Investigational New Drugs

, Volume 20, Issue 2, pp 209–219

Suramin's Development: What Did we Learn?

  • Maninderjeet Kaur
  • Eddie Reed
  • Oliver Sartor
  • William Dahut
  • William D. Figg
Article

Abstract

Suramin, a polysulphonated napthylurea, has been extensively evaluatedover the past 10 years as an anticancer agent, with the most interest inthe treatment of prostate cancer. Early clinical results were promisingwith response rates of up to 70% being reported. However, a recentdouble-blind study showed only modest palliative effect in patients withandrogen independent prostate cancer. In retrospect, it appears thoseinitial reports failed to control for confounding variables such asantiandrogen withdrawal and hydrocortisone.

Suramin causes numerous reversible toxicities (lethargy, rash, fatigue,anemia, hyperglycemia, hypocalcemia, coagulopathies, neutropenia, renaland hepatic complications). Neurotoxicity has been the most significantcomplication and appears to be related to the intensity of the dosingregimen. An optimal therapeutic dose has not been determined, but it isclear that adaptive controls add little benefit.

Aside from moderate toxicities and the low therapeutic index in patientswith prostate cancer, suramin's development has taught us some valuablelessons (i.e., anti-androgen withdrawal was noted during suramin'sdevelopment, the use of PSA as an indicator of tumor burden was initiatedduring the evaluation of suramin). These lessons can be applied to allclinical trials in hormone refractory prostate cancer. Suramin hassignificantly enhanced the evolution of our knowledge in several areas ofprostate cancer biology and treatment.

