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Journal of Clinical Oncology, Vol 19, Issue 13 (July), 2001: 3260-3266
© 2001 American Society for Clinical Oncology

Toxicity, Efficacy, and Pharmacology of Suramin in Adults With Recurrent High-Grade Gliomas

By Stuart A. Grossman, Surasak Phuphanich, Glenn Lesser, Jack Rozental, Louise B. Grochow, Joy Fisher, Steven Piantadosi, for the New Approaches to Brain Tumor Therapy CNS Consortium

From the Johns Hopkins Oncology Center, Baltimore, MD; Moffitt Cancer Center, Tampa, FL; Wake Forest University, Winston-Salem, NC; and Northwestern University, Chicago, IL.

Address reprint requests to Stuart A. Grossman, MD, The Johns Hopkins Oncology Center, 1650 Orleans St, Rm G93, Baltimore, MD 21231; email: grossman{at}jhmi.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To determine the toxicity, efficacy, and pharmacology of suramin in patients with recurrent or progressive recurrent high-grade gliomas.

PATIENTS AND METHODS: Fifty adults were to receive suramin. However, if no responses were seen in the first ten patients, the study was to be terminated. A total of 12 patients were enrolled onto this trial. Ten patients had glioblastoma multiforme, and 11 had received prior nitrosoureas.

RESULTS: Drug-related toxicities were modest and reversible. Three patients developed grade 3 to 4 neutropenia, constipation, diarrhea, or nausea. No CNS bleeding was observed. Median time to progression was 55 days (range, 17 to 242 days) and median survival was 191 days (range, 42 to 811 days). No partial or complete responses were seen at 12 weeks. However, the clinical outcome of three patients suggests that evidence of suramin activity may be delayed. One patient who "progressed" after 12 weeks of suramin had a subsequent marked reduction in tumor size and has maintained an excellent partial response for over 2 years without other therapy. Two others had disease stabilization and lived for 16 and 27 months. Pharmacokinetics from 11 patients revealed that all reached target suramin concentrations.

CONCLUSION: This study demonstrates that suramin is well tolerated by patients with recurrent high-grade gliomas and may have efficacy in this disease. Its pharmacology seems unaffected by anticonvulsants. As a result of this data, suramin and radiation are now being administered concurrently to patients with newly diagnosed glioblastoma multiforme, with survival as the primary outcome.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
SURAMIN IS A polysulfonated napthylurea that was originally developed as a treatment for African trypanosomiasis and later found useful in the treatment of onchocerciasis. There was renewed interest in this drug when it was found to inhibit platelet-derived growth factor and fibroblast growth factor, thereby antagonizing their proliferative and transforming interactions with cellular receptors.1-6 However, suramin is a complex drug that has many other potential mechanisms of action, including potent inhibition of angiogenesis and of oxidative metabolism in mitochondria.7,8 Clinical trials have demonstrated that suramin has modest antineoplastic activity in hormone-refractory prostate cancer,9-15 and it has also been studied in follicular lymphoma, renal cell cancer, breast cancer, ovarian cancer, and AIDS.16-21

Initial trials of suramin in patients with malignancies were associated with severe fatigue, malaise, lethargy, sensory-motor neurotoxicity, adrenal insufficiency, anemia, lymphopenia, and a coagulopathy that resulted in occasional CNS bleeding.22-24 These toxicities are now known to result from excessively high suramin levels. Suramin has an extremely long half-life, and repetitive dosing results in drug accumulation. The use of modified dosing schedules has shown that maintaining plasma suramin levels between 100 and 300 µg/mL dramatically reduces the toxicities of suramin without compromising antineoplastic activity in patients with prostate cancer.25-27

Novel therapeutic approaches are needed for patients with high-grade gliomas, because standard chemotherapeutic agents have limited activity in this malignancy. These tumors are associated with extensive neovascularization, which could be an excellent target for antiangiogenesis agents. The study reported here was designed to evaluate the toxicity, efficacy, and pharmacology of suramin in patients with recurrent high-grade gliomas. The primary concerns in administering suramin to patients with recurrent high-grade gliomas relate to the coagulopathy and neurotoxicity reported with this agent. Patients with these tumors may bleed spontaneously into their brain tumors and have a high incidence of thromboembolic disease.28-30 In addition, they have existing neurologic deficits from the brain tumor, surgery, and associated brain edema and have received cranial irradiation. Another important aspect of this trial relates to the recently described impact of P450-inducing anticonvulsant drugs on the pharmacology of antineoplastic agents.31-33 A standard prostate cancer dosing regimen for suramin was used to assess the toxicity, and the pharmacology of suramin and volumetric response criteria were used to judge the efficacy of this novel antiangiogenesis agent in patients with recurrent high-grade gliomas.25


