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Titolo:
PHASE-I STUDY OF BRYOSTATIN-1 - ASSESSMENT OF INTERLEUKIN-6 AND TUMOR-NECROSIS-FACTOR-ALPHA INDUCTION IN-VIVO
Autore:
PHILIP PA; REA D; THAVASU P; CARMICHAEL J; STUART NSA; ROCKETT H; TALBOT DC; GANESAN T; PETTIT GR; BALKWILL F; HARRIS AL;
Indirizzi:
CHURCHILL HOSP,IMPERIAL CANC RES FUND,CLIN ONCOL UNIT OXFORD OX3 7LJ ENGLAND CHURCHILL HOSP,IMPERIAL CANC RES FUND,CLIN ONCOL UNIT OXFORD OX3 7LJ ENGLAND ARIZONA STATE UNIV,CANC RES INST TEMPE AZ 85287 IMPERIAL CANC RES FUND,BIOL THERAPY LAB LONDON WC2A 3PX ENGLAND
Titolo Testata:
Journal of the National Cancer Institute
fascicolo: 22, volume: 85, anno: 1993,
pagine: 1812 - 1818
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROTEIN-KINASE-C; CARCINOMA-CELLS; ACTIVATORS; MELANOMA; GROWTH; AGENT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
25
Recensione:
Indirizzi per estratti:
Citazione:
P.A. Philip et al., "PHASE-I STUDY OF BRYOSTATIN-1 - ASSESSMENT OF INTERLEUKIN-6 AND TUMOR-NECROSIS-FACTOR-ALPHA INDUCTION IN-VIVO", Journal of the National Cancer Institute, 85(22), 1993, pp. 1812-1818

Abstract

Background: Many oncogenes have been shown to code for growth factor receptors that are involved in regulation of cell growth and proliferation and can activate transcription via protein kinase C. Bryostatin 1, a partial agonist of protein kinase C, has demonstrated potent antitumor activity in vitro and in vivo in human tumor xenografts. Purpose:The aim of this phase I study was to determine the optimal dosage andtoxicity profile of bryostatin 1 and its influence on cytokine release in vivo. Methods: Three successive cohorts consisting of 35 patientswith various malignant tumors were treated with bryostatin 1 by intravenous infusion over 1 hour as follows: cohort A-35 mug/m2 (three patients) or 50 mug/m2 (eight patients) once every 2 weeks; cohort B-25 mug/m2 once a week (eight patients); and cohort C-25 mug/m2 once a week for 3 weeks, with no treatment during the 4th week (16 patients). Plasma levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 6(IL-6) were measured by immunoradiometric assay and by radioimmunoassay, respectively. Results: The dose-limiting toxicity was grade 3 or 4myalgia in four of 11 patients in cohort A, in two of eight in cohortB, and in none of 16 in cohort C. Occurrence of myalgia was dose related. There was no significant myelosuppression, apart from a small andtransient fall in platelet count. Six patients experienced acute but transient skin flushing, dyspnea, hypotension, and bradycardia, probably related to the bryostatin 1 vehicle. TNF-alpha and IL-6 were detected in plasma at 2 and 24 hours after treatment, respectively, and the levels were dose related (P = .02). Two patients with metastatic malignant melanoma had partial remission after three or four cycles of therapy; remission lasted 6 weeks and 10+ months, respectively. Conclusions: The dose-limiting toxicity of bryostatin 1 was myalgia. Plasma IL-6and TNF-alpha concentrations were increased within 24 hours of therapy. Antitumor activity against malignant melanoma was observed early inthe course of treatment. Implications: The recommended dosage of bryostatin 1 for phase II studies is 25 mug/m2 by intravenous infusion for1 hour once a week for 3 weeks, with no treatment in the 4th week. IL-6 and TNF-alpha plasma concentrations may be useful in monitoring biological activity of bryostatin 1. Future studies should explore use ofthis drug with other conventional immune modulators and conventional cytotoxic drugs.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 24/09/20 alle ore 23:20:51