Search
Close
Search
Advanced Search
Search Menu

Abstract

Suramin is a polysulfonated naphthylurea that inhibits the function of growth factors and growth factor receptors implicated in glioma progression, angiogenesis, and radioresistance. The safety and benefits of combining inhibitors of angiogenesis and growth factors with cytotoxic therapies in patients with neoplasms of the central nervous system remain unclear. The objectives of this phase 2 study were to determine the safety of administering suramin with standard cranial radiotherapy (RT) and to estimate survival using this approach in patients with newly diagnosed glioblastoma multiforme (GBM). Fifty-five patients with newly diagnosed GBM (Karnofsky performance status≥ 60) were enrolled in this multicenter phase 2 study. Patients received suramin by a conventional intermittent fixed-dosing regimen for 1 week prior to and during cranial RT (60 Gy in 30 fractions, weeks 2-7). Patients with stable or responsive disease at week 18 received an additional 4 weeks of suramin (weeks 19-22). The median survival for suramin-treated patients was 11.6 months, with 1-year and 18-month survival rates of 49% (95% confidence interval [CI], 36%-62%) and 18% (95% CI, 8%-28%), respectively. Overall, 55% of the patients (30/55) had greater than grade 2 toxicity at least possibly related to suramin therapy. Two patients died of possibly related neurologic events (i.e., stroke, elevated intracranial pressure). Otherwise, toxicities were generally transient and self-limited. Administration of suramin using an intermittent fixed-dosing regimen during cranial RT was generally well tolerated. However, overall survival is not significantly improved when compared with the New Approaches to Brain Tumor Therapy GBM database or other comparable patient populations.

References

Bernsen, H.J., Rijken, P.F., Peters, J.P., Bakker, J.H., Boerman, R.H., Wesseling, P., and van der Kogel, A.J. (

1999
) Suramin treatment of human glioma xenografts; effects on tumor vasculature and oxygenation status.
J. Neurooncol.
44
,
129
-136.

Butler, S.J., Kelly, E.C., McKenzie, F.R., Guild, S.B., Wakelam, M.J., and Milligan, G. (

1988
) Differential effects of suramin on the coupling of receptors to individual species of pertussis-toxin-sensitive guanine-nucleotide-binding proteins.
Biochem. J.
251
,
201
-205.

Coffey, R.J. Jr., Leof, E.B., Shipley, G.D., and Moses, H.L. (

1987
) Suramin inhibition of growth factor receptor binding and mitogenicity in AKR-2B cells.
J. Cell Physiol.
132
,
143
-148.

Coomber, B.L. (

1995
) Suramin inhibits C6 glioma-induced angiogenesis in vitro.
J. Cell Biochem.
58
,
199
-207.

Coughlin, C., Scott, C., Langer, C., Coia, L., Curran, W., and Rubin, P. (

2000
) Phase II, two-arm RTOG trial (94-11) of bischloroethyl-nitrosourea plus accelerated hyperfractionated radiotherapy (64.0 or 70.4 Gy) based on tumor volume (20 or >2 ≤20 cm, respectively) in the treatment of newly-diagnosed radiosurgery-ineligible glioblastoma multiforme patients.
Int. J. Radiat. Oncol. Biol. Phys.
48
,
1351
-1358.

Cox, D.R. (

1972
) Regression models and life-tables (with discussion).
J. R. Stat. Soc. B
34
,
187
-220.

Del Rowe, J., Scott, C., Werner-Wasik, M., Bahary, J.P., Curran, W.J., Urtasun, R.C., and Fisher, B. (

2000
) Single-arm, open-label phase II study of intravenously administered tirapazamine and radiation therapy for glioblastoma multiforme.
J. Clin. Oncol.
18
,
1254
-1259.

Eisenberger, M.A., Reyno, L.M., Jodrell, D.I., Sinibaldi, V.J., Tkaczuk, K.H., Sridhara, R., Zuhowski, E.G., Lowitt, M.H., Jacobs, S.C., and Egorin, M.J. (

1993
) Suramin, an active drug for prostate cancer: Interim observations in a phase I trial.
J. Natl. Cancer Inst.
85
,
611
-621 [erratum in J. Natl. Cancer Inst. 86, 639-640, 1994].

Galvani, A.P., Cristiani, C., Carpinelli, P., Landonio, A., and Bertolero, F. (

1995
) Suramin modulates cellular levels of hepatocyte growth factor receptor by inducing shedding of a soluble form.
Biochem. Pharmacol.
50
,
959
-966.

Grossman, S.A., Fisher, J.D., Piantadosi, S., and Brem, H. (

1998
) The New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium: Organization, objectives and activities.
Cancer Control
5
,
107
-114.

Grossman, S.A., Phuphanich, S., Lesser, G., Rozental, J., Grochow, L.B., Fisher, J., and Piantadosi, S. (

2001
) New Approaches to Brain Tumor Therapy CNS Consortium. Toxicity, efficacy, and pharmacology of suramin in adults with recurrent high-grade gliomas.
J. Clin. Oncol.
19
,
3260
-3266.

Grossman, S.A., O'Neill, A., Grunnet, M., Mehta, M., Pearlman, J.L., Wagner, H., Gilbert, M., Newton, H.B., and Hellman, R. (

2003
) Phase III study comparing three cycles of infusional carmustine and cisplatin followed by radiation therapy with radiation therapy and concurrent carmustine in patients with newly diagnosed supratentorial glioblastoma multiforme: Eastern Cooperative Oncology Group trial 2394.
J. Clin. Oncol.
21
,
1485
-1491.