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This study was conducted by the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium, which is funded by the National Cancer Institute.34 Participating institutions included The Johns Hopkins Oncology Center, Moffitt Cancer Center, Wake Forest University, and Northwestern University. This clinical research protocol was reviewed by the Cancer Therapy Evaluation Program at the National Cancer Institute and approved by the institutional review boards of all participating institutions. Informed consent was obtained from each patient who joined this research study. All patients eligible for this study were registered through the NABTT Consortium’s Central Operations Office in Baltimore, MD.

Patient Population
Patients were eligible for this study if they were over the age of 18 years, had a life expectancy of greater than 2 months, were able to give informed consent, and were able to understand the investigational nature of the study and its potential risks and benefits. In addition, they were required to have the following: histologically proven glioblastoma multiforme or anaplastic astrocytoma; progressive disease after treatment with radiation therapy; measurable disease on computed tomographic (CT) or magnetic resonance imaging (MRI) scans; a Karnofsky performance status score of 60 or higher; a 4-week interval since their last antineoplastic therapy (hormone therapy, radiation therapy, or chemotherapy) unless this contained a nitrosourea or mitomycin, in which case a 6-week delay was required; no more than two prior chemotherapy regimens; adequate bone marrow (platelet count > 100,000; hemoglobin level > 9 g/dL; and absolute neutrophil count > 1,500/µL), renal (creatinine < 1.5 mg/dL, creatinine clearance < 70 mg/dL, or blood urea nitrogen < 50 mg/dL), and hepatic function (albumin > 3.0 g/dL; bilirubin < 2.0 mg/dL; and AST < two times the normal limit); normal coagulation parameters (prothrombin time and partial thromboplastin time within normal range); a negative pregnancy test; and a willingness to use appropriate birth control measures. Patients were ineligible if they were receiving concurrent anticoagulants or other investigational agents, or had a history of disseminated intravascular coagulation, bleeding disorder, venous thrombosis requiring coumadin, prior intracranial or intratumoral hemorrhage, a serious active infection, or other medical problem that would interfere with survival, protocol therapy, or evaluation of response.

Drug Administration and Toxicity Assessment
Suramin was administered in a manner identical to that used in patients with prostate cancer.25 The first and second cycles of suramin were given at doses shown in Table 1. The second course of suramin was administered 12 weeks after completion of the first cycle if the patient was stable or responding and had not experienced untoward side effects. Cycle 2 used a lower dose of suramin on day 1 (750 mg/m2 instead of 1,100 mg/m2) and lasted 4 weeks instead of 12. The National Cancer Institute’s common toxicity criteria were used to quantify suramin toxicities. Suramin administration was postponed if a patient developed grade 3 or 4 suramin-related nonhematologic toxicities or grade 2 CNS or peripheral neurosensory toxicities. Treatment was resumed if toxicity resolved within 2 weeks. Suramin was permanently discontinued if a patient’s toxicities did not resolve within 2 weeks, if the patient developed a venous thrombosis requiring anticoagulation, or if there was evidence of tumor progression as defined by the NABTT CNS Consortium’s response criteria. Lifetime cortisone replacement began on day 1 of suramin therapy. This consisted of 25 mg every morning and 12.5 mg every evening, which was increased to 75 mg every morning and 25 mg every evening when stress doses were required. Patients were also instructed to wear a Med-Alert bracelet stating that they had adrenal insufficiency.


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  		Table 1. Suramin Dosing Schedule
 
Response Assessment
The primary objective of this study was to determine the percentage of patients with a complete or partial response, stable disease, or disease progression. Volumetric MRI or CT scans were obtained monthly and the NABTT CNS Consortium’s standard response criteria were used for this purpose. In order to qualify as a response, this was required to persist for least 4 weeks. A complete response required disappearance of all tumors on MRI/CT scan in a patient who was not receiving glucocorticoids (except for the required replacement corticosteroids) with a stable or improving neurologic examination. A partial response required a 50% or greater reduction in contrast-enhancing volume on a stable or decreasing dose of glucocorticoids, along with a stable or improving neurologic examination. Progressive disease required progressive neurologic abnormalities or more than 25% increase in the volume of the tumor by MRI/CT scans. If the patient had less than a 25% increase in tumor volume with worsening of his neurologic status on a stable or increasing dose of corticosteroids, or if new lesions appeared on serial MRI/CT, further chemotherapy was discontinued. Patients with stable disease were those whose clinical status and tumor volumes did not meet the above criteria for partial response or progressive disease.