prostate cancer suramin 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Armand JP, Cvitkovic E: Suramin: a new therapeutic concept. Eur J Cancer 26: 417–419, 1990Google Scholar
  2. 2.
    Walther MM, Figg WD, Lineham WM: Intravesical suramin: a novel agent for the treatment of superficial transitional-cell carcinoma of the bladder. World J Urol 14Suppl 1: S8–11, 1996Google Scholar
  3. 3.
    Eisenberger MA, Sinibaldi V, Reyno L: Suramin. Cancer Pract 3: 187–189, 1995Google Scholar
  4. 4.
    Broder S, Yarchoan R, Collins JM, Lane HC, Markham PD, Klecker RW, Redfield RR, Mitsuya H, Hoth DF, Gelmann E: Effects of suramin on HTLV-III/1AV infection presenting as Kaposi's sarcoma or AIDS-related complex: clinical pharmacology and suppression of virus replication in vivo. Lancet 2: 627–630, 1985Google Scholar
  5. 5.
    Cheson BD, Levine AM, Mildvan D, Kaplan LD, Wolfe P, Rios A, Groopman JE, Gill P, Volberding PA, Poiesz BJ: Suramin therapy in AIDS and related disorders. JAMA 258: 1347–1351, 1987Google Scholar
  6. 6.
    Armand JP: New anticancer drugs in Europe. Chin Med J 110: 297–308, 1997Google Scholar
  7. 7.
    Eisenberger MA, Fontana JA: 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 84: 3–5, 1992Google Scholar
  8. 8.
    Myers C, Cooper M, Stein C, LaRocca R, Walther MM, Weiss G, Choyke P, Dawson N, Steinberg S, Uhrich M: Suramin: a novel growth factor antagonist with activity in hormone-refractory metastatic prostate cancer. J Clin Oncol 10: 881–889, 1992Google Scholar
  9. 9.
    Stein CA, LaRocca R, Thomas R, McAtee N, Horne M, Myers CE: Suramin - an anticancer drug with a unique mechanism of action. J Clin Oncol 7: 449–508, 1989Google Scholar
  10. 10.
    Myers C, LaRocca R, Cooper M: Role of Suramin in Cancer Biology and Treatment. Baltimore, Williams and Wilkins, 1991.Google Scholar
  11. 11.
    Scher HI, Steineck G, Kelly WK: Hormone-refractory (D3) prostate cancer: refining the concept. Urology 46: 142–148, 1995Google Scholar
  12. 12.
    Eisenberger MA, Reyno LM, Jodrell DI, Sinibaldi VJ, Tkaczuk KH, Sridhara R, Zuhowski EG, Lowitt MH, Jacobs SC, Egorin MJ: Suramin, an active drug for prostate cancer: interim observations in a phase I trial. J Natl Cancer Inst 85: 611–621, 1993Google Scholar
  13. 13.
    Kobayshi K, Vokes EE, Vogelzang NJ, Janisch L, Soliven B, Ratain MJ: Phase I study of suramin given by intermittent infusion without adaptive control in patients with advanced cancer. J Clin Oncol 13: 2196–2207, 1995Google Scholar
  14. 14.
    Panvichian R, Pienta KJ: The treatment of hormone refractory prostate cancer. Compr Ther 22: 81–87, 1996Google Scholar
  15. 15.
    Small EJ, Meyer M, Marshall ME, Reyno L, Meyers F, Natale R, Meyer M, Lenehan P, Chen L, Slichenmyer WJ, Eisenberger M: Suramin therapy for patients with symptomatic hormone refractory prostate cancer; results of a phase III trial comparing suramin plus hydrocortisone to placebo plus hydrocortsone. J Clin Oncol 18(7): 1440–1450, 2000Google Scholar
  16. 16.
    Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, Figg WD, Freidlin B, Halabi S, Hudes G, Hussain M, Kaplan R, Myers C, Oh W, Petrylak DP, Reed E, Roth B, Sartor O, Scher H, Simons J, Sinibaldi V, Small EJ, Smith MR, Trump DL, Vollmer R, Wilding G: Eligibility and response guidelines for phase II clinical trials in androgen independent prostate cancer: Recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 17: 3461–3467, 1999Google Scholar
  17. 17.
    Thalmann GN, Sikes RA, Chang S, Johnston DA, VonEschenbach AC, Chung WK: Suramin-induced decrease in prostate-specific antigen expression with no effect on tumor growth in the LNCaP model of human prostate cancer. J Natl Cancer Inst 88: 174–801, 1996Google Scholar
  18. 18.
    Cooper EH, Robinson MR, Whelan P, Ferro MA: Tumor markers in prostate cancer. Cancer 70(Suppl 1): 225–229, 1992Google Scholar
  19. 19.
    Ferro MA, Barnes I, Roberts JB, Smith PJ: Tumour markers in prostatic carcinoma: a comparison of prostate specific antigens with acid phosphatase. Br J Urol 60: 69–73, 1987Google Scholar
  20. 20.
    Eisenberger MA, Nelson MA: How much can we rely on the level of prostate-specific antigen as an end point for evaluation of clinical trials? A word of caution! J Natl Cancer Inst 88: 779–781, 1996Google Scholar
