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.

Repurposing suramin for the treatment of breast cancer lung metastasis with glycol chitosan-based nanoparticles.

Suramin (SM), a drug for African sleeping sickness and river blindness therapy, has been investigated in various clinical trials for cancer therapy. However, SM was eventually withdrawn from the market because of its narrow therapeutic window and the side effects associated with multiple targets. In this work, we developed a simple but effective system based on a nontoxic dose of SM combined with a chemotherapeutic agent for the treatment of metastatic triple-negative breast cancer (TNBC). SM and glycol chitosan (GCS) formed nanogels because of the electrostatic effect, whereas doxorubicin (DOX) was incorporated into the system through the hydrophilic and hydrophobic interactions between DOX and GCS as well as the ionic interactions between DOX and SM to yield GCS-SM/DOX nanoparticles (NPs). GCS-SM/DOX NPs have a size of approximately 186 nm and a spherical morphology. In vitro experiments showed that GCS-SM NPs could effectively inhibit cancer cell migration and invasion, as well as angiogenesis. Furthermore, in a TNBC lung metastasis animal model, GCS-SM/DOX NPs significantly reduced tumor burden and extended the lifespan of animals, while not inducing cardio and renal toxicities associated with the DOX and SM, respectively. As all the components used in this system are biocompatible and easy for large-scale fabrication, the GCS-SM/DOX system is highly translatable for the metastatic breast cancer treatment. STATEMENT OF SIGNIFICANCE: The doxorubicin-loaded glycol chitosan-suramin nanoparticle (GCS-SM/DOX) is novel in the following aspects: SM acts as not only a gelator for the first time in the preparation of the nanoparticle but also an active pharmaceutical agent in the dosage form. GCS-SM/DOX NP significantly reduced tumor burden and extended the lifespan of animals with triple-negative breast cancer lung metastasis. GCS-SM/DOX NPs attenuate cardio and renal toxicities associated with the DOX and SM. The GCS-SM/DOX system is highly translatable because of its simple, one-pot, and easy-to-scale-up preparation protocol.

Self-assembled nanocomplex of PEGylated protamine and heparin-suramin conjugate for accumulation at the tumor site.

Heparin-like sulfated polysaccharides are potential drug candidates owing to their ability to interact with angiogenic factors and inhibit angiogenesis, tumor growth, and metastasis. This study aimed to improve the delivery of heparin-like anticancer polysaccharides for accumulation at the tumor site. We designed a nanocarrier system using protamine attached to polyethylene glycol (PEG) and evaluated the stability, tumor targeting, and tumor growth inhibition of the nanocarrier loaded with heparin derivatives. When mixed with various polyanionic heparin derivatives, the polycationic PEG-protamine formed stable self-assembled nanocomplexes via ionic interactions, with flexible PEG chains located on the outside. Among the complexes, a nanocomplex loaded with a low-molecular-weight heparin-suramin conjugate (LHsura) had the most suitable average size (101.9nm) for the enhanced permeability and retention effect and allowed accumulation of LHsura at the tumor site for up to 48h. In a tumor-bearing mouse model, the PEG-protamine and LHsura nanocomplex (10mg/kg/3days, intravenously), which could be extravasated through the tumor vasculature, significantly inhibited tumor growth, more than LHsura alone did. Overall, the self-assembled nanocomplexation of PEG-protamine and LHsura helped control the release and extravasation of LHsura, which resulted in an antitumor effect on the target tumor cells.

Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy.

