RESUMEN
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.
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Pueblos del Este de Asia , Suramina , Humanos , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Semivida , Voluntarios Sanos , Suramina/administración & dosificación , Suramina/efectos adversos , Suramina/sangre , Suramina/farmacocinética , Suramina/orinaRESUMEN
The development of a polymer membrane-based electrode to measure the anionic drug suramin in buffered saline and biological samples is described. A large non-equilibrium, steady state EMF response is observed toward suramin, and judicious choice of the polymer membrane components allows for adjustment of the dynamic range of the electrode. The optimized membrane for use in the toxic suramin range consists of 25 wt% tridodecylmethyl ammonium chloride, 55 wt% bis-2-ethylhexyl sebacate, and 20 wt% Pellethane. Although this electrode can be used to directly quantify suramin in human plasma, determination of suramin that is not affected by the background concentration of small anions is best achieved by simple potentiometric titrations with polycationic protamine monitored with a protamine-sensitive electrode.
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Técnicas Electroquímicas/métodos , Polímeros/química , Suramina/sangre , Electrodos , Humanos , Poliuretanos/química , Compuestos de Amonio Cuaternario/químicaRESUMEN
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Suramina/administración & dosificación , Suramina/efectos adversos , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Quimioterapia Adyuvante , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Docetaxel , Esquema de Medicación , Sinergismo Farmacológico , Humanos , Infusiones Intravenosas , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Nomogramas , Radioterapia Adyuvante , Suramina/sangre , Suramina/farmacocinética , Taxoides/administración & dosificación , Taxoides/efectos adversos , Resultado del Tratamiento , GemcitabinaRESUMEN
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.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Suramina/farmacocinética , Tripanocidas/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/deficiencia , Animales , Unión Competitiva/efectos de los fármacos , Barrera Hematoencefálica , Butanoles/farmacocinética , Fenómenos Químicos , Química Física , Plexo Coroideo/metabolismo , Cromatografía Líquida de Alta Presión , Interpretación Estadística de Datos , Técnicas In Vitro , Circulación Hepática/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Perfusión , Unión Proteica , Suramina/sangre , Suramina/líquido cefalorraquídeo , Tripanocidas/sangre , Tripanocidas/líquido cefalorraquídeoRESUMEN
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Neoplasias/veterinaria , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Perros , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Sinergismo Farmacológico , Femenino , Masculino , Neoplasias/sangre , Neutropenia/inducido químicamente , Neutropenia/veterinaria , Recuento de Plaquetas/veterinaria , Suramina/administración & dosificación , Suramina/efectos adversos , Suramina/sangre , Suramina/farmacocinética , Trombocitopenia/inducido químicamente , Trombocitopenia/veterinariaRESUMEN
PURPOSE: To assess the feasibility of administering a combination of suramin and hydrocortisone in addition to androgen deprivation in a cooperative group setting; to assess the feasibility of treatment with multiple courses of suramin; and to assess progression-free and overall survival in patients with newly diagnosed metastatic prostate cancer who underwent such treatment. PATIENTS AND METHODS: Patients with newly diagnosed metastatic prostate cancer who had adequate hematologic, hepatic, renal, neurologic, and coagulation parameters were treated by combined androgen deprivation and suramin plus hydrocortisone. Suramin was administered on a 78-day fixed dosing schedule (one cycle), and suramin treatment cycles were repeated every 6 months for a total of four cycles. The statistical design was developed on the basis of the feasibility of administering suramin, as judged by the number of patients who developed neurotoxicity of grade 3 or higher or by treatment interruption of 4 weeks or longer due to any persistent suramin-related toxicity. RESULTS: Of the 62 patients enrolled onto the study between August 1994 and January 1997, 59 were eligible and assessable for toxicity on the first cycle. Thirty-two (54%) of 59 patients received a second cycle, 13 (22%) of 59 patients received a third cycle, and only five patients (8%) received a fourth cycle. During the first cycle, 27 patients were removed from the study: 17 because of toxicity, five because of disease progression, two who had died, and three because of other reasons. There was one therapy-related death. Grade 4 toxicities were noted in 11 and three patients during first and second courses, respectively. Neurotoxicity of grade 3 or higher was observed in nine and seven patients during the first and second cycles, respectively. Fifteen patients had treatment interruptions of 4 weeks or longer. Overall, only 54% (95% confidence interval, 41% to 67%) of the patients demonstrated acceptable limits of toxicity. CONCLUSION: Suramin plus hydrocortisone and androgen deprivation has limited applicability in the treatment of patients with newly diagnosed metastatic prostate cancer.
