Phase I, Single-Dose Study to Assess the Pharmacokinetics and Safety of Suramin in Healthy Chinese Volunteers.

Purpose: Suramin is a multifunctional molecule with a wide range of potential applications, including parasitic and viral diseases, as well as cancer. Methods: A double-blinded, randomized, placebo-controlled single ascending dose study was conducted to investigate the safety, tolerability, and pharmacokinetics of suramin in healthy Chinese volunteers. A total of 36 healthy subjects were enrolled. All doses of suramin sodium and placebo were administered as a 30-minute infusion. Blood and urine samples were collected at the designated time points for pharmacokinetic analysis. Safety was assessed by clinical examinations and adverse events. Results: After a single dose, suramin maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUClast) increased in a dose-proportional manner. The plasma half-life (t1/2) was dose-independent, average 48 days (range 28-105 days). The cumulative percentages of the dose excreted in urine over 7 days were less than 4%. Suramin can be detected in urine samples for longer periods (more than 140 days following infusion). Suramin was generally well tolerated. Treatment-emergent adverse events (TEAEs) were generally mild in severity. Conclusion: The PK and safety profiles of suramin in Chinese subjects indicated that 10 mg/kg or 15 mg/kg could be an appropriate dose in a future multiple-dose study.

Purinergic Antagonist Suramin Aggravates Myocarditis and Increases Mortality by Enhancing Parasitism, Inflammation, and Reactive Tissue Damage in Trypanosoma cruzi-Infected Mice.

Suramin (Sur) acts as an ecto-NTPDase inhibitor in Trypanosoma cruzi and a P2-purinoceptor antagonist in mammalian cells. Although the potent antitrypanosomal effect of Sur has been shown in vitro, limited evidence in vivo suggests that this drug can be dangerous to T. cruzi-infected hosts. Therefore, we investigated the dose-dependent effect of Sur-based chemotherapy in a murine model of Chagas disease. Seventy uninfected and T. cruzi-infected male C57BL/6 mice were randomized into five groups: SAL = uninfected; INF = infected; SR5, SR10, and SR20 = infected treated with 5, 10, or 20 mg/kg Sur. In addition to its effect on blood and heart parasitism, the impact of Sur-based chemotherapy on leucocytes myocardial infiltration, cytokine levels, antioxidant defenses, reactive tissue damage, and mortality was analyzed. Our results indicated that animals treated with 10 and 20 mg/kg Sur were disproportionally susceptible to T. cruzi, exhibiting increased parasitemia and cardiac parasitism (amastigote nests and parasite load (T. cruzi DNA)), intense protein, lipid and DNA oxidation, marked myocarditis, and mortality. Animals treated with Sur also exhibited reduced levels of nonprotein antioxidants. However, the upregulation of catalase, superoxide dismutase, and glutathione-S-transferase was insufficient to counteract reactive tissue damage and pathological myocardial remodeling. It is still poorly understood whether Sur exerts a negative impact on the purinergic signaling of T. cruzi-infected host cells. However, our findings clearly demonstrated that through enhanced parasitism, inflammation, and reactive tissue damage, Sur-based chemotherapy contributes to aggravating myocarditis and increasing mortality rates in T. cruzi-infected mice, contradicting the supposed relevance attributed to this drug for the treatment of Chagas disease.

Suramin-Induced Neurotoxicity: Preclinical Models and Neuroprotective Strategies.

Suramin is a trypan blue analogon originally developed to treat protozoan infections, which was found to have diverse antitumor effects. One of the most severe side effects in clinical trials was the development of a peripheral sensory-motor polyneuropathy. In this study, we aimed to investigate suramin-induced neuropathy with a focus on calcium (Ca2+) homeostasis as a potential pathomechanism. Adult C57Bl/6 mice treated with a single injection of 250 mg/kg bodyweight suramin developed locomotor and sensory deficits, which were confirmed by electrophysiological measurements showing a predominantly sensory axonal-demyelinating polyneuropathy. In a next step, we used cultured dorsal root ganglia neurons (DRGN) as an in vitro cell model to further investigate underlying pathomechanisms. Cell viability of DRGN was significantly decreased after 24-hour suramin treatment with a calculated IC50 of 283 µM. We detected a suramin-induced Ca2+ influx into DRGN from the extracellular space, which could be reduced with the voltage-gated calcium channel (VGCC) inhibitor nimodipine. Co-incubation of suramin and nimodipine partially improved cell viability of DRGN after suramin exposure. In summary, we describe suramin-induced neurotoxic effects on DRGN as well as potentially neuroprotective agents targeting intracellular Ca2+ dyshomeostasis.

