RESUMEN
Gossypol, a polyphenolic compound which depletes cellular energy by inhibition of several intracellular dehydrogenases, has been shown to have antiproliferative activity against human glial tumor cell lines in vitro and in nude mouse xenografts. Human trials of gossypol as a male contraceptive have demonstrated safety of long-term administration. We studied the activity of Gossypol 10 mg PO bid in 27 patients with pathologically confirmed glial tumors which had recurred after radiation therapy. Fifteen patients had glioblastoma, 11 patients anaplastic astrocytoma, 1 patient relapsed low grade glioma. Response was assessed every 8 weeks using CT/MRI scan and clinical criteria including decadron requirement. Treatment was continued until disease progression. Two patients had partial response (PR); 4 had stable disease for 8 weeks or more. One patient maintained a PR with improved KPS for 78 weeks. The other had a PR lasting 8 weeks. Toxicity was mild: 2 heavily pretreated patients had mild thrombocytopenia, 5 patients developed hypokalemia, 3 patients developed grade 2 hepatic toxicity and peripheral edema. Gossypol levels measured by HPLC did not correlate with response or toxicity in this study. We conclude that gossypol is well tolerated and has a low, but measurable, response rate in a heavily pretreated, poor-prognosis group of patients with recurrent glioma. The presumed novel mechanism of action, lack of significant myelosuppression, and activity in patients with advance glioma support further study of gossypol as an antineoplastic agent.
Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Gosipol/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Neoplasias Encefálicas/mortalidad , Supervivencia sin Enfermedad , Femenino , Glioma/mortalidad , Gosipol/efectos adversos , Gosipol/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidadRESUMEN
Etoposide phophate is a phosphate ester prodrug of etoposide designed to improve the pharmaceutical characteristics of the parent compound. A Phase I dose-escalating study of etoposide phosphate was conducted concurrently at two institutions to determine its toxicity, pharmacokinetics, and maximum tolerated dose. Etoposide phosphate was administered i.v. for 30 min on days 1, 3, and 5 every 21 days or on recovery from toxicity. Cohorts of at least three patients received etoposide phosphate at dose levels from 50 mg/m2 to 150 mg/m2 expressed as molar equivalents of etoposide. Blood and urine samples were obtained from all patients during the first cycle of treatment and the concentrations of etoposide phosphate and etoposide were measured. Thirty-nine patients with documented cancers received a total of 75 cycles of etoposide phosphate. The dose-limiting toxicity was myelosuppression which occurred at the 150-mg/m2 etoposide equivalent dose. Etoposide phosphate was rapidly and extensively converted to etoposide. No measurable etoposide phosphate was detectable in the plasma by 15-60 min after the end of the infusion. The mean half-life of etoposide at the different dose levels ranged from 5.5 to 9.3 h. The pharmacokinetics of etoposide, generated from etoposide phosphate, was linear over the dose range studied and was comparable to results reported in the literature for i.v. etoposide. In summary, i.v. etoposide phosphate is rapidly and extensively converted to etoposide. The maximum tolerated dose of etoposide phosphate when given on days 1, 3, and 5 is 150 mg/m2/day. The dose-limiting toxicity is myelosuppression. The maximum tolerated dose and adverse event profile are consistent with those of etoposide.
Asunto(s)
Antineoplásicos/efectos adversos , Etopósido/análogos & derivados , Neoplasias/tratamiento farmacológico , Compuestos Organofosforados/efectos adversos , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Etopósido/administración & dosificación , Etopósido/efectos adversos , Etopósido/farmacocinética , Femenino , Semivida , Hemoglobinas/análisis , Humanos , Infusiones Intravenosas , Leucopenia/inducido químicamente , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Neoplasias/sangre , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/farmacocinética , Trombocitopenia/inducido químicamenteRESUMEN
A previously described transferrin binding protein from chicken oviduct has been identified as a heat shock protein, HSP108, by microsequencing of RP-HPLC purified tryptic peptides. The protein purified from oviduct by SDS-PAGE or from liver by ovotransferrin-affinity chromatography reacts with a monoclonal antibody raised against HSP108. The cDNA sequence predicts of KDEL peptide at the carboxyl terminus, but the protein does not react with anti-KDEL monoclonal antibodies, suggesting that HSP108 is processed in a way that eliminates the KDEL epitope.