Bryostatin 1, a novel antineoplastic agent and protein kinase C activator, induces human myalgia and muscle metabolic defects: a 31P magnetic resonance spectroscopic study

Abstract

Summary Bryostatin 1, a novel antineoplastic agent and protein kinase C (PKC) activator, has been found to induce myalgia (muscle pain) 48 h after administration in clinical trials. This is the dose-limiting toxicity and has restricted the duration of therapy in phase I trials. To investigate the mechanisms and try to increase toleration of the drug, we studied calf muscle metabolism of 14 patients at rest and during exercise and subsequent recovery using 31P magnetic resonance spectroscopy (MRS) before and 4 h, 48 -72 h and 1-2 weeks following bryostatin therapy. In resting muscle there was a significant (P<0.001) increase in the phosphodiester/adenosine 5'-triphosphate (PDE/ATP) ratio 48 h post bryostatin and in patients with myalgia compared with pre-bryostatin control studies. Following exercise, patients with myalgia showed significantly slower phosphocreatine (PCr) and ADP recovery half-time (P <0.05) suggesting impaired mitochondrial (oxidative) energy production, possibly due to a direct effect on the mitochondria or secondary to reduced blood flow. The apparent proton efflux rate following exercise was significantly reduced 4 h after bryostatin (P <0.05), suggesting reduced blood flow. The rate of post-exercise reoxygenation was studied in four patients by near-infrared spectroscopy 4 h post bryostatin. In three of these the rate was reduced, consistent with reduced muscle blood flow. Bryostatin 1 appeared to cause a long-lasting impairment of oxidative metabolism and proton washout from muscle, consistent with a vasoconstrictive action. Thus these studies provide evidence for two mechanisms of the dose-limiting toxicity for bryostatin. Prospective studies on the use of vasodilators to improve the tolerance of the drug should be carried out.

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

“…In the absence of nifedipine, bryostatin caused a decrease in proton efflux from the muscle and a decrease in mitochondrial function (Hickman et al, 1995). These changes could be explained as resulting from bryostatin-induced vasoconstnction in vivo, as has been observed in the isolated perfused rat heart (K Clarke and P Hickman, personal communication).…”

“…Nifedipine had no independent effect on proton efflux, but the previously reported reduced proton efflux following bryostatin infusion (Hickman et al, 1995) was abolished by pretreatment with nifedipine (Table II) After the initial studies (study 1), subjects were started on slow release nifedipine 10mg twice daily orally throughout the remainder of the protocol. One week following commencement of nifedipine, subjects were examined again (study 2), after which the patient received an infusion of bryostatin (25 Mg m-2).…”

“…There is recent evidence of vasoconstriction following treatment with bryostatin ex vivo (K Clarke and P Hickman, personal communication) and probably in vivo as well (Hickman et al, 1995). Separate to, or because of, this vasoconstriction, bryostatin has caused mitochondrial dysfunction and reduced proton efflux from skeletal muscle during recovery from exercise (Hickman et al, 1995).In patients with disseminated malignant melanoma scheduled to receive bryostatin, we have examined the effect of pretreatment with a vasodilating agent, nifedipine, on muscle oxidative and non-oxidative ATP synthesis, muscle reoxygenation rate and on the occurrence and severity of myalgia. Nifedipine is an L-type calcium channel blocker and belongs to the dihydropyridine group of drugs that cause smooth muscle relaxation and hence vasodilatation.…”

“…Investigations including analysis of plasma creatine phosphokinase, urine myoglobin excretion and electromyography have failed to show evidence of either muscle inflammation or peripheral neuropathy. There is recent evidence of vasoconstriction following treatment with bryostatin ex vivo (K Clarke and P Hickman, personal communication) and probably in vivo as well (Hickman et al, 1995). Separate to, or because of, this vasoconstriction, bryostatin has caused mitochondrial dysfunction and reduced proton efflux from skeletal muscle during recovery from exercise (Hickman et al, 1995).…”

A phase II study of bryostatin 1 in metastatic malignant melanoma

“…Its aetiolo5v is unknown. and appears to be a direct drug effect on muscle (Hickman et al 1995: Thompson et al 1996. Other studies have shown that the myalgia is not reversed by nifedipine.…”