Concomitant Benznidazole and Suramin Chemotherapy in Mice Infected with a Virulent Strain of Trypanosoma cruzi.

Although suramin (Sur) is suggested as a potential drug candidate in the management of Chagas disease, this issue has not been objectively tested. In this study, we examined the applicability of concomitant treatment with benznidazole (Bz) and suramin in mice infected with a virulent strain of Trypanosoma cruzi. Eighty 12-week-old male C57BL/6 mice were equally randomized in eight groups: (i) noninfected mice (negative control) and mice infected with T. cruzi Y strain receiving (ii) no treatment (positive control), (iii) Bz, 100 mg/kg of body weight per day, (iv) Sur, 20 mg/kg/day, and (v to viii) Sur, 20 mg/kg/day, combined with Bz, 100, 50, 25, or 5 mg/kg/day. Bz was administered by gavage, and Sur was administered intraperitoneally. Sur dramatically increased the parasitemia, cardiac content of parasite DNA, inflammation, oxidative tissue damage, and mortality. In response to high parasitic load in cardiac tissue, Sur stimulated the immune system in a manner typical of the acute phase of Chagas disease, increasing tissue levels of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) and inducing a preferential IgG2a anti-T. cruzi serum pattern. When Sur and Bz were combined, the infection severity was attenuated, showing a dose-dependent Bz response. Sur therapy had a more harmful effect on the host than on the parasite and reduced the efficacy of Bz against T. cruzi infection. Considering that Sur drastically reinforced the infection evolution, potentiating the inflammatory process and the severity of cardiac lesions, the in vivo findings contradicted the in vitro anti-T. cruzi potential described for this drug.

Phase I/II trial of non-cytotoxic suramin in combination with weekly paclitaxel in metastatic breast cancer treated with prior taxanes.

PURPOSE: Suramin, a polysulfonated naphthylurea, inhibits the actions of polypeptide growth factors including acidic and basic fibroblast growth factors (aFGF and bFGF), which confer broad spectrum chemotherapy resistance. We hypothesized that suramin at non-cytotoxic doses in combination with weekly paclitaxel would be well tolerated and demonstrate anti-tumor activity. METHODS: Women with metastatic breast cancer who had been previously treated with a taxane in the adjuvant or metastatic setting were eligible. The primary objective of the phase I was to determine the dose of intravenous (IV) weekly suramin that resulted in plasma concentrations between 10 and 50 umol/l over 8-48 h (or the target range) in combination with IV 80 mg/m(2) of weekly paclitaxel. The primary objective of the phase II trial was to determine the anti-tumor activity of the dosing regimen defined in phase I. Therapy was continued until disease progression or development of unacceptable toxicity. RESULTS: Thirty-one patients were enrolled (9: phase I; 22: phase II). In phase I, no dose-limiting toxicities were observed. Pharmacokinetics during the first cycle showed suramin concentrations within the target range for 21 of 24 weekly treatments (88 %). In phase II, the objective response rate (ORR) was 23 % (95 % CI 8-45 %), the median progression-free survival was 3.4 months (95 % CI 2.1-4.9 months), and the median overall survival was 11.2 months (95 % CI 6.6-16.0 months). CONCLUSIONS: Non-cytotoxic doses of suramin in combination with weekly paclitaxel were well tolerated. The efficacy was below the pre-specified criteria required to justify further investigation.

Phase I trial of non-cytotoxic suramin as a modulator of docetaxel and gemcitabine therapy in previously treated patients with non-small cell lung cancer.