Pharmacokinetics
Plasma was collected for pharmacokinetic purposes immediately before and after the suramin on days 1, 4, 8, 22, 57, and 78 during the first cycle of therapy. The sampling schedule was the same during the second cycle of therapy but occurred only on days 1, 4, 8, 22, and 29. Additional samples were obtained at 1, 2, and 3 months after treatment and every 3 months thereafter, where possible. The blood samples were taken from the arm opposite the suramin infusion and rapidly centrifuged. The plasma was harvested and frozen at -20°C in a labeled plastic tube. Pharmacokinetic analysis was performed as previously reported.25-27 Suramin was released from plasma by deproteinizing the plasma protein with tetrabutylammonium hydrogen sulfate and methanol. Suramin concentrations were then quantified using liquid chromatography with an ultraviolet spectrophotometer and O-tolythiourea as an internal standard.

Statistical Considerations
The primary objective of this study was to estimate the response rate to suramin. A response rate of 25% was considered one that might warrant further evaluation. A total of 50 patients were required to estimate this response rate with a precision of 15% (95% confidence limits). The study was to be terminated if none of the first 10 patients achieved at least a partial response. This would allow us to be 95% certain that the true response rate is less than 25%. It was also to be terminated if any of the first 13 patients developed severe toxicities from suramin.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Population
A total of 12 adults with recurrent high-grade gliomas were entered onto this study. The details of each patient’s histologic diagnosis, age, Karnofsky performance status, anticonvulsant therapy, and prior chemotherapy are outlined in Table 2. The median age of these patients was 55 years (range, 26 to 67 years). Their median Karnofsky performance status score was 80 (range, 70 to 100). Ten patients had recurrent glioblastoma multiforme. One had a recurrent anaplastic astrocytoma, and one had a mixed anaplastic astrocytoma/oligodendroglioma. All patients had undergone surgery at least once, and many had had multiple surgical procedures. All patients had received prior radiation therapy. One patient had received no prior chemotherapy, seven had received one prior chemotherapy regimen, and four had received two prior chemotherapy regimens. Eleven patients had received prior nitrosoureas.


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  		Table 2. Patient Characteristics
 
Toxicities
The observed suramin-related toxicities in this patient population were modest and reversible. Three patients developed transient grade 3 to 4 toxicities. Patient no. 1 had grade 4 neutropenia and grade 3 leukopenia. Patient no. 2 had grade 3 creatinine elevation and grade 4 diarrhea. Patient no. 12 had grade 3 nausea and grade 4 constipation. No coagulopathy or CNS bleeding was observed.

Efficacy
Neuroimaging studies were repeated and response determinations were conducted after 12 weeks of therapy, as specified in the protocol. No partial or complete responses were seen at the 12-week point. The median time to progression was 55 days (range, 17 to 242 days). The median survival from the time patients received their first suramin was 191 days (range, 42 to 811 days) (Fig 1). As defined in the statistical section of this protocol, accrual was halted when 10 consecutive patients failed to respond to therapy. By the time the 10th patient was assessable for response, a total of 12 patients had been enrolled onto this study. The survival curve for all patients on this study is presented in Fig 2. Despite the lack of responses after 12 weeks of therapy, the clinical outcome in three (25%) of the 12 patients suggests that suramin may have efficacy in patients with recurrent high-grade gliomas.



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  		Fig 1. Survival curve for all patients (N = 12) from date of first administration of suramin. Eleven patients died; the median survival time was 191 days.

 


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  		Fig 2. Serial MRI scans from patient no. 3: (A) before suramin, February 1998; (B) progressive disease after 12 weeks of suramin, June 1998; and follow-up scans, (C) July 1998; (D) August 1998; (E) October 1998; and (F) January 1999.