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Andrógenos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Suramina/uso terapéutico , Adulto , Anciano , Andrógenos/deficiencia , Antineoplásicos Hormonales/uso terapéutico , Progresión de la Enfermedad , Esquema de Medicación , Estudios de Factibilidad , Goserelina/uso terapéutico , Humanos , Hidrocortisona/uso terapéutico , Leuprolida/uso terapéutico , Masculino , Persona de Mediana Edad , Orquiectomía , Neoplasias de la Próstata/cirugía , Suramina/administración & dosificación , Suramina/efectos adversos , Suramina/sangre , Resultado del TratamientoRESUMEN
OBJECTIVES: Suramin, a polysulfonated naphtylurea with anti-growth factor activity, was used in the treatment of metastatic, hormone- and chemotherapy-refractory prostate cancer. Recent studies have proved the effect of suramin on prostate cancer. METHODS: Between March 1990 and January 1994, 27 patients with metastatic prostate cancer were enrolled in this study. Treatment regimen consisted of a loading phase, allowing patients to reach suramin serum levels between 180 and 250 microg/mL using a suramin dose of 1.4 g/m2 at 3-day intervals. Constant suramin serum levels were maintained by a 0.5 to 1-g/m2 dose every 7 to 10 days. Because previous studies showed suramin to have serious toxicity, compromised organ status was excluded by repeated examinations. RESULTS: Six patients did not complete the suramin loading phase because of side effects and were removed from the study. With an average cumulative suramin dose of 14.2 g, 33% of the assessable patients (7 of 21) experienced a more than 50% reduction of prostate-specific antigen (PSA) and/or alkaline phosphatase (AP) serum levels. Mean survival in these suramin-responsive patients was 495 days. Two of these patients experienced a remarkable reduction of metastases in bone scan examinations. Another 48% of the patients (10 of 21) had essentially unchanged AP and PSA serum levels during suramin treatment, indicating stable disease. Mean survival of these patients was 341 days. In 4 patients undergoing suramin treatment, continuous clinical progression of the disease was observed (mean survival 79 days). Toxicity was less or comparable to prior reported studies; the most common side effects were polyneuropathy, allergic skin rash, and vortex keratopathy. CONCLUSIONS: Suramin has limited, but significant, efficacy even in chemotherapy- and hormone-refractory prostate cancer, without serious toxicity.