Autism spectrum disorders (ASDs) now affect 1-2% of the children born in the United States. Hundreds of genetic, metabolic and environmental factors are known to increase the risk of ASD. Similar factors are known to influence the risk of schizophrenia and bipolar disorder; however, a unifying mechanistic explanation has remained elusive. Here we used the maternal immune activation (MIA) mouse model of neurodevelopmental and neuropsychiatric disorders to study the effects of a single dose of the antipurinergic drug suramin on the behavior and metabolism of adult animals. We found that disturbances in social behavior, novelty preference and metabolism are not permanent but are treatable with antipurinergic therapy (APT) in this model of ASD and schizophrenia. A single dose of suramin (20 mg kg(-1) intraperitoneally (i.p.)) given to 6-month-old adults restored normal social behavior, novelty preference and metabolism. Comprehensive metabolomic analysis identified purine metabolism as the key regulatory pathway. Correction of purine metabolism normalized 17 of 18 metabolic pathways that were disturbed in the MIA model. Two days after treatment, the suramin concentration in the plasma and brainstem was 7.64 µM pmol µl(-1) (±0.50) and 5.15 pmol mg(-1) (±0.49), respectively. These data show good uptake of suramin into the central nervous system at the level of the brainstem. Most of the improvements associated with APT were lost after 5 weeks of drug washout, consistent with the 1-week plasma half-life of suramin in mice. Our results show that purine metabolism is a master regulator of behavior and metabolism in the MIA model, and that single-dose APT with suramin acutely reverses these abnormalities, even in adults.

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.

Tissue protective and anti-fibrotic actions of suramin: new uses of an old drug.

Suramin is a polysulfonated naphthylurea, which was originally synthesized and designed as a treatment for trypanosomiasis and selected malignancies and metastatic diseases. Increasing evidence indicates that suramin is also effective in interfering with many other pathophysiological processes in animal models. For example, suramin can enhance renal regeneration after ischemia/reperfusion injury, attenuate liver damage following CD95 stimulation and endotoxic shock, reduce brain injury induced by ischemia, and suppress myocardial inflammation. Further, suramin has an anti-fibrotic effect in liver and muscle. Mechanistic studies show that suramin inhibits apoptosis, suppresses expression of proinflammatory cytokines, inactivates myofibroblasts and stimulates proliferation of renal epithelial cells. This review highlights the novel actions of suramin in a variety of tissues and organs.

Bladder tissue pharmacokinetics of intravesical mitomycin C and suramin in dogs.

Suramin, at non-cytotoxic doses, reverses chemoresistance and enhances the activity of mitomycin C (MMC) in mice bearing human bladder xenograft tumors. The present study evaluated the pharmacokinetics of the intravesical suramin and MMC, alone or in combination, in dogs. Animals received either high dose suramin (20 mg/ml), low dose suramin (6 mg/ml), MMC (2 mg/ml), or combination of low dose suramin and MMC, instilled for 2 h. The dosing volume was 20 ml. All groups showed dilution of drug levels over time due to continued urine production. For single agent suramin, the results showed (a) 5% to 10% penetration into bladder tissues, (b) minimal and clinically insignificant systemic absorption (i.e., undetectable at low dose or a peak concentration that was 6,000× lower than urine concentrations), and (c) disproportionally higher drug penetration and concentrations in bladder tissues at the higher dose. Results for single agent MMC are consistent with our earlier observations. The co-administration of MMC did not alter the plasma, urine, or tissue pharmacokinetics of suramin. Adding suramin did not alter plasma or tissue pharmacokinetics of MMC, but lowered the MMC concentrations in urine by about 20%. This may be in part due to accelerated MMC degradation by co-incubation of suramin or due to variations in urine production rate (because animals were allowed for water during treatment). Suramin readily penetrates the urothelium and into deeper bladder tissues, indicating its potential utility in intravesical therapy.

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.