  21. 21.
    Bauer KS, Figg WD, Hamilton JM, Jones EC, Premkumar A, Steinberg SM, Dyer V, Linehan WM, Pluda JM, Reed E: A pharmacokinetically guided phase II study of carboxyamidotriazole in androgen-independent prostate cancer. Clin Cancer Res 5: 2324–2329, 1999Google Scholar
  22. 22.
    Wasilenko WJ, Palad AJ, Somers KD, Blackmore PF, Kohn EC, Rhim JS, Wright GLJr., Schellhammer PF: Effects of the calcium influx inhibitor carboxyamido-triazole on the proliferation and invasiveness of human prostate tumor cell lines. Int J Cancer 68: 259–264, 1996Google Scholar
  23. 23.
    Dixon SC, Knopf KB, Figg WD: The Control of Prostate-Specific Antigen Expression and Gene Regulation by Pharmacological Agents. Pharmacol Rev 53(1): 73–92, 2001Google Scholar
  24. 24.
    Scher HI, Kelly WK: Flutamide withdrawal syndrome: its impact on clinical trials in hormone refractory prostate cancer. J Clin Oncol 11: 1566–1572, 1993Google Scholar
  25. 25.
    Figg WD, Sartor O, Cooper M, Thibault A, Bergman RC, Dawson N, Reed E, Myers CE: Prostate specific antigen decline following the discontinuation of flutamide in patients with stage D2 prostate cancer. Am J Med 98: 412–414, 1995Google Scholar
  26. 26.
    Figg WD, Middleman MN, Sartor O: Therapeutic options in patients with hormone-refractory prostate cancer. Am J Med 100: 243–244, 1996Google Scholar
  27. 27.
    Rosen PJ, Mendoza EF, Landow EM, Mondino B, Graves MC, McBride JH, Turcillo P, DeKernion J, Belldegrun A: Suramin in hormone refractory metastatic prostate cancer: a drug with limited efficacy. J Clin Oncol 14: 1626–1636, 1996Google Scholar
  28. 28.
    Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart L, Rider W: Treatment of metastatic prostate cancer with low dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol 7: 590–597, 1989Google Scholar
  29. 29.
    Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, Armitage GR, Wilson JJ, Venner RM, Coppin CM: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 14: 1756–1764, 1996Google Scholar
  30. 30.
    Sartor O, Weinberger M, Moore A, Li A, Figg WD: Effect of prednisone on prostatespecific antigen in patients with hormone-refractory prostate cancer. Urology 52: 252-256, 1998Google Scholar
  31. 31.
    Dawson NA, Cooper MR, Figg WD, Headlee DJ, Thibault A, Bergan RC, Steinberg SM, Sausville EA, Myers CE, Sartor O: Antitumor activity of suramin in hormone-refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables. Cancer 76: 453–462, 1995Google Scholar
  32. 32.
    Kelly WK, Curley T, Leibertz C, Dnistrian A, Schwartz M, Scher HI: Prospective evaluation of hydrocortisone and suramin in patient with androgen-independent prostate cancer. J Clin Oncol 13: 2208–2213, 1995Google Scholar
  33. 33.
    Eisenberger MA, Sinibaldi VJ, Reyno LM, Sridhara R, Jodrell DI, Zuhowski EG, Tkaczuk KH, Lowitt MH, Hemady RK, Jacobs SC: Phase I and clinical evaluation of a pharmacologically guided regimen of suramin in patients with hormone-refractory prostate cancer. J Clin Oncol 13: 2174–2186, 1995Google Scholar
  34. 34.
    Dawson N, Figg WD, Brawley OW, Bergman R, R CM, Senderowicz A, Headlee D, Steinberg SM, Sutherland M, Patronas N: Phase II study of suramin plus aminoglutethimide in two cohorts of patients with androgen-independent prostate cancer: simultaneous antiandrogen withdrawal and prior antiandrogen withdrawal. Clin Cancer Res 4: 37–44, 1998Google Scholar
  35. 35.
    Middleman MN, Lush RM, Sartor O, Reed E, Figg WD: Treatment approaches for metastatic cancer of the prostate based on recent molecular evidence. Cancer Treat Rev 22: 105–118, 1996Google Scholar
  36. 36.
    Dawson NA, Figg WD, Cooper MR, Sartor O, Bergan RC, Senderowicz AM, Steinberg SM, Tompkins A, Weinberger B, Sausville EA: Phase II trial of suramin, leuprolide, and flutamide in previously untreated metastatic prostate cancer. J Clin Oncol 15: 470-477, 1997Google Scholar
  37. 37.
    Hussain M, Fisher EI, Petrylak DP, O'Connor JO, Wood DP, Small EJ, Eisenberger MA, Crawford ED: Androgen deprivation and four courses of fixed-schedule suramin treatment in patients with newly diagnosed metastatic prostate cancer: a southwest oncology group study. J Clin Oncol 18: 1043–1049, 2000Google Scholar
  38. 38.