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Antineoplásicos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Suramina/uso terapéutico , Anciano , Analgesia , Antineoplásicos/sangre , Humanos , Masculino , Persona de Mediana Edad , Dolor/tratamiento farmacológico , Dolor/etiología , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/fisiopatología , Suramina/sangre , Tasa de SupervivenciaRESUMEN
In this study, we determined the maximum tolerated plasma concentration of suramin (within the predetermined study target range) when combined with doxorubicin in the treatment of androgen-independent prostate cancer. Twenty-four patients received suramin dosages based on proportional adjustment of the steady-state plasma suramin concentration to achieve the targeted plasma concentrations of 50-100, 101-150, 151-200, or 201-250 microg/ml. Doxorubicin (20 mg/m2) was administered i.v. over 24 h at weekly intervals. Suramin was given i.v. over 2 h twice weekly. Patients received treatment until dose-limiting toxicity or disease progression. Side effects similar to those reported for suramin and doxorubicin administered as individual agents were observed. Dose-limiting motor neuropathy developed in three patients (13%). Twelve of 24 evaluable patients (50%; 95% confidence interval, 28-71%) and 6 of 10 evaluable patients (60%; 95% confidence interval, 26-88%) had a >50% decrease of prostate-specific antigen and measurable lesions, respectively. The maximum tolerated plasma level of suramin when combined with doxorubicin was 151-200 microg/ml. Future studies on suramin combined with doxorubicin or other agents could be performed using a fixed dosing scheme with a targeted suramin steady-state plasma concentration of 200 microg/ml.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangre , Sistema Digestivo/efectos de los fármacos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/sangre , Corazón/efectos de los fármacos , Humanos , Riñón/efectos de los fármacos , Pulmón/efectos de los fármacos , Masculino , Persona de Mediana Edad , Neuronas/efectos de los fármacos , Neoplasias de la Próstata/sangre , Piel/efectos de los fármacos , Suramina/administración & dosificación , Suramina/efectos adversos , Suramina/sangre , Resultado del TratamientoRESUMEN
Suramin was administered to 49 patients in a Phase I cancer trial with real-time pharmacokinetic monitoring and dose individualization to achieve targeted mean plasma concentrations of 210 and 155 mg/liter during the 7-day period between days 15 and 22. Pharmacokinetic sampling after doses on days 1, 3, 5, and 8 was used to modify weekly suramin doses, beginning on day 15, in an attempt to achieve specific averaged plasma concentrations of 210 and 155 mg/liter. A 200-mg test dose was not effective in prospectively determining individual pharmacokinetic parameters and dosage requirements. Patients with peak plasma suramin concentrations in excess of 350 mg/liter may be more likely to experience neurotoxicity (P = 0.06), but there was no statistically significant effect of peak suramin concentration or of cumulative dose. Biopsy and autopsy tissue samples demonstrated low penetration of suramin into brain tissue and muscle but good penetration into prostate and other visceral organs. Prospective use of surrogate substrates for CYP1A2, CYP3A3/4, and CYP2D6 showed no consistent effect of suramin on these enzymes. Although a correlation between creatinine clearance and suramin renal clearance was found (r2 = 0.38; P < 0.00005), there was no correlation between creatinine clearance and total suramin clearance (P = 0.21). No suramin dose modification for renal or hepatic dysfunction can be supported at this time. Three of four ovarian cancer patients demonstrated a drop in CA-125 serum concentrations during suramin treatment.
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Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antígeno Ca-125/sangre , Riñón/metabolismo , Neoplasias/tratamiento farmacológico , Suramina/efectos adversos , Suramina/farmacocinética , Adulto , Afecto , Anciano , Antineoplásicos/sangre , Recuento de Células Sanguíneas/efectos de los fármacos , Femenino , Hemoglobinas/efectos de los fármacos , Humanos , Infusiones Intravenosas , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Suramina/sangre , Distribución TisularRESUMEN
Suramin inhibits the growth of non-small cell lung cancer (NSCLC) and breast cancer in vitro by blocking the action of most known growth factors. The clinical efficacy of suramin was evaluated in patients with unresectable or relapsed NSCLC (n = 16) and advanced breast cancer (ABC) resistant to conventional therapies (n = 12). A plasma level > or = 200 micrograms/ml was maintained by three times weekly administrations using adaptive control with feedback. Treatment was continued until documented progression of disease or unacceptable toxicity. No clinical responses were observed in any patient. Median overall survival was 4.5 months in NSCLC and 9 months in ABC patients. Mean treatment duration was 6.6 weeks in NSCLC patients and 15.9 weeks in ABC patients. Treatment was discontinued due to disease progression in 14 patients, unacceptable adverse effects in 11 patients, while three patients refused to continue therapy. We cannot recommend this drug for further clinical trials in NSCLC and ABC.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Suramina/uso terapéutico , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Neoplasias de la Mama/sangre , Carcinoma de Pulmón de Células no Pequeñas/sangre , Femenino , Humanos , Neoplasias Pulmonares/sangre , Masculino , Persona de Mediana Edad , Suramina/efectos adversos , Suramina/sangreRESUMEN
A simple and reproducible micellar electrokinetic chromatography (MEKC) method has been developed for the quantitation of suramin serum levels to be used for its therapeutic drug monitoring (TDM). A running buffer solution of 20 mM sodium borate, 75 mM sodium dodecyl sulfate (SDS), and 4 M urea at pH 9.2 were employed and samples were introduced directly into the capillary. The voltage applied for sample separation was 25 kV and UV detection was at 254 nm. Linearity was proved over the range 47.6 micrograms/mL-523.6 micrograms/mL of suramin (r: 0.9996). Orange G was used as internal standard and no interferences of common drugs simultaneously administered to patients were observed. Recovery values of the intraday and interday assays were between 92.5 and 97.2%.