Phase I/II trial of 5-fluorouracil and a noncytotoxic dose level of suramin in patients with metastatic renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is recognized as a neoplasm resistant to chemotherapy. In vitro experiments demonstrated that suramin, at noncytotoxic doses, enhanced the activity of chemotherapy including 5-fluorouracil (5-FU) in xenograft models. PATIENTS AND METHODS: A phase I/II trial of noncytotoxic suramin in combination with weekly 5-FU in patients with metastatic RCC was conducted. The treatment consisted of intravenous (i.v.) suramin followed by a 500 mg/m2 i.v. bolus of 5-FU given 4.5 hours after starting suramin. In the phase I portion, a cohort of 6 patients received a suramin dose calculated to achieve a plasma level of 10-50 micromol/L. Therapy was administered once weekly for 6 doses, followed by 2 weeks off. This was followed by a phase II portion in which the primary goal was to determine the objective response rate. RESULTS: Twenty-three patients were enrolled in the study: 6 in the phase I portion and 17 in phase II. Seventy-eight percent of patients were men, the mean age was 58.8 years, 96% had previous nephrectomy, and 70% had received previous systemic therapy. Histologic subtype was clear cell in 91%. Dose-limiting toxicity was observed in 1 of 6 patients (grade 3 hypersensitivity related to suramin infusion). The suramin dosing nomogram used in phase I and II portions of the trial yielded the desired plasma level of 10-50 micromol/L from 4.5 hours to 48 hours after infusion in 94 of 115 treatments. No objective responses were noted, and the median time to treatment failure was 2.5 months. The major toxicities (all grades) were fatigue (83%), nausea/vomiting (78%), diarrhea (61%), and chills (61%). CONCLUSION: Suramin levels expected to reverse fibroblast growth factor-induced resistance can be achieved with the dosing regimen used in this study. The toxicity observed with suramin and 5-FU was acceptable. The combination does not have clinical activity in patients with metastatic RCC.

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.

Distribution of suramin, an antitrypanosomal drug, across the blood-brain and blood-cerebrospinal fluid interfaces in wild-type and P-glycoprotein transporter-deficient mice.

Although 60 million people are exposed to human African trypanosomiasis, drug companies have not been interested in developing new drugs due to the lack of financial reward. No new drugs will be available for several years. A clearer understanding of the distribution of existing drugs into the brains of sleeping sickness patients is needed if we are to use the treatments that are available more safely and effectively. This proposal addresses this issue by using established animal models. Using in situ brain perfusion and isolated incubated choroid plexus techniques, we investigated the distribution of [(3)H]suramin into the central nervous systems (CNSs) of male BALB/c, FVB (wild-type), and P-glycoprotein-deficient (Mdr1a/Mdr1b-targeted mutation) mice. There was no difference in the [(3)H]suramin distributions between the three strains of mice. [(3)H]suramin had a distribution similar to that of the vascular marker, [(14)C]sucrose, into the regions of the brain parenchyma that have a blood-brain barrier. However, the association of [(3)H]suramin with the circumventricular organ samples, including the choroid plexus, was higher than that of [(14)C]sucrose. The association of [(3)H]suramin with the choroid plexus was also sensitive to phenylarsine oxide, an inhibitor of endocytosis. The distribution of [(3)H]suramin to the brain was not affected by the presence of other antitrypanosomal drugs or the P-glycoprotein efflux transporter. Overall, the results confirm that [(3)H]suramin would be unlikely to treat the second or CNS stage of sleeping sickness.

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.

Nontoxic suramin as a chemosensitizer in patients: dosing nomogram development.

PURPOSE: We reported that suramin produced chemosensitization at nontoxic doses. This benefit was lost at the approximately 10-fold higher, maximally tolerated doses (MTD). The aim of the current study was to identify in patients the chemosensitizing suramin dose that delivers 10-50 microM plasma concentrations over 48 h. METHODS: Nonsmall cell lung cancer patients were given suramin, paclitaxel, and carboplatin, every 3 weeks. The starting chemosensitizing suramin dose was estimated based on previous results on MTD suramin in patients, and adjusted by using real-time pharmacokinetic monitoring. A dosing nomogram was developed by using population-based pharmacokinetic analysis of phase I results (15 patients, 85 treatment cycles), and evaluated in phase II patients (19 females, 28 males, 196 treatment cycles). RESULTS: The chemosensitizing suramin dose showed a terminal half-life of 202 h and a total body clearance of 0.029 L h(-1) m(-2) (higher than the 0.013 L h(-1) m(-2) value for MTD of suramin). The dosing nomogram, incorporating body surface area as the major covariate of intersubject variability and the time elapsed since the previous dose (to account for the residual concentrations due to the slow elimination), delivered the target concentrations in >95% of treatments. CONCLUSIONS: The present study identified and validated a dosing nomogram and schedule to deliver low and nontoxic suramin concentrations that produce chemosensitization in preclinical models.

