A phase II study of bryostatin 1 in metastatic malignant melanoma.

Bryostatin 1 is a protein kinase C partial agonist which has both antineoplastic and immune-stimulatory properties, including the induction of cytokine release and expansion of tumour-specific lymphocyte populations. In phase I studies, tumour responses have been observed in patients with malignant melanoma, lymphoma and ovarian carcinoma. The dose-limiting toxicity is myalgia. Sixteen patients (age 35-76 years, median 57 years) with malignant melanoma were treated. All had received prior chemotherapy. In each cycle of treatment, patients received bryostatin 25 degrees g m(-2) weekly for three courses followed by a rest week. The drug was given in PET diluent (10 microg bryostatin ml(-1) of 60% polyethylene glycol, 30% ethanol, 10% Tween 80) and infused in normal saline over 1 h. The principal toxicities were myalgia (grade 2, eight patients and grade 3, six patients) and grade 2 phlebitis (four patients), fatigue (three patients) and vomiting (one patient). Of 15 patients evaluable for tumour response, 14 developed progressive disease. One patient developed stable disease for 9 months after bryostatin treatment. In conclusion, single-agent bryostatin appears ineffective in the treatment of metastatic melanoma in patients previously treated with chemotherapy. It should, however, be investigated further in previously untreated patients.

Modulation of bryostatin 1 muscle toxicity by nifedipine: effects on muscle metabolism and oxygen supply.

Bryostatin 1, an anti-neoplastic agent and protein kinase C activator, has dose-limiting toxicity manifesting as myalgia. Studies in vivo have suggested that this myalgia may be caused by impairment of oxidative metabolism as mitochondrial capacity, muscle reoxygenation and proton washout from muscle are reduced by bryostatin, possibly as a result of vasoconstriction. To investigate these mechanisms further, and to enable use of bryostatin for prolonged periods, the effect of a vasodilator on the established effects of bryostatin on calf metabolism was studied using 31P magnetic resonance spectroscopy and near infrared spectroscopy. Six patients with disseminated melanoma were examined on four occasions: before and 1 week after initiation of long-term nifedipine (10 mg twice daily) treatment and then 4 and 48 h after bryostatin infusion (25 micrograms m(-2)). Nifedipine impaired muscle oxidative metabolism but had no effect on proton efflux or muscle reoxygenation rate. In the presence of nifedipine, two of the effects of bryostatin, impaired reoxygenation rate and reduced proton efflux, were abolished, but the impaired mitochondrial activity remained. These results show that nifedipine counteracted the vasoconstrictive effect of bryostatin 1. However, because nifedipine itself had an unexpected effect on mitochondrial metabolism, it was not possible to assess whether nifedipine modified bryostatin's effect on this variable. There was no additive detrimental effect of bryostatin on mitochondrial metabolism and nifedipine did not reduce the clinical toxicity of bryostatin 1, which cannot therefore be due to vasoconstriction.