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Antineoplásicos/sangre , Cromatografía Capilar Electrocinética Micelar , Suramina/sangre , HumanosRESUMEN
A high-performance liquid chromatography (HPLC) method for the determination of suramin, its precursors and analogues in aqueous solutions and in plasma samples with advantages compared to earlier methods is described. Due to the method's high sensitivity (detection limit of suramin in plasma samples: 7 ng/ml; in aqueous solutions: 5 ng/ml) and selectivity (suramin tR: 7.05 min, precursor amine 2 tR: 4.68 min), it is possible to analyze degradation products, impurities and possible metabolites of suramin besides suramin. Tetrabutylammonium hydrogensulfate (TBAHS) (5 mM) is used as ion-pairing reagent in a mixture of 36% methanol and 0.02 M phosphate buffer pH 6.5 is used as the mobile phase. After sample injection, a linear gradient from 36 to 62.9% methanol is run. A C8 stationary phase (100 x 2.1 mm I.D.) is used and ultraviolet (UV) detection at 238 nm is applied. Plasma extraction is performed with tetrabutylammonium bromide (pH 8.0) and acetonitrile. This procedure allows the determination of suramin and its precursor amine 2 in the range of 0.05-400 micrograms/ml with high precision [relative standard deviation of peak areas at 0.05 microgram/ml: 2.10% (n = 5)] and nearly complete recovery (> 96.5%). Because of the high flexibility of the chromatographic system and subsequently the universality of the method, the analysis of a broad range of suramin analogues is possible. The result of the purity check of two suramin analogues is given.
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Cromatografía Líquida de Alta Presión/métodos , Suramina/sangre , Humanos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrofotometría Ultravioleta , Suramina/análogos & derivadosRESUMEN
This paper presents a retrospective review of 6 cases of severe neutropenia attributed to suramin, the response to granulocyte-colony stimulating factor (G-CSF) and the possible mechanism. Plasma suramin concentrations, G-CSF, platelet-derived growth factor-AB (PDGF-AB) and fibroblast growth factor basic (FGF basic) levels were measured and correlated with neutropenic course. The time course of neutropenia was unpredictable and occurred both during and following discontinuation of suramin. Neutropenia rapidly resolved with G-CSF. Neither the measured growth factor levels nor plasma suramin concentrations correlated with neutropenia. We conclude that neutropenia secondary to suramin is unpredictable and responds to G-CSF administration permitting further suramin therapy. The mechanism remains unknown.
