. 1992; 10: 1-5
        • Horwitz S.B.
        • Chang C.S.C.K.
        • Grollman A.P.
        Studies on camptothecin: I. Effects on nucleic acid and protein synthesis.
        Mol Pharmacol. 1971; 7: 632-644
        • Slichenmyer W.J.
        • Rowinsky E.K.
        • Donehouwer R.C.
        • et al.
        The current status of camptothecin analogues as antitumor agents.
        J Natl Cancer Inst. 1993; 85: 271-291
        • Tsuruo T.
        • Matsuzaki T.
        • Matsushita M.
        • et al.
        Anti-tumor effect of CPT-11, a new derivative of camptothecin, against pleiotropic drug-resistant tumours in vitro.
        Cancer Chemother Pharmacol. 1988; 21: 71-74
        • Kaufmann S.H.
        Antagonism between camptothecin and topoisomerase II-directed chemotherapeutic agents in a human leukemia cell line.
        Cancer Res. 1991; 51: 1129-1136
        • D'Arpa P.
        • Beardmore C.
        • Liu L.F.
        Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons.
        Cancer Res. 1990; 50: 6919-6924
        • Bertrand R.
        • O'Connor P.M.
        • Kerrigan D.
        • Pommier Y.
        Sequential administration of camptothecin and etoposide circumvents the antagonistic cytotoxicity of simultaneous drug administration in slowly growing human colon carcinoma HT-29 cells.
        Eur J Cancer. 1992; 28A: 743-748
        • Eisenberger M.A.
        • Fontana J.A.
        Suramin, an active nonhormonal cytotoxic drug for treatment of prostate cancer: compelling reasons for testing in patients with hormone-refractory breast cancer.
        J Natl Cancer Inst. 1992; 84: 3-5
        • Skehan P.
        • Storeng P.
        • Scudiero D.
        • et al.
        New colorimetric cytotoxicity assay for anticancer-drug screening.
        J Natl Cancer Inst. 1990; 82: 1113-1118
        • Keepers Y.P.
        • Pizao P.E.
        • Peters G.J.
        • et al.
        Comparison of the sulforhodamine B protein and the tetrazolium (MTT) assays for in vitro chemosensitivity testing.
        Eur J Cancer. 1991; 27: 897-900
        • Chou T.C.
        • Talalay P.
        Quantitative analysis of dose-effect relationship: the combined effects of multiple drugs on enzyme inhibitors.
        in: Weber G. Advance in Enzyme Regulation. Pergamon Press, New York1983: 27-55
        • Davis L.G.
        • Dibner M.D.
        • Battey J.F.
        New Methods in Molecular Biology.
        in: Elsevier Science Publishing, New York1983: 27-55
        • Tsai-Pflugfelder M.
        • Liu L.F.
        • Liu A.A.
        Cloning and sequencing of DNA encoding human DNA topoisomerase II and localization of the gene to chromosome region 17q21-22.
        in: Proc Natl Acad Sci USA. 85. 1988: 7177-7181
        • Juan C.C.
        • Hwang J.
        • Liu A.A.
        • Whang-Peng J.
        • et al.
        Human DNA topoisomerase I is encoded by a single-copy gene that maps to chromosome region 20q12-13.2.
        in: Proc Natl Acad Sci USA. 85. 1988: 8910-8913
        • Fort P.
        • Marty L.
        • Piechaczyk M.
        • et al.
        Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family.
        Nucleic Acids Res. 1985; 13: 1431-1442
        • Lopez-Lopez R.
        • Peters G.J.
        • Loenen A.C.van
        • et al.
        The effect of schedule, protein binding and growth factors on the activity of suramin.
        Int J Cancer. 1992; 51: 921-926
        • Myers C.
        • Cooper M.
        • Stein C.
        • et al.
        Suramin: a novel growth factor antagonist with activity in hormone-refractory metastatic prostate cancer.
        J Clin Oncol. 1992; 10: 881-889
        • Fruehauf J.P.
        • Myers C.E.
        • Sinha B.K.
        Synergistic activity of suramin with tumor necrosis factor α and doxorubicin on human prostate cancer cell lines.
        J Natl Cancer Inst. 1990; 82: 1206-1209
        • Stein C.A.
        Suramin: a novel antineoplastic agent with multiple potential mechanisms of action.
        Cancer Res. 1993; 53: 2239-2248
        • Li L.H.
        • Fraser T.J.
        • Olin E.J.
        • Bhuyan B.K.
        Action of camptothecin on mammalian cells in culture.
        Cancer Res. 1972; 32: 2643-2650
        • Karato A.
        • Sasaki Y.
        • Shinkai T.
        • et al.
        Phase I study of CPT-II and etoposide in patients with refractory solid tumors.
        J Clin Oncol. 1993; 11: 2030-2035
        • Anzai H.
        • Fost P.
        • Abbruzzese J.L.
        Synergistic cytotoxicity with 2′-deoxy-5-azacytidine and topotecan in vitro and in vivo.
        Cancer Res. 1992; 52: 2180-2185