PURPOSE: In preclinical models, non-cytotoxic suramin (concentrations <50 µM) potentiates the activity of multiple chemotherapeutic agents. The present study evaluated the safety and tolerability of suramin in combination with docetaxel or gemcitabine in previously chemotherapy-treated patients with advanced non-small cell lung cancer. METHODS: Patients received suramin intravenously in combination with either docetaxel on day 1 or gemcitabine on days 1 and 8, of each 21-day treatment cycle. After 3 cycles, patients with partial response (PR) or better continued on the same combination, whereas patients with stable disease (SD) or worse crossed-over to the other combination. Pharmacokinetic analyses were performed before and after each treatment. RESULTS: Eighteen patients received a total of 79 courses (37 suramin plus docetaxel, 42 suramin plus gemcitabine). The dose-limiting toxicity (DLT) was febrile neutropenia, observed in three of six patients treated with suramin and docetaxel 75 mg/m(2). No DLTs were observed with suramin plus docetaxel 56 mg/m(2) or suramin plus gemcitabine 1,250 mg/m(2). Common adverse events included neutropenia, thrombocytopenia, anemia, fatigue, nausea, vomiting, skin rash, hyperglycemia, and electrolyte abnormalities. The target plasma suramin concentration range of 10-50 µM was achieved in 90% of treatments. Discernable antitumor activity was noted in 11 patients (2 PR, 9 SD). CONCLUSIONS: Non-cytotoxic suramin, in combination with docetaxel 56 mg/m(2) or gemcitabine 1,250 mg/m(2), was reasonably well-tolerated with a manageable toxicity profile. Target plasma concentrations were correctly predicted by our previously described dosing nomogram. The observed preliminary evidence of antitumor activity encourages evaluation of this strategy in efficacy trials.

Noncytotoxic suramin as a chemosensitizer in patients with advanced non-small-cell lung cancer: a phase II study.

BACKGROUND: The purpose of this study was to evaluate the potential of noncytotoxic doses of suramin to reverse chemotherapy resistance in advanced chemonaive and chemoresistant non-small-cell lung cancer patients. PATIENTS AND METHODS: Patients received paclitaxel (Taxol) (200 mg/m(2)) and carboplatin (area under the concentration-time curve 6 mg/ml/min) every 3 weeks. The total suramin per cycle dose was calculated using a nomogram derived from the preceding phase I trial to obtain the desirable plasma concentration range of 10-50 microM. RESULTS: Thirty-nine response-assessable chemonaive patients (arm A) received 213 cycles. Thirty-eight cycles were administered to 15 patients with demonstrated resistance to paclitaxel and carboplatin (arm B). The pattern/frequency of toxic effects was similar to those expected for paclitaxel/carboplatin, and pharmacokinetic analyses (199 cycles) showed suramin plasma concentrations maintained between 10 and 50 microM in 94% of cycles. In arm A, response evaluation criteria in solid tumors (RECIST) response rate was 36% (95% confidence interval 22% to 54%; two complete, 12 partial); 15 patients (38%) had disease stabilization for > or =4 months; median progression-free survival (intention to treat) was 6.4 months; median overall survival (OS) 10.4 months and 1-year survival rate 38%. In arm B, no RECIST responses occurred; four patients had disease stabilization for > or =4 months; median OS was 132 days and 1-year survival rate 7%. Plasma basic fibroblast growth factor levels were higher in chemopretreated/refractory patients compared with chemonaive patients (P = 0.05). Sequence analysis of the EGFR tyrosine kinase domain in a long-term disease-free survivor revealed an ATP-binding pocket mutation (T790M). CONCLUSIONS: Noncytotoxic suramin did not increase paclitaxel/carboplatin's toxicity and the suramin dose was predicted from clinical parameters. No clinically significant reversal of primary resistance was documented, but a modulatory effect in chemotherapy-naive patients cannot be excluded. Controlled randomization is planned for further evaluation of this treatment strategy.

Phase I evaluation of low-dose suramin as chemosensitizer of doxorubicin in dogs with naturally occurring cancers.