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Antineoplásicos/efectos adversos , Neutropenia/inducido químicamente , Suramina/efectos adversos , Adulto , Anciano , Antineoplásicos/uso terapéutico , Teorema de Bayes , Factor 2 de Crecimiento de Fibroblastos/sangre , Factor Estimulante de Colonias de Granulocitos/sangre , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Neutropenia/sangre , Neutropenia/terapia , Factor de Crecimiento Derivado de Plaquetas/análisis , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Estudios Retrospectivos , Suramina/sangre , Suramina/uso terapéuticoRESUMEN
PURPOSE: To confirm the previously reported high response rates and prolonged survival in hormone-refractory prostate cancer treated with suramin. PATIENTS AND METHODS: Thirty-six eligible patients with hormone-refractory prostate cancer with either measurable disease or bone disease only and a prostate-specific antigen (PSA) level greater than 50 ng/mL were enrolled. Treatment consisted of two 8-week courses of outpatient-based therapy with an interposed rest period. A bayesian adaptive control strategy and a three-compartment pharmacokinetic model that accommodates clearance changes was used to guide individual dosing. A rapid infusion of 1,000 mg/m2 suramin was followed by five daily infusions that targeted 285 micrograms/mL peak plasma levels during the first week. All patients received concomitant hydrocortisone. For the next 7 weeks, patients received one to two doses per week that targeted levels in the 150 to 285 micrograms/mL range and integrated weekly averages of 200 ug/mL. RESULTS: Nine patients (28%) had a partial response to suramin based on a > or = 50% decrease in PSA levels coupled with either relief of bone pain or by a 50% decrease in measurable disease. The median overall survival time for all patients is 31 weeks (95% confidence interval [CI], 23 to 51). Treatment was generally well tolerated, with fatigue being the most common significant toxicity, but fatal idiosyncratic myelosuppression (grade V) was observed in one patient. CONCLUSION: Using this dosing schedule, suramin has limited activity against hormone-refractory metastatic prostate cancer. Recent data suggest that hydrocortisone administered with suramin may be partly responsible for the benefit attributed to the drug. Although a small cohort of patients appeared to benefit, we were unable to confirm the previously reported high rate of activity and durability of remission using this agent.
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Adenocarcinoma/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Suramina/efectos adversos , Adenocarcinoma/mortalidad , Anciano , Anciano de 80 o más Años , Atención Ambulatoria , Semivida , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/mortalidad , Suramina/sangre , Suramina/farmacocinética , Análisis de SupervivenciaRESUMEN
INTRODUCTION: Suramin is a synthetic polysulfonated naphthylurea which has been used for the treatment of African trypanosomiasis and onchocerciasis, but since the mid-1980s has received attention as a possible antiretroviral and antineoplastic agent. OBJECTIVE: This clinical trial of suramin was undertaken as a phase I/II study in patients with hormone-refractory prostate cancer, with the hypothesis that the intensity of therapy with suramin could be increased significantly if measures were undertaken to maintain the plasma concentrations of the drug under 300 microg/ml. METHODS: We report the clinical results of this trial, wherein patients were treated at three different targeted plasma suramin concentrations (275, 215 and 175 microg/ml) for varying periods of time (2, 4 or 8 weeks), with delivery of the drug by continuous intravenous infusion. RESULTS: The major toxicity observed in this trial was neurologic, consisting of a motor and sensory peripheral neuropathy that resulted in both paresis and paralysis of the limbs. Nearly all of this severe (CTEP grade III, IV) neurologic toxicity was observed in the patients treated at a plasma suramin concentration of 275 microg/ml for 4 or more weeks. A single patient treated at 215 microg/ml for 8 weeks developed moderate (CTEP grade III) proximal lower extremity weakness, and no patient treated at 175 microg/ml developed this toxicity. The second most common toxicity observed was infection of the central venous catheter. The overall response rate for all of the evaluable patients was 17% (13 of 75 patients). In addition, prostate-specific antigen (PSA)-defined responses were observed in six patients receiving therapy at 175 microg/ml, but these responses were confounded by cessation of therapy with flutamide during suramin treatment. CONCLUSIONS: In summary, although plasma suramin concentrations were maintained below 300 microg/ml, neurologic toxicity nonetheless occurred with high frequency in patients treated at 275 microg/ml for 4 or more weeks. Therapy at 215 and 175 microg/ml was in general well tolerated, but central venous catheter-related infection, as well as the inconvenience and expense of continuous infusional therapy, make this method of drug delivery impractical. Only moderate antitumor activity was observed during this trial, but it is possible that both continuation of flutamide and flutamide withdrawal during suramin therapy confounded the assessment of suramin's activity in hormone-refractory prostate cancer.