Phase I trial of intravesical Suramin in recurrent superficial transitional cell bladder carcinoma.

Suramin is an antitrypanosomal agent with antineoplastic activity, but with serious systemic side effects. We administered Suramin intravesically to determine a concentration with low toxicity but with evidence of a pharmacodynamic effect, to recommend a dose level for phase II trials. This was an open-labelled, non-randomized dose-escalation phase I study. In all, 12 patients with a history of recurrent superficial bladder cancer were grouped into four dose levels (10-150 mg ml(-1) in 60 ml saline). Six catheter instillations at weekly intervals were used. Cystoscopy and biopsy were performed before and 3 months after the start of treatment. Suramin was assayed using high-performance liquid chromatography, vascular endothelial growth factor (VEGF) using ELISA (enzyme-linked immunosorbent assay), and urinary protein profile using surface-enhanced laser desorption ionisation mass spectroscopy (SELDI). Minimal systemic absorption of Suramin was found at the highest dose of 150 mg ml(-1). Urinary VEGF was affected by Suramin at doses above 50 mg ml(-1), corresponding to the estimated threshold of saturation of Suramin binding to urine albumin. SELDI showed a specific disappearance of urinary protein peaks during treatment. Intravesical Suramin shows lack of toxicity and low systemic absorption. The results of this phase I trial support expanded clinical trials of efficacy at a dose of 100 mg ml(-1) intravesically.

Suramin as a chemosensitizer: oral pharmacokinetics in rats.

PURPOSE: The purpose of this study was to determine if the 10-50 microM plasma concentrations of suramin required to produce chemosensitization could be achieved by oral administration. METHODS: Rats were given an oral dose of 100, 300, or 500 mg/kg unlabeled suramin by oral gavage. Rats receiving the 300 mg/kg oral dose of suramin also received a concomitant intravenous bolus injection of 50 microCi/kg of [3H]suramin, administered 57 min after the oral dose. The intravenous data were used to calculate the clearance. Serial plasma samples were collected over 24-336 h. Plasma concentration-time profiles were analyzed using noncompartmental and compartmental methods. The pharmacokinetic parameters derived for the 300 mg/kg oral and 50 microCi/kg intravenous doses were used to calculate the bioavailability and AUC at the three oral dose levels. RESULTS: Plasma concentrations declined biexponentially following intravenous administration, with a distribution half-life of approximately 2 h and an estimated terminal half-life of 276 h. Suramin absorption following oral gavage was variable and incomplete with mean maximal plasma concentrations of 9.04, 72.6, and 64.4 microg/ml at doses of 100, 300, and 500 mg/kg, respectively. Seven of 15 rats exhibited two peak plasma concentrations at approximately 1 h and 3 to 12 h, suggesting the existence of multiple absorption sites and/or enterohepatic circulation. Oral bioavailability, calculated using the clearance of the intravenous tracer dose, was <3% at all three dose levels. CONCLUSIONS: While plasma concentrations resulting from the 300 and 500 mg/kg oral doses of suramin were in the concentration range required to produce chemosensitization, the low bioavailability limits the usefulness of oral administration.

Suramin: potential in acute liver failure.