    Petrylak DP, Scher HI, Li Z, Myers CE, Geller NL: Prognostic factors for survival of patients with bidimentionally measurable metastatic hormone refractory prostatic cancer treated with single-agent chemotherapy. Cancer 70: 2870–2878, 1992Google Scholar
  39. 39.
    Berry WR, Laszlo J, Cox E, Walker A, Paulson D: Prognostic factor in metastatic and hormonally unresponsive carcinoma of the prostate. Cancer 44: 763–765, 1979Google Scholar
  40. 40.
    Garcia-Schürmann JM, Schulze H, Haupt G, Pastor J, Allolio B, Senge T: Suramin treatment in hormone-and chemotherapy-refractory prostate cancer. Urology 53: 535-541, 1999Google Scholar
  41. 41.
    Bok R, Halabi S, Shaal M, Fei D, Rodriguez C, Hayes D, Vogelzang NJ, Small EJ: VEGF and Basic FGF urine levels as predictors of response to therapy with suramin in CALGB 9480, a phase III study of hormone refractory prostate cancer (HRPC) patients. Proc Am Soc Clin Oncol 19: 1367, 2000Google Scholar
  42. 42.
    Cooper MR, Lieberman R, La Rocca RV, Gernt PR, Weinberger MS, Headlee DJ, Kohler DR, Goldspiel BR, Peck CC, Myers CE: Adaptive control with feedback strategies for suramin dosing. Clin Pharmacol Ther 52(1): 11–23, 1992Google Scholar
  43. 43.
    Voogd TE, Vansterkenberg EL, Wilting J: Recent research on the biological activity of suramin. Pharmacol Rev 45: 177–203, 1993Google Scholar
  44. 44.
    Eisenberger MA, Reyno LM: Suramin. Cancer Treat Rev 20: 259–273, 1994Google Scholar
  45. 45.
    Bitton RJ, Figg WD, Venzon DJ, Dalakak MC, Bowden C, Headlee D, Reed E, Myers CE, Cooper MR: Pharmacologic variables associated with the development of neurologic toxicity in patients treated with suramin. J Clin Oncol 13: 2223–2229, 1995Google Scholar
  46. 46.
    La Rocca RV, Meer J, Gilliatt RW, Stein CA, Cassidy J, Myers CE, Dalakas MC: Suramin-induced polyneuropathy. Neurology. 40(6): 954–960, 1990Google Scholar
  47. 47.
    Halabi S, Small EJ, Ansari RH, Wilding G, Petrylak DP, Palchak DL, Marshall E, Rago RP, Hars V, Vogelzang NJ: Results of CALB 9480, phase III trial of 3 different doses of suramin for the treatment of hormone refractory prostate cancer (HRPC). Proc Am Soc Clin Oncol 19: 1291, 2000Google Scholar
  48. 48.
    Sinibaldi VJ, Long GS, Chaudhry V, Carducci MA, Reyno LM, O'Reilly S, Chen TL, Sridhara R, Eisenberger MA: Phase I and pharmacologic evaluation of a monthly, daily times five days (d), schedule (sch) of suramin (s) in patients (pts) with hormone refractory prostate cancer (hrpc). Proc Am Soc Clin Oncol 17: 845, 1998Google Scholar
  49. 49.
    AUA: Prostate-specific antigen (PSA) best practice policy. Oncol 14: 267–286, 2000Google Scholar
  50. 50.
    Bowden CJ, Figg WD, Dawson NA, Sartor O, Bitton RJ, Weinberger MS, Headlee D, Reed E, Myers CE, Cooper MR: A phase I/II study of continuous infusion suramin in patients with hormone-refractory prostate cancer: toxicity and response. Cancer Chemother Pharmacol 39: 1–8, 1996Google Scholar
  51. 51.
    Srinivas S, Small EJ: The antiandrogen withdrawal syndrome: experience in a large cohort of unselected advanced prostate cancer patients. Proc Amer Urol Assoc 153: 448, 1995Google Scholar
  52. 52.
    Herrada J, Dieringer P, Logothetis CJ: Characterization of patients with androgenindependent prostatic carcinoma whose serum prostate specific antigen decreased following flutamide withdrawal. J Urol 155: 620–623, 1996Google Scholar
  53. 53.
    Reyno LM, Egorin MJ, Eisenberger MA, Sinibaldi VJ, Zuhowski EG, Sridnara R: Development and validation of a pharmacokinetically based fixed dosing scheme for suramin. J Clin Oncol 13: 2187–2195, 1995Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Maninderjeet Kaur
    • 1
  • Eddie Reed
    • 2
  • Oliver Sartor
    • 2
  • William Dahut
    • 3
  • William D. Figg
    • 4
  1. 1.Molecular Pharmacology Section, Cancer Therapeutic Branch, Center for Cancer ResearchNational Cancer Institute, National Institute of HealthBethesdaUSA
  2. 2.Mary Babb Randolph Cancer CenterWest Virginia UniversityMorgantownUSA
  3. 3.Stanley Scott Cancer CenterLouisiana State UniversityNew OrleansUSA
  4. 4.Molecular Pharmacology Section, Cancer Therapeutic Branch, Center for Cancer ResearchNational Cancer Institute, National Institute of HealthBethesdaUSA

Personalised recommendations