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Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Neoplasias de la Próstata/tratamiento farmacológico , Suramina/administración & dosificación , Suramina/efectos adversos , Anciano , Anciano de 80 o más Años , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Antineoplásicos Hormonales/uso terapéutico , Relación Dosis-Respuesta a Droga , Flutamida/uso terapéutico , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Suramina/sangre , Suramina/farmacocinéticaRESUMEN
Suramin, a polysulphonated naphthylurea used in the treatment of human African trypanosomiasis (HAT), is known to cause adrenocortical insufficiency in doses exceeding the quantity used for treatment of HAT. We have previously reported that Trypanosoma brucei rhodesinese infection causes a combined central and peripheral adrenal insufficiency. To evaluate whether suramin therapy acts as an additional adrenotoxic factor, we assessed adrenocortical function in 72 patients suffering from HAT at different times during treatment with either suramin or melarsoprol by a rapid adrenocorticotropic hormone test. We found a significantly diminished peak cortisol response to stimulation in the acutely ill patients (P = 0.001), indicating impaired adrenocortical function, as well as a high incidence of partial adrenocortical insufficiency (27%). During and after trypanocidal therapy the incidence of partial adrenal insufficiency gradually declined (to 25% and 18% respectively). Stimulated peak cortisol levels did not differ significantly between patients receiving suramin and those given melarsoprol. No correlation was found between serum suramin concentration and the cortisol response to stimulation (r = 0.09, P = 0.47). Thus we conclude that suramin in trypanocidal doses neither causes nor worsens the adrenocortical dysfunction observed in Rhodesian HAT.
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Enfermedad de Addison/inducido químicamente , Suramina/efectos adversos , Tripanosomiasis Africana/tratamiento farmacológico , Enfermedad de Addison/sangre , Pruebas de Función de la Corteza Suprarrenal , Hormona Adrenocorticotrópica/sangre , Adulto , Femenino , Humanos , Hidrocortisona/sangre , Masculino , Persona de Mediana Edad , Suramina/sangre , Tripanosomiasis Africana/sangreRESUMEN
OBJECTIVES: To examine the effects of intravesical suramin on N-methyl-N-nitrosurea (MNU)-induced bladder tumors in Fischer 344 rats. METHODS: Multiple cohorts of female rats received four biweekly intravesical instillations of MNU. A control group received no other treatment, the experimental group received 25 mg/kg intravesical suramin twice a week beginning at week 6. RESULTS: After 18 weeks from the first instillation of MNU, 60% to 65% of control animals developed papillary transitional cell carcinoma, compared with only 0% to 10% of the suramin-treated animals (P = 0.01 to P = 0.0007). There was no local or systemic toxicity observed. CONCLUSIONS: Intravesical suramin is an effective chemopreventative therapy for transitional cell carcinoma in vivo with minimal toxicity.
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Carcinoma de Células Transicionales/prevención & control , Suramina/administración & dosificación , Neoplasias de la Vejiga Urinaria/prevención & control , Administración Intravesical , Animales , Femenino , Metilnitrosourea , Ratas , Ratas Endogámicas F344 , Suramina/sangre , Suramina/toxicidad , Neoplasias de la Vejiga Urinaria/inducido químicamenteRESUMEN
OBJECTIVE: No satisfactory treatment for adrenocortical carcinoma (ACC) is available. We investigated the efficacy and toxicity of suramin in the treatment of metastatic ACC since suramin has been recently reported to be active as a single agent therapy for patients with ACC and prostatic carcinoma. DESIGN: We collected data on 9 patients with metastatic ACC treated with suramin in four centres in Germany between 1987 and 1992. PATIENTS: Nine patients (5 women, 4 men; age range 32-67 years) were included. Biochemical evidence of steroid excess was found in 6/9, in three leading to clinical symptoms (hypertension, hyperglycaemia, hirsutism, gynaecomastia). MEASUREMENTS: Tumour responses were assessed by radiological and biochemical evaluation. Other investigations included regular measurements of blood cell counts, coagulation, hepatic and renal function parameters, and serum suramin concentrations. RESULTS: The patients received cumulative doses ranging from 8.2 to 30.2 g suramin over periods of 1-15 months. 3/9 achieved a partial response, 2/9 disease stabilization and 4/9 experienced progressive disease. Tumour responses were transient. Suramin treatment was without direct influence on steroid excess. Serious side-effects included coagulopathy (6/9), thrombocytopenia (6/9), polyneuropathy (2/9) and allergic skin reactions (4/9); the death of two patients was possibly related to suramin therapy. Both toxicity and tumour response were strongly associated with serum level or cumulative dose of suramin. CONCLUSIONS: (1) Suramin is of antineoplastic efficacy in the treatment of metastatic adrenocortical carcinoma. (2) The clinical use of suramin is limited by a narrow therapeutic window with the risk of serious and possibly lethal toxicity at one extreme, and loss of efficacy at the other. Strict monitoring of suramin serum levels is mandatory aiming at levels between 200 and 250 mg/l. Suramin should not be considered as first-line treatment for metastatic adrenocortical carcinoma. (3) To improve treatment options in adrenocortical carcinoma as well as for further investigation on the usefulness of suramin, controlled prospective trials are urgently needed.