BACKGROUND: Low and nontoxic concentrations (10-50 microM) of suramin, which is a nonspecific inhibitor of multiple growth factors, including fibroblast growth factors, enhances the activities of cytotoxic chemotherapeutic agents, such as doxorubicin and paclitaxel, both in vitro and in vivo. Suramin has not been evaluated as a chemosensitizing agent in dogs with cancer. HYPOTHESIS: Nontoxic suramin can be used safely as a chemosensitizer in dogs. ANIMALS: Sixteen dogs of various breeds with measurable tumors were treated; 1 dog that had undergone amputation for osteosarcoma received adjuvant therapy. METHODS: The dogs received 53 courses of treatment with suramin in combination with doxorubicin. The suramin dosage was 6.75 mg/kg IV 3 h before standard doxorubicin administration every 2 weeks. The pharmacokinetics and clinical efficacy were determined. RESULTS: The pharmacokinetics of low-dose suramin followed a 2-compartment model with half-lives of 2 h and 6 days. The distribution volume was a 0.34 +/- 0.12 L/kg, and clearance was 1.86 +/- 0.76 mL/kg/h. During the time interval that doxorubicin was present at therapeutically active concentrations (ie, from the start of infusion to 24 hours), the plasma concentrations were maintained within 20% of the target range (8-60 microM) in 72% of the treatments. The toxicity of the suramin/doxorubicin combination was mild and comparable to the toxicity expected for doxorubicin monotherapy. Objective partial responses were observed in 2 out of 16 evaluable dogs (13%). All 5 dogs that previously received doxorubicin showed improved responses to the suramin/doxorubicin combination. CONCLUSIONS AND CLINICAL IMPORTANCE: A fixed, low-dose suramin regimen yields the desired target plasma concentrations in most dogs, and appears to enhance the activity of doxorubicin without enhancing toxicity.

The morphogenesis of the exstrophy-epispadias complex: a new concept based on observations made in early embryonic cases of cloacal exstrophy.

BACKGROUND: The term exstrophy-epispadias complex (EEC) has been coined for a group of congenital malformations that includes epispadias, bladder exstrophy and cloacal exstrophy. It is usually thought that these malformations develop against a similar embryological background. This background, however, is still obscure. This is mainly due to the lack of availability of abnormal human or non-human embryos showing the crucial developmental steps in the morphogenesis of EEC malformations. In this paper, we present chick embryos that show cloacal exstrophy at early developmental stages. To the best of our knowledge, this is the first documentation of this rare malformation in young embryos. MATERIALS AND METHODS: Embryos with cloacal exstrophy (n=4) were found among embryos from two experimental series (n=50) that were primarily performed to document the early morphogenesis of facial and cardiovascular malformations. The malformations were induced by the administration of suramin according to established protocols. Suramin can induce a spectrum of malformations including facial clefts, heart defects, and cloacal exstrophy. RESULTS AND CONCLUSIONS: Besides the presence of an abnormal opening into the cloaca, all embryos were characterised by an abnormal broadening of the caudal trunk at the level of the leg buds, which, in the youngest embryos, was associated with the abnormal presence of large aneurysmatic swellings of the dorsal aortae at this side. We postulate that these aneurysmatic swellings might be the primary defects leading to the development of EEC malformations. These space-occupying anomalies seem to cause abnormal distensions of the developing pelvis and of the infra-umbilical portion of the developing body wall. In consequence, the mid-portion of the developing ventral body wall between the origin of the umbilical cord and the cloacal plate becomes stretched and thinned out. Tension and thinning of the ventral body wall might ultimately lead to its rupture with exposure of the lumen of the embryonic cloaca and allantois. This new concept on the morphogenesis of the EEC is the first not to be inferred from the conditions seen in fetal or postnatal human cases but is based entirely on data from malformed embryos.

Chemotherapy-induced peripheral neurotoxicity.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major clinical problem because it represents the dose-limiting side effects of a significant number of antineoplastic drugs. The incidence of CIPN varies depending on the drugs and schedules used, and this can be quite high, particularly when neurophysiological methods are used to make a diagnosis. However, even when CIPN is not a dose-limiting side effect, its onset may severely affect the quality of life of cancer patients and cause chronic discomfort. In this review the features of CIPN due to the administration of the most widely used drugs, such as platinum drugs, taxanes and vinca alkaloids, and of two old drugs with new clinical applications, suramin and thalidomide, will be discussed. Moreover, the earliest data regarding the neurotoxicity of some new classes of very promising antineoplastic agents, such as epothilones and proteasome inhibitors, will be discussed. Finally, the data available on neuroprotectants, evaluated in the attempt to prevent CIPN, will be summarised.

