Abstract
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.
Highlights
MethodsSix physically active patients with malignant melanoma were recruited from a Cancer Research Campaign phase I clinical trial of bryostatin 1 in disseminated malignancies unresponsive to conventional treatment
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 mitochondial metabolism and nifedipine did not reduce the clinical toxicity of bryostatin 1, which cannot be due to vasoconstriction
Summary
Six physically active patients with malignant melanoma were recruited from a Cancer Research Campaign phase I clinical trial of bryostatin 1 in disseminated malignancies unresponsive to conventional treatment. Subjects were examined by both 31P-MRS and NIRS on two separate occasions. After the initial combined MRS and NIRS studies, the subject was treated throughout the Bryostatin courseb. AMaximal myalgia experienced by patient:'grade 0, no pain; grade 1, mild pain not requiring analgesia; grade 2, moderately severe pain with irregular analgesia; grade 3, moderate to severe pain requiring nonopiate analgesia(Philip et al, 1993). I myalgia.cMyalgia impossible to assess due to the development of spinal nerve compression that prevented evaluation of the aetiology of any muscle pain. Patient 7 did not receive nifedipine before bryostatin infusion
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