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Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Carcinoma/tratamiento farmacológico , Suramina/efectos adversos , Suramina/uso terapéutico , Neoplasias de la Corteza Suprarrenal/sangre , Neoplasias de la Corteza Suprarrenal/secundario , Adulto , Anciano , Coagulación Sanguínea/efectos de los fármacos , Médula Ósea/efectos de los fármacos , Carcinoma/sangre , Carcinoma/secundario , Erupciones por Medicamentos/etiología , Femenino , Humanos , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Persona de Mediana Edad , Sistema Nervioso/efectos de los fármacos , Piel/efectos de los fármacos , Suramina/sangreRESUMEN
The use of suramin, a polysulfonated naphthylurea, in the treatment of advanced prostate cancer currently is being investigated. A 52-year-old man developed acute renal dysfunction after receiving nine doses of suramin. His suramin therapy was discontinued, but his serum creatinine level continued to rise to 10.8 mg/dl during the next 6 days. The patient was not rechallenged with suramin, and his renal function returned to baseline within the next 3 weeks. Future investigators of this drug should be aware of the possibility of such a reaction with parenteral administration.
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Lesión Renal Aguda/inducido químicamente , Carcinoma/tratamiento farmacológico , Riñón/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Suramina/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/radioterapia , Carcinoma/secundario , Terapia Combinada , Creatinina/sangre , Creatinina/orina , Flutamida/administración & dosificación , Humanos , Hidrocortisona/administración & dosificación , Leuprolida/administración & dosificación , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/radioterapia , Suramina/administración & dosificación , Suramina/sangre , Suramina/farmacocinéticaRESUMEN
BACKGROUND: Suramin is an antiparasitic drug being evaluated as an antitumor compound. Suramin therapy commonly causes weakness and is known to cause neuropathy. Two potential causes of suramin-induced muscular weakness are described. METHODS: Suramin was administered to 15 patients with advanced cancer as part of a Phase I study. Weekly dosing was adjusted to achieve mean plasma concentrations of 210 micrograms/ml. RESULTS: Serum phosphate levels fell significantly (P < 0.0001) in all 15 patients on the 42nd day of treatment from a pretreatment average of 4.0 mg/dl (standard deviation [SD] +/- 0.37) to 3.0 mg/dl (SD +/- 0.20). Absolute hypophosphatemia developed in two patients with more prolonged suramin treatment due to Fanconi's syndrome. The patient who received the largest amount of suramin (19.2 g over 14 weeks) had severe proximal muscle weakness despite 6 weeks of effective phosphate repletion. A muscle biopsy was performed, which demonstrated markedly decreased cytochrome c oxidase activity by muscle histochemistry and biochemistry. Electron microscopy revealed subsarcolemmal collections of abnormal mitochondria. This mitochondrial myopathy resolved clinically 7 weeks after discontinuing suramin. CONCLUSIONS: This report indicates that suramin is associated with hypophosphatemia of Fanconi's syndrome and a mitochondrial myopathy. The clinical combination of mitochondrial myopathy and Fanconi's syndrome is similar to descriptions of congenital mitochondrial cytochrome c oxidase deficiency of de Toni-Fanconi-Debré syndrome. These findings in humans correlate with the authors' in vitro observations that suramin causes toxic mitochondrial changes, indicating a mechanism of suramin's toxicity and possibly its antitumor effect.