RESUMEN
PURPOSE: The purpose of this study was to determine the dose-limiting toxicities (DLTs), the maximum tolerated dose, and the pharmacokinetics of the novel glutathione analog TLK286 administered by i.v. infusion. EXPERIMENTAL DESIGN: Patients with advanced malignancies received i.v. TLK286 administered as a 30-min constant rate infusion once every 3 weeks in escalating doses from 60 to 1280 mg/m(2). Patients underwent tumor assessment on day 43 and continued on treatment until disease progression or unacceptable toxicity. RESULTS: A total of 35 patients were treated with 109 cycles of TLK286. At 1280 mg/m(2), 3 of 5 patients developed one of two observed dose limiting toxicities (DLTs). The DLTs were: mild pancreatitis (1 of 5) and bladder symptoms (2 of 5) consisting of hematuria, dysuria, and urinary frequency. All of the patients with DLTs continued on TLK286 treatment at 960 mg/m(2) (one dose below maximum tolerated dose) without recurrence of DLTs. DLTs were transient, resolved without sequelae, and noncumulative. TLK286-related toxicities included grade 1-2 nausea, vomiting, fatigue, transient microscopic hematuria, and anemia. Of 31 evaluable patients, 10 patients continued therapy (median six cycles; range, four to nine cycles). Pharmacokinetic studies of TLK286 on cycle 1 revealed a mean elimination half-life of 18 min (95% confidence interval, 16.1-19.9). Dose-proportional increases in both maximum blood concentrations and area under the blood-concentration-time curve were observed over the dose range of 60-960 mg/m(2). CONCLUSION: TLK286 was well tolerated in this study. TLK286 safety and pharmacokinetics support disease-specific evaluations of TLK286 at doses <1280 mg/m(2) administered once every three weeks in the treatment of patients with advanced malignancies.
Asunto(s)
Citotoxinas/administración & dosificación , Citotoxinas/farmacocinética , Glutatión/análogos & derivados , Glutatión/administración & dosificación , Glutatión/farmacocinética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Citotoxinas/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Glutatión/efectos adversos , Humanos , Infusiones Intravenosas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Neoplasias/sangreRESUMEN
Through the application of TRAP (target-related affinity profiling), we identified a novel class of heteroaroylphenylureas that inhibit human CCL2-induced chemotaxis of monocytes/macrophages both in vitro and in vivo. This inhibition was concentration-dependent and selective with regard to other chemokines. The compounds, however, did not antagonize the binding of (125)I-labeled CCL2 to the CCR2 receptor nor did they block CCR2-mediated signal transduction responses such as calcium mobilization. Optimization of early leads for potency and pharmacokinetic parameters resulted in the identification of 17, a potent inhibitor of chemotaxis (IC(50) = 80 nM) with excellent oral bioavailability in rats (F = 60%). Compound 17 reduced swelling and joint destruction in two rat models of rheumatoid arthritis and delayed disease onset and produced near complete resolution of symptoms in a mouse model of multiple sclerosis.