Quality of life impact of three different doses of suramin in patients with metastatic hormone-refractory prostate carcinoma: results of Intergroup O159/Cancer and Leukemia Group B 9480.

BACKGROUND: Research has suggested that men with hormone-refractory prostate carcinoma have a lower quality of life (QOL) compared with men who have hormone-sensitive prostate carcinoma and that quality of life (QOL) steadily declines over the last year of life for men with prostate carcinoma. The primary purpose of the current study was to evaluate whether there was evidence of palliative effects associated with suramin at any of the three doses administered in the original clinical trial. METHODS: Patients with histologically confirmed advanced hormone-refractory adenocarcinoma of the prostate were randomized to receive suramin at a low dose (n = 129; median age, 69 years), an intermediate dose (n = 129; median age, 71 years), or a high dose (n = 127; median age, 70 years) as part of the Intergroup 0159/Cancer and Leukemia Group B 9480 trial. Patients completed a battery of assessment tools, including the Functional Assessment of Cancer Therapy (FACT)-Prostate, the Center for Epidemiological Studies-Depression Scale (CES-D), the Brief Pain Inventory, and an opioid medication log, at baseline, on Day 1 of the sixth week of active therapy, during the second week after treatment termination, and 3 months after administration of the final suramin dose. RESULTS: Patients who received low-dose suramin reported improvement in QOL (FACT-General: P < 0.01; FACT-Treatment Outcome Index: P < 0.01) and decreased levels of depression (CES-D: P < 0.0006) during treatment compared with patients in the intermediate- and high-dose arms. After treatment, all groups experienced equal decreases in FACT and CES-D scores. CONCLUSIONS: The pattern of results suggests that the lowest dose of suramin administered had a palliative effect in terms of improvement in QOL and decreased levels of depression and that this effect was lost once suramin was discontinued.

Suramin and radiotherapy in newly diagnosed glioblastoma: phase 2 NABTT CNS Consortium study.

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 >or= 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.

Novel mechanism of enhanced nociception in a model of AIDS therapy-induced painful peripheral neuropathy in the rat.

To elucidate the underlying mechanisms involved in AIDS therapy-induced peripheral neuropathy, we have developed a model of nucleoside analog reverse transcriptase inhibitor-induced painful peripheral neuropathy in the rat, using 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddI) and 2',3'-didehydro-3'-deoxythymidine (d4T), AIDS chemotherapeutic drugs that are also components of AIDS highly active anti-retroviral therapy. Administration of ddC, ddI and d4T produced dose-dependent mechanical hypersensitivity and allodynia. Peripheral administration of inhibitors of protein kinase A, protein kinase C, protein kinase G, p42/p44-mitogen-activated protein kinase (ERK1/2) and nitric oxide synthase, which have demonstrated anti-hyperalgesic effects in other models of metabolic and toxic painful peripheral neuropathies, had no effect on ddC-, ddI- and d4T-induced hypersensitivity. Since suramin, an anti-parasitic and anti-cancer drug, which shares with the anti-retroviral nucleoside analogs, mitochondrial toxicity, altered regulation of intracellular calcium, and a sensory neuropathy in humans, also produced mechanical hypersensitivity that was not sensitive to the above second messenger inhibitors we evaluated the role of intracellular calcium. Intradermal or spinal injection of intracellular calcium modulators (TMB-8 and Quin-2), which had no effect on nociception in control rats, significantly attenuated and together eliminated ddC and suramin-induced mechanical hypersensitivity. In electrophysiology experiments in ddC-treated rats, C-fibers demonstrated alterations in pattern of firing as indicated by changes in the distribution of interspike intervals to sustained suprathreshold stimuli without change in mechanical activation thresholds or in number of action potentials in response to threshold and suprathreshold stimulation. This study provides evidence for a novel, calcium-dependent, mechanism for neuropathic pain in a model of AIDS therapy-induced painful peripheral neuropathy.