Hensey, C.E., Boscoboinik, D., and Azzi, A. (

1989
) Suramin, an anti-cancer drug, inhibits protein kinase C and induces differentiation in neuroblastoma cell clone NB2A.
FEBS Lett.
258
,
156
-158.

Hosang, M. (

1985
) Suramin binds to platelet-derived growth factor and inhibits its biological activity.
J. Cell Biochem.
29
,
265
-273.

Howard, S.P., Groch, K.M., Lindstrom, M.J., Messing, E.M., and Gould, M.N. (

1995
) Proliferation-independent growth factor modulation of the radiation sensitivity of human prostate cells.
Radiat. Res.
143
,
229
-233.

Huang, S.S., and Huang, J.S. (

1988
) Rapid turnover of the platelet-derived growth factor receptor in sis-transformed cells and reversal by suramin. Implications for the mechanism of autocrine transformation.
J. Biol. Chem.
263
,
12608
-12618.

Kalbfleisch, J.D., and Prentice, R.L. (

1980
)
The Statistical Analysis of Failure Time Data
. New York: John Wiley & Sons, pp.
16
-19.

Kaplan, E.L., and Meier, P. (

1958
) Nonparametric estimation from incomplete observations.
J. Am. Stat. Assoc.
53
,
457
-481.

Langer, C.J., Ruffer, J., Rhodes, H., Paulus, R., Murray, K., Mousas, B., and Curran, W. (

2001
) Phase II Radiation Therapy Oncology Group trial of weekly paclitaxel and conventional external beam radiation therapy for supratentorial glioblastoma multiforme.
Int. J. Radiat. Oncol. Biol. Phys.
51
,
113
-119.

LaRocca, R.V., Cooper, M.R., Uhrich, M., Danesi, R., Walther, M.M., Linehan, W.M., and Myers, C.E. (

1991
) Use of suramin in treatment of prostatic carcinoma refractory to conventional hormonal manipulation.
Urol. Clin. North Am.
18
,
123
-129.

Moscatelli, D., and Quarto, N. (

1989
) Transformation of NIH 3T3 cells with basic fibroblast growth factor or the hst/K-fgf oncogene causes down-regulation of the fibroblast growth factor receptor: Reversal of morphological transformation and restoration of receptor number by suramin.
J. Cell Biol.
109
,
2519
-2527.

Myers, C., Cooper, M., Stein, C., LaRocca, R., Walther, M.M., Weiss, G., Choyke, P., Dawson, N., Steinberg, S., Uhrich, M.M., Cassidy, J., Kohler, D.R., Trepel, J., and Linehan, W.M. (

1992
) Suramin: A novel growth factor antagonist with activity in hormone-refractory metastatic prostate cancer.
J. Clin. Oncol.
10
,
881
-889.

NCI. National Cancer Institute (

1999
)
Common Toxicity Criteria version 2.0
. Available at https://webapps.ctep.nci.nih.gov/ctcv2/plsql/ctc000w$.startup.

Olson, J.J., Polk, D.M., and Reisner, A. (

1994
) The efficacy and distribution of suramin in the treatment of the 9L gliosarcoma.
Neurosurgery
34
,
297
-308.

Palayoor, S.T., Bump, E.A., Teicher, B.A., and Coleman, C.N. (

1997
) Apoptosis and clonogenic cell death in PC3 human prostate cancer cells after treatment with gamma radiation and suramin.
Radiat. Res.
148
,
105
-114.

Reyno, L.M., Egorin, M.J., Eisenberger, M.A., Sinibaldi, V.J., Zuhowski, E.G., and Sridhara, R. (

1995
) Development and validation of a pharmacokinetically based fixed dosing scheme for suramin.
J. Clin. Oncol.
13
,
2187
-2195.

Small, E.J., Meyer, M., Marshall, M.E., Reyno, L.M., Meyers, F.J., Natale, R.B., Lenehan, P.F., Chen, L., Slichenmyer, W.J., and Eisenberger, M. (

2000
) Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: Results of a randomized phase III trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone.
J. Clin. Oncol.
18
,
1440
-1450.

Takano, S., Gately, S., Engelhard, H., Tsanaclis, A.M., and Brem, S. (

1994
) Suramin inhibits glioma cell proliferation in vitro and in the brain.
J. Neurooncol.
21
,
189
-201.

Teicher, B.A., Dupuis, N.P., Robinson, M.F., Emi, Y., and Goff, D.A. (

1995
) Antiangiogenic treatment (TNP-470/minocycline) increases tissue levels of anticancer drugs in mice bearing Lewis lung carcinoma.
Oncol. Res.
7
,
237
-243.

Teicher, B.A., Holden, S.A., Ara, G., Korbut, T., and Menon, K. (

1996
) Comparison of several antiangiogenic regimens alone and with cytotoxic therapies in the Lewis lung carcinoma.
Cancer Chemother. Pharmacol.
38
,
169
-177.

Waltenberger, J., Mayr, U., Frank, H., and Hombach, V. (

1996
) Suramin is a potent inhibitor of vascular endothelial growth factor. A contribution to the molecular basis of its antiangiogenic action.
J. Mol. Cell. Cardiol.
28
,
1523
-1529.

Author notes

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231 (J.J.L., S.A.G., K.A.C);Department of Hematology and Oncology, Wake Forest University Baptist Medical Center, Winston-Salem, NC 27157 (G.J.L.);Brain Tumor Center, Massachusetts General Hospital, Boston, MA 02114 (F.H.H.); andDepartment of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030 (M.R.G.); USA

© 2004 by the Society for Neuro-Oncology
Topic:
Issue Section:
Clinical Therapy Trials—Drug
Download all slides