Apoptosis is the first cellular response of the liver to many toxic events, including viral hepatitis, alcohol-induced liver disease and ischaemia/reperfusion injury. When apoptosis is induced with an antibody to APO-1, suramin is antiapoptotic in a variety of cell lines (e.g., Jurkat cells, HepG2). Jo2 is an antibody to mouse CD95, which kills C57Bl/6 mice, and was used as a model of fulminant liver failure in mice. Suramin protected 40% of Jo2-treated mice from death and delayed death in the other mice. In mice, D-galactosamine and endotoxin cause apoptotic liver damage, which is mediated by TNF. Suramin reduced this liver damage as assessed by serum aminotransferase levels, gross liver appearance and apoptosis levels. In contrast, suramin does not inhibit necrotic cell death in a rat model of liver transplantation. Inhibition of apoptosis with suramin or other more selective agents is an approach that should be further investigated in liver failure.

Phase I study of low-dose suramin as a chemosensitizer in patients with advanced non-small cell lung cancer.

PURPOSE: Our preclinical studies have shown that acidic and basic fibroblastic growth factors confer broad spectrum chemoresistance and that low concentrations (10-50 microM) of suramin, a nonspecific fibroblastic growth factor inhibitor, enhance the antitumor activity of paclitaxel in vivo. The present Phase I study evaluated low-dose suramin in combination with paclitaxel/carboplatin in advanced non-small cell lung cancer patients. EXPERIMENTAL DESIGN: Patients received suramin followed by paclitaxel (175-200 mg/m(2)) and carboplatin area under the concentration-time curve of 6 mg/ml/min, every 3 weeks. The initial suramin dose for the first cycle was 240 mg/m(2), and the doses for subsequent cycles were calculated based on the 72-h pretreatment plasma concentrations. The recommended suramin dose would yield plasma concentrations of 10-20 microM at 48 h in >or=5 of 6 patients. RESULTS: Fifteen patients (11 stage IV, 4 stage IIIB, 9 chemonaive, and 6 previously treated) received 85 courses. The most common toxicities were neutropenia, nausea/vomiting, malaise/fatigue, and peripheral neuropathy. No treatment-related hospitalizations, adrenal dysfunction, or episodes of sepsis occurred. The initial suramin dose resulted in the targeted concentrations of 10-20 microM at 48 h in 5 of the first 6 patients treated but also resulted in peak concentrations > 50 microM in all patients. Dividing the suramin dose to be administered in two doses, 24 h apart, yielded the target concentrations and avoided undesirable peak concentrations. Discernable antitumor activity occurred in 7 of 10 patients with measurable disease, including 2 with prior chemotherapy. The median time to tumor progression is 8.5 months (range, 3-27+ months) for 12 evaluable patients. CONCLUSIONS: Low-dose suramin does not increase the toxicity of paclitaxel/carboplatin combination. The suramin dose can be calculated based on clinical parameters. Because of the preliminary antitumor activity observed, efficacy studies in chemonaive and chemorefractory patients are under way.

Current chemotherapy of human African trypanosomiasis.

Human African trypanosomiasis is a fatal disease caused by Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense that has re-emerged in recent years. However, very little progress has been made in the development of new drugs against this disease. Most drugs still in use were developed one or more decades ago, and are generally toxic and of limited effectiveness. The most recently introduced compound, eflornithine, is only useful against sleeping sickness caused by T. b. gambiense, and is prohibitively expensive for the African developing countries. We present here an overview of today's approved and clinically used drugs against this disease.

Arsenicals (melarsoprol), pentamidine and suramin in the treatment of human African trypanosomiasis.

Human African trypanosomiasis (HAT), otherwise known as sleeping sickness, has remained a disease with no effective treatment. Recent progress in HAT research suggests that a vaccine against the disease is far from being successful. Also the emergence of drug-resistant trypanosomes makes further work in this area imperative. So far the treatment for the early stage of HAT involves the drugs pentamidine and suramin which have been very successful. In the second stage of the disease, during which the trypanosomes reside in the cerebrospinal fluid (CSF), treatment is dependent exclusively on the arsenical compound melarsoprol. This is largely due to the inability to find compounds that can cross the blood brain barrier and kill the CSF-residing trypanosomes. This review summarises our current understanding on the treatment of HAT.

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.