 
Patient no. 1. A 42-year-old woman presented in 1984 with a mixed oligoastrocytoma. She underwent surgery and radiation therapy and did well until 1991, when she had clinical and radiologic progression. She had a biopsy of the recurrent brain tumor, and the pathologic analysis revealed a malignant glioma with features of anaplastic astrocytoma, anaplastic oligodendroglioma, and a focus of pseudopalisading necrosis and vascular proliferation. She was treated with three cycles of procarbazine, lomustine, and vincristine but had no response. In 1992, she had additional radiation therapy to the right frontal lobe. In 1995, she had tumor progression outside of this radiation field and began suramin in September 1995. Twelve weeks after completion of suramin, a re-evaluation revealed radiologic and clinical progression. The patient and family declined further therapy. She was placed in a nursing home where she remained stable without any further antineoplastic therapy and died 811 days after beginning suramin.

Patient no. 2. A 50-year-old man presented in October 1996 with a glioblastoma multiforme. He was treated with surgery and external-beam radiotherapy. In June 1997 he underwent stereotactic radiosurgery for a recurrence. By September 1997 he had further tumor progression and was started on suramin. His scans subsequently stabilized, and he lived 479 days from the time suramin was initiated without further surgery, radiation, or chemotherapy.

Patient no. 3. A 26-year-old man presented with a grand mal seizure in October 1996. Needle biopsy of a large contrast-enhancing mass was diagnostic for an anaplastic astrocytoma. He completed radiation therapy in January 1997 but required debulking surgery in March 1997 for progressive disease. Gliadel wafers (Aventis Pharmaceuticals, Bridgewater, NJ) were inserted at surgery, but by September 1997, the tumor again began to progress. He received two cycles of procarbazine, lomustine, and vincristine chemotherapy, but repeat imaging in December 1997 revealed progressive disease. He underwent a third partial surgical debulking, and the pathologic analyses revealed progressive high-grade astrocytoma. In February 1998, treatment with suramin was begun. His presuramin MRI scan is shown in Fig 2, panel 1. After 12 weeks of therapy, the suramin was discontinued in June 1998 because of worsening of his disease (Fig 2, panel 2). As he was asymptomatic and not receiving dexamethasone, he was followed closely and scanned every 2 to 3 months without further therapy. His MRI scans have revealed gradual but persistent tumor shrinkage since June 1998, as shown in a scan from April 1999 (Fig 2, panel 6). As of August 2000, 29 months since beginning his suramin, he remains clinically well, and his scans have continued to improve. He has received no additional antineoplastic therapy or glucocorticoids.

Pharmacokinetics
Pharmacokinetic data were available on 11 of the 12 patients. Target serum concentrations of 100 to 300 µg/mL were achieved in each of these patients (Fig 3, A and B). Nine of 11 patients were receiving P450-inducing anticonvulsants. Their suramin levels did not seem appreciably different than those of the patients who were not receiving P450-inducing anticonvulsants or patients previously reported to have received suramin for prostate cancer.25-27



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  		Fig 3. Suramin pharmacokinetics: suramin levels in plasma for (A) patients no. 1 through 6 and (b) patients no. 7 through 11.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Antiangiogenesis agents represent a unique class of agents with considerable potential to improve the outcome for patients with cancer. Primary brain tumors have been considered excellent testing ground for these novel agents, because the tumors are highly vascular and there are no other effective therapies.35,36 To date, thalidomide and SU101 have been studied in this patient population with limited success.37-39 Suramin has demonstrated efficacy in primary brain tumors using in vitro methods.40-44 In addition, the compound has been shown, using quantitative autoradiography techniques in animal models, to enter intracranial tumors.43,45 This was not unexpected, given the neurotoxicity seen in patients with prostate cancer treated with suramin. Furthermore, preliminary data suggest that the response to suramin correlates with the intensity and staining of platelet-derived growth factor in human high-grade gliomas.46

This study demonstrates that suramin is well tolerated by patients with recurrent high-grade gliomas. Overall, the observed drug-related toxicities in these patients were mild and reversible. No significant neurotoxicity or bleeding into the CNS or brain tumor was observed. Furthermore, there was no evidence to suggest that suramin triggers a coagulopathy in these patients who have an increased risk of thromboembolic disease.

In addition, this study demonstrates that suramin pharmacology seems to be unaffected by P450-inducing anticonvulsants. Recent studies have demonstrated that phenobarbital, phenytoin, and carbamazepine can dramatically affect the metabolism and serum levels of paclitaxel, 9-aminocamptothecan, and irinotecan.31-33 This can lead to subtherapeutic levels and can compromise the evaluation of efficacy in studies of novel agents in patients with primary brain tumors. However, this does not seem to be an issue in the evaluation of suramin in this patient population.

