Treatment of patients with metastatic melanoma with bryostatin-1--a phase II study.
Bryostatin-1 is a protein kinase C regulator which has shown antitumour activity against B16 melanoma in animal models. Safety trials revealed this agent to be minimally toxic, thus a phase II trial of bryostatin-1 was conducted to determine its efficacy In patients with melanoma. Eighteen patients with metastatic melanoma, seven of whom had been previously treated, were enrolled in the study. Patients received bryostatin-1 25 microg/m2 intravenously weekly over 1 h for 3 out of 4 weeks. No objective responses were observed. One patient who had not previously received chemotherapy had stable disease for 4 months, and two patients (one previously treated) had a marked decrease in the skin component of their disease. The major toxicity was myalgia (one patient with grade III, two patients with grade II and five patients with grade I), with no grade IV toxicities reported. To Indirectly evaluate the stimulation of protein kinase C, a sensitive assay that measures the upregulation of the activated form of CD62 (glycoprotein IIb/IIIa) on platelets was performed. There was a statistically significant upregulation of this antigen 1 h after bryostatin-1 therapy. A bioassay based on the ability of bryostatin-1 to bind protein kinase C was used to measure bryostatin-1 levels in serum. This assay showed that bryostatin-1 has a volume of distribution of 2.1 l/m2, an elimination clearance of 32.9 ml/min per m2 and a half-life of 43.9 min. In conclusion, this phase II trial demonstrates that, although it is relatively non-toxic, bryostatin-1 therapy had minimal activity in metastatic melanoma.
Gonzalez
R
R
Division of Medical Oncology, University of Colorado Health Sciences Center, Denver 80262, USA.
Ebbinghaus
S
S
Henthorn
T K
TK
Miller
D
D
Kraft
A S
AS
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D054713:Bryostatins; D005260:Female; D006801:Humans; D007783:Lactones / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D018942:Macrolides; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects
D000970:Antineoplastic Agents; D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; C046785:bryostatin 1