A phase I study of intravesical suramin for the treatment of superficial transitional cell carcinoma of the bladder.

PURPOSE: Suramin is a polysulfonated naphthylurea that inhibits proliferation and DNA synthesis of transitional cell carcinoma cell lines. Its large molecular size and negative charge inhibit bladder absorption, making suramin an excellent candidate for intravesical chemotherapy. Intravesical suramin was evaluated in a phase I study to define dose limiting toxicity and systemic absorption, determine a starting dose and regimen for phase II studies and provide a preliminary assessment of in vivo antitumor activity. MATERIALS AND METHODS: Intravesical suramin treatment was administered in 9 patients with histologically identified transitional cell carcinoma (Tcis, Ta or T1) in whom at least 1 course of standard intravesical chemotherapy (bacillus Calmette-Guerin, thiotepa or mitomycin C) had failed. Suramin was administered once weekly for 6 weeks. Patients were treated in groups of 3 using a 60 cc volume and intrapatient dose escalation schedule. Suramin doses of 0.3 to 614.4 mg./ml. were administered intravesically. The last group was treated with the same weekly dose for 6 weeks. RESULTS: The 9 patients underwent 54 treatments with suramin. Plasma suramin concentration after treatment was 1.9 to 38.0 microg./ml. and was not related to treatment dose. The dose escalation phase was limited by the solubility of suramin in solution. Complications included self-limited bladder spasms (less than 24 hours) in 4 of 54 treatments (7%) and new or worsening vesicoureteral reflux in 3 ureters (17%). Another patient who was treated after the Foley balloon was inflated in the urethra experienced bladder spasms, skin flushing and fever (39C). Mean bladder capacity before and after treatment was 600 and 540 ml., respectively. At followup 7 patients had stage Ta tumors and 2 had carcinoma in situ. CONCLUSIONS: An intravesical suramin dose of 153 mg./ml was defined as a safe treatment parameter with acceptable plasma concentrations and minimal side effects. Phase II studies are needed to assess the antitumor activity of suramin in patients with transitional cell carcinoma of the bladder.

Recent advances in drug-induced neuropathies.

PURPOSE OF REVIEW: Peripheral neuropathy is a common neurotoxic effect of medications. When medications are used to treat life-threatening illnesses, balancing the toxic effects of peripheral neuropathy with the therapeutic benefits of the drug can be difficult. This article examines recent research into the cellular mechanisms associated with neuropathy after treatment with medications to treat cancer, and HIV, and to prevent transplant rejection. RECENT FINDINGS: Cisplatin and suramin induce a length, dose, and time-dependent axonal sensorimotor polyneuropathy. Cisplatin and suramin both result in apoptosis in dorsal root ganglion neurons that may partially explain the neuropathy that develops with treatment. In contrast, nerve growth factor prevents initiation of the programmed cell death associated with cisplatin neurotoxicity. Suramin causes accumulation of lamellar inclusion bodies in dorsal root ganglion neurons related to dose of administration and severity of the neuropathy. Nucleoside reverse transcriptase inhibitors affect mitochondrial function and lead to depletion of the nerve's mitochondrial DNA and inhibition of DNA polymerase. These effects on the mitochondrion may be related to the polyneuropathy that develops in these patients. In contrast to the axonal neuropathies, tacrolimus and rarely suramin can result in a demyelinating neuropathy that may mimic Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy. Many of these neuropathies can be reversed by early recognition of the symptoms or by using sensitive electrophysiological testing. In certain instances, specific therapies may ameliorate the neuropathy. Glutamine may reduce paclitaxel-induced toxicity, while some patients with tacrolimus or suramin-induced demyelinating neuropathy may respond to intravenous immunoglobulin or plasmapheresis. SUMMARY: Improved understanding of neurotoxic mechanisms in the peripheral nervous system associated with chemotherapeutic and anti-HIV medications, coupled with early improved diagnosis, promises to help limit neurotoxicity associated with these medications.