The formal evaluation of efficacy in this phase II study was designed using a standard chemotherapy algorithm. After 12 weeks of therapy, a repeat CT or MRI scan was obtained, and if no responses were seen in the first 10 patients, the study was to be closed and the agent considered ineffective. If responses were seen, a total of 50 patients were to have been accrued to estimate the true response rate. This study was closed early as no complete or partial responders were seen at the 12-week evaluation point specified by the protocol. However, three patients, 25% of those entered onto trial, may have benefitted from suramin. Each had late clinical stabilization or improvement of their scans and lived over 400 days after the initiation of suramin. Two of these patients were relatively young, and one had an oligodendroglial component. These may have contributed to their survival time after receiving suramin. Nevertheless, it is possible that suramin has efficacy in high-grade gliomas, but responses may take months to become evident.

In reality, a noncytotoxic agent, such as suramin, is likely to be overwhelmed by a fully vascularized, rapidly recurring, high-grade astrocytoma. Survival in this situation is limited, and these agents do not work immediately. Even in patients with benign hemangiomas that ultimately respond to antiangiogenesis therapy, responses are often seen many months after the therapy is initiated.47 Furthermore, laboratory studies suggest that antiangiogenesis agents are most effective when coupled with other antineoplastic therapies.48 Thus, the study design used in this protocol provided needed information on the toxicity and pharmacology of suramin, but was probably suboptimal in providing accurate information on the efficacy of this cytostatic agent in high-grade gliomas. The toxicity and pharmacology data provided by this study and the potential efficacy seen in three patients has led the NABTT CNS Consortium to conduct another study of suramin that should be more instructive. This phase II study will include 50 patients with newly diagnosed glioblastoma multiforme who will receive suramin and radiation concurrently. Survival, rather than response, will be the primary study end point and this will be compared to the NABTT Glioblastoma Database.49 This study design has several distinct advantages. First, the radiation should allow patients to live long enough to derive a benefit from this cytostatic therapy if it has activity in this disease. Second, the suramin will be administered with radiation therapy, which has the potential to exert a synergistic effect. Finally, the end point is more appropriate for an antiangiogenesis inhibitor as cytostatic agents may not yield responses in 12 weeks. This trial design is also being used by the NABTT CNS Consortium for other noncytotoxic agents in an effort to determine whether these agents can improve survival in patients with glioblastoma multiforme.


   ACKNOWLEDGMENTS
 
The New Approaches to Brain Tumor Therapy CNS Consortium is funded by National Cancer Institute grant no. UO1-CA62475.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Hosang M: Suramin binds to platelet-derived growth factor and inhibits its biological activity. J Cell Biochem 29: 265-273, 1985[Medline]

2. Huang SS, Huang JS: 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, 1988[Abstract/Free Full Text]

3. Betsholtz C, Johnsson A, Heldin CH, et al: Efficient reversion of simian sarcoma virus-transformation and inhibition of growth-factor-induced mitogenesis by suramin. Proc Natl Acad Sci U S A 83: 6440-6444, 1986[Abstract/Free Full Text]

4. Coffey R, Leof E, Shipley G, et al: Suramin inhibition of growth factor receptor binding and mitogenicity in AKR-2B cells. J Cell Physiol 132: 143-148, 1987[Medline]

5. Rifkin DB, Moscatelli D: Recent developments in the cell biology of basic fibroblast growth factor. J Cell Biol 109: 1-6, 1989[Free Full Text]

6. Moscatelli D, Quarto N: Transformation of NIH-3T3 cells with basic fibroblast growth factor of the hst/K-fgf oncogene causes downregulation of the fibroblast growth factor receptor: Reversal of morphological transformation and restoration of receptor number by suramin. J Cell Biol 109: 2519-2527, 1989[Abstract/Free Full Text]

7. Hensey CE, Boscoboinik D, Azzi A: Suramin, anti-cancer drug, inhibits protein kinase C and induces differentiation in neuroblastoma cell clone NB2A. FEBS Lett 258: 156-158, 1989[Medline]

8. Butler SJ, Kelly EC, McKenzie FR, et al: Differential effects of suramin on the coupling of receptors to individual species of pertussis-toxin sensitive quanine-nucleotide-binding proteins. Biochem J 251: 201-205, 1988[Medline]

