MODULATION OF BRYOSTATIN-1 MUSCLE TOXICITY BY NIFEDIPINE - EFFECTS ONMUSCLE 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 ha ve suggested that this myalgia may be caused by impairment of oxidativ e metabolism as mitochondrial capacity, muscle reoxygenation and proto n washout from muscle are reduced by bryostatin, possibly as a result of vasoconstriction. To investigate these mechanisms further, and to e nable use of bryostatin for prolonged periods, the effect of a vasodil ator on the established effects of bryostatin on calf metabolism was s tudied using P-31 magnetic resonance spectroscopy and near infrared sp ectroscopy. Six patients with disseminated melanoma were examined on F our occasions: before and 1 week after initiation of long-term nifedip ine (10 mg twice daily) treatment and then 4 and 48 h after bryostatin infusion (25 mu g m(-2)). Nifedipine impaired muscle oxidative metabo lism but had no effect on proton efflux or muscle reoxygenation rate. In the presence of nifedipine, two of the effects of bryostatin, impai red 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. H owever, because nifedipine itself had an unexpected effect on mitochon drial metabolism, it was not possible to assess whether nifedipine mod ified bryostatin's effect on this variable. There was no additive detr imental effect of bryostatin on mitochondial metabolism and nifedipine did not reduce the clinical toxicity of bryostatin 1, which cannot th erefore be due to vasoconstriction.