Randomized study of three different doses of suramin administered with a fixed dosing schedule in patients with advanced prostate cancer: results of intergroup 0159, cancer and leukemia group B 9480.

PURPOSE: To test the hypothesis that the efficacy and toxicity of suramin in the treatment of patients with hormone-refractory prostate cancer was dose dependent. PATIENTS AND METHODS: Patients were randomized with equal probability to receive low-, intermediate-, or high-dose suramin (total doses 3.192, 5.320, and 7.661 g/m(2), respectively). Overall survival, time to progression, and response rate (prostate-specific antigen [PSA] and objective) for each treatment arm were compared. Relationships between plasma suramin concentrations and response, toxicity, and survival were also evaluated. RESULTS: Three hundred ninety patients were randomized. For the low-, intermediate-, and high-dose arms, the median survival time was 16, 14, and 13 months, respectively (P =.49). The objective response rate was 9%, 7%, and 15%, respectively (P =.10). PSA response rates were 24%, 28%, and 34%, respectively (P =.082). Landmark analyses of a 50% decline in PSA at 20 weeks showed a significant correlation with survival. There was a dose-response relationship between dose and toxicity. After adjusting for treatment arm, the measured suramin concentration was not associated with clinical response, PSA response, survival, or toxicity. CONCLUSION: Although high-dose suramin was associated with higher objective and PSA response rates, these were not statistically significant. Overall, no dose-response relationship was observed for survival or progression-free survival, but toxicity was increased with the higher dose. Patients treated with the low-dose level experienced modest toxicity, making it the preferred arm on this study. The lack of a dose-response relationship and the toxicity profile observed raise questions regarding the utility of suramin, particularly high-dose suramin, as administered on this schedule.

Suramin's development: what did we learn?

Suramin, a polysulphonated napthylurea, has been extensively evaluated over the past 10 years as an anticancer agent, with the most interest in the treatment of prostate cancer. Early clinical results were promising with response rates of up to 70% being reported. However, a recent double-blind study showed only modest palliative effect in patients with androgen independent prostate cancer. In retrospect, it appears those initial reports failed to control for confounding variables such as antiandrogen withdrawal and hydrocortisone. Suramin causes numerous reversible toxicities (lethargy, rash, fatigue, anemia, hyperglycemia, hypocalcemia, coagulopathies, neutropenia, renal and hepatic complications). Neurotoxicity has been the most significant complication and appears to be related to the intensity of the dosing regimen. An optimal therapeutic dose has not been determined, but it is clear that adaptive controls add little benefit. Aside from moderate toxicities and the low therapeutic index in patients with prostate cancer, suramin's development has taught us some valuable lessons (i.e., anti-androgen withdrawal was noted during suramin's development, the use of PSA as an indicator of tumor burden was initiated during the evaluation of suramin). These lessons can be applied to all clinical trials in hormone refractory prostate cancer. Suramin has significantly enhanced the evolution of our knowledge in several areas of prostate cancer biology and treatment.

A phase I study of suramin with once- or twice-monthly dosing in patients with advanced cancer.

PURPOSE: The optimal schedule of administration of suramin has not been well defined. The purpose of this study was to determine the maximum tolerated dose and toxicities of suramin when administered using a fixed dosing scheme on a once- or twice-monthly schedule. METHODS: A total of 40 patients were treated on this phase I dose-escalation study employing a once-monthly (day 1 of each 28-day cycle) and a twice-monthly (days 1 and 8 of each 28-day cycle) schedule. RESULTS: The most common dose-limiting events included fatigue, neuropathy, and anorexia. We identified the 1440 mg/m(2) dose level to be the maximal tolerated dose for both schedules, with 83% of patients developing dose-limiting toxicity (DLT) on the twice-monthly schedule, and 67% developing DLT on the monthly schedule. At the 1200 mg/m(2) dose level, only 25% developed DLT on the twice-monthly schedule and 33% developed DLT on the monthly schedule. Trough suramin levels gradually increased with higher dose levels but fell well below the putative toxic concentration of 350 microg/ml. CONCLUSION: Suramin can be safely administered using a monthly schedule without using plasma concentrations to guide dosing.