9. Small EJ, Meyer M, Marshall ME, et al: 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, 2000[Abstract/Free Full Text]

10. Dawson NA, Cooper MR, Figg WD, et al: Antitumor activity of suramin in hormone-refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables. Cancer 76: 453-462, 1995[Medline]

11. Garcia-Schurmann JM, Schurlze H, Haupt G, et al: Suramin treatment in hormone- and chemotherapy-refractory prostate cancer. Urology 53: 535-541, 1999[Medline]

12. Eisenberger MA, Reyno LM, Jodrell DI, et al: Suramin, an active drug for prostate cancer: Interim observations in a phase I trial. J Natl Cancer Inst 85: 611-621, 1993[Abstract/Free Full Text]

13. Hussain M, Fisher EI, Petrylak DP, et al: 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, 2000[Abstract/Free Full Text]

14. LaRocca RV, Cooper MR, Uhrich M, et al: Use of suramin in treatment of prostatic carcinoma refractory to conventional hormonal manipulation. Urol Clin North Am 18: 123-129, 1991[Medline]

15. Myers CE, Cooper MR, LaRocca RV, et al: Suramin: A novel growth factor antagonist with activity in hormone-refractory metastatic prostate cancer. J Clin Oncol 10: 881-889, 1992[Abstract]

16. Arbuck SG, Sorensen JM, Christian MC, et al: New drugs in non-Hodgkin’s lymphoma. Ann Oncol Suppl 1: 119-128, 1997

17. LaRocca RV, Myers CE, Stein CA, et al: Effect of suramin in patients with refractory nodular lymphomas requiring systemic therapy. Proc Am Soc Clin Oncol 9: 268a, 1990 (abstr 1041)

18. Westermann AM, Dubbelman R, Basars JP, et al: Feasibility and pharmacokinetics of intraperitoneal suramin in advanced malignancy. Cancer Chemother Pharmacol 46: 57-62, 2000[Medline]

19. Gradishar WJ, Soff G, Liu J, et al: A pilot trial of suramin in metastatic breast cancer to assess antiangiogenic activity in individual patients. Oncology 58: 324-333, 2000[Medline]

20. Dreicer R, Smith DC, Williams RD, et al: Phase II trial of suramin in patients with metastatic renal cell carcinoma. Invest New Drugs; 17: 183-186, 1999[Medline]

21. Cheson BD, Levine AM, Mildvan D, et al: Suramin therapy in AIDS and related disorders: Report of the US Suramin Working Group. JAMA 258: 1347-1351, 1987[Abstract]

22. Tracy JW, Webster LT: Drugs used in the chemotherapy of protoczoal infections, in Hardman JG, Limbird LE, Molinoff PB, et al (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics. New York, NY, McGraw-Hill, 1996, pp 1003-1004

23. Broder S, Yarchoan R, Collins JM, et al: Effects of suramin on HTLV-III/LAV infection presenting as Kaposi’s sarcoma or AIDS-related complex: Clinical pharmacology and suppression of virus replication in vivo. Lancet 2: 627-630, 1985[Medline]

24. Collins JM, Klecker RW, Yarchoan R, et al: Clinical pharmacokinetics of suramin in patients with HTLV-III/LAV infection. J Clin Pharmacol 26: 22-26, 1986[Abstract]

25. Reyno LM, Egorin MJ, Eisenberger MA, et al: Development and validation of a pharmacokinetically based fixed dosing scheme for suramin. J Clin Oncol 13: 2187-2195, 1995[Abstract/Free Full Text]

26. Scher HI, Jodrell DI, Iversen JM, et al: Use of adaptive control with feedback to individualize suramin dosing. Cancer Res 52: 64-70, 1992[Abstract/Free Full Text]

27. Jodrell DI, Reyno LM, Sridhara R, et al: Suramin: Development of a population pharmacokinetic model and its use with intermittent short infusions to control plasma drug concentration in patients with prostate cancer. J Clin Oncol 12: 166-175, 1994[Abstract]

28. Vukovich TC, Gabrief A, Schaeffer B, et al: Hemostasis activation in patients undergoing brain tumor surgery. J Neurosurg 87: 508-511, 1997[Medline]

29. Dhami MS, Bona RD, Calogero JA, et al: Venous thromboembolism and high grade gliomas. Thromb Haemost 70: 393-396, 1993[Medline]

30. Norris L, Grossman SA: Treatment of thromboembolic complications in patients with primary brain tumors. J Neurooncol 22: 127-137, 1994[Medline]

31. Fetell MR, Grossman SA, Fisher J, et al: Preirradiation paclitaxel in glioblastoma multiforme: Efficacy, pharmacology, and drug interactions. J Clin Oncol 15: 3121-3128, 1997[Abstract]

32. Grossman SA, Hochberg F, Fisher JD, et al: Increased 9-aminocamptothecin requirements in patients on anticonvulsants. Cancer Chemother Pharmacol 42: 118-126, 1998[Medline]

33. Gilbert MR, Supko J, Grossman SA, et al: Dose requirements, pharmacology, and activity of CPT-11 in patients with recurrent high-grade glioma: A NABTT CNS Consortium trial. Proc Am Soc Clin Oncol 19: 616a, 2000 (abstr 622)

34. Grossman SA, Brem H, Piantadosi S, et al: The NABTT CNS Consortium: Organization, objectives, and progress. Cancer Control 5: 107-114, 1998[Medline]

35. Moreira AL, Friedlander DR, Shif B, et al: Thalidomide and a thalidomide analogue inhibit endothelial cell proliferation in vitro. J Neurooncol 43: 109-114, 1999[Medline]

36. Johnson JP, Bruce JN: Angiogenesis in human gliomas: Prognostic and therapeutic implications. EXS 79: 29-46, 1977

37. Fine HA, Figg WD, Jaeckle K, et al: Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 18: 708-715, 2000[Abstract/Free Full Text]

38. Vlassenko AG, Thiessen B, Beattie BJ, et al: Evaluation of early response to SU101 target-based therapy in patients with recurrent supratentorial malignant gliomas using FDG PET and Gd-DTPA MRI. J Neurooncol 46: 249-259, 2000[Medline]

39. Shawver LK, Schwartz DP, Mann E, et al: Inhibition of platelet-derived growth factor-mediated signal transduction on tumor growth by N-[4-(trifluoromethyl)-phenyl]5-methylisoxazole-4-carboxamide. Clin Cancer Res 3: 1167-1177, 1997[Abstract]

40. Takano S, Gately S, Engelhard H, et al: Suramin inhibits glioma cell proliferation in vitro and in the brain. J Neurooncol 21: 189-201, 1994[Medline]

41. Bernsen HJ, Rijken PF, Peters JP, et al: Suramin treatment of human glioma xenografts: Effects on tumor vasculature and oxygenation status. J Neurooncol 44: 129-136, 1999[Medline]

42. Coomber BL: Suramin inhibits C6 glioma-induced angiogenesis in vitro. J Cell Biochem 58: 199-207, 1995[Medline]

43. Olson JJ, Polk DM, Reisner A: The efficacy and distribution of suramin in the treatment of the 9L gliosarcoma. Neurosurgery 34: 297-308, 1994[Medline]

44. Fantini J, Guo XJ, Marvaldi J, et al: Suramin inhibits proliferation of rat glioma cells and alters N-CAM cell surface expression. Int J Cancer 45: 554-561, 1990[Medline]

45. Lesser G, Grossman SA, Eller S: 14C-suramin readily enters and persists within intracranial malignant gliomas following intravenous administration in rats. Proc Am Soc Clin Oncol 16: 404a, 1997 (abstr 1443)

46. Olson JJ, He J, Gilbert M: Response to suramin correlates with tumor growth factor quantification. Proc Am Soc Clin Oncol 19: 163a, 2000 (abstr 633)

47. Chang E, Boyd A, Nelson CC, et al: Successful treatment of infantile hemangiomas with interferon-alph-2b. J Pediatr Hematol Oncol 19: 237-244, 1997[Medline]

48. Lund EL, Bastholm L, Dristjansen PE: Therapeutic synergy of TNP-47 and ionizing radiation: Effects on tumor growth, vessel morphology, and angiogenesis in human glioblastoma multifore xenografts. Clin Cancer Res 6: 971-978, 2000[Abstract/Free Full Text]

49. Grossman SA, Fisher J, Piantadosi S: The NABTT Glioblastoma Database: An objective means to select novel agents for phase III testing. Proc Am Soc Clin Oncol 17: 406a, 1998 (abstr 1565)

Submitted August 25, 2000; accepted March 30, 2001.




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