A phase I study of intravenous bryostatin 1 in patients with advanced cancer

Prendiville, Joseph A; Crowther, Derek; Thatcher, Nick; Woll, Penella J.; Fox, Brian W; McGown, Alan T.; Testa, Nydia G; Stern, Peter L.; McDermott, R. H.; Potter, M; Pettit, George R.

doi:10.1038/bjc.1993.352

Cited by 132 publications

(55 citation statements)

References 22 publications

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“…During Phase I evaluation of bryostatin-1, myalgia was shown to be the main dose-limiting toxicity (Philip et al, 1993;Prendiville et al, 1993;Varterasian et al, 1998), although the mechanism for this is not fully understood. A maximum tolerated dose of 25 mg m À2 week À1 was identified when a weekly 24-h infusion was used (Jayson et al, 1995).…”

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confidence: 99%

A phase II trial of bryostatin-1 administered by weekly 24-hour infusion in recurrent epithelial ovarian carcinoma

et al. 2003

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A phase II trial of bryostatin-1 administered by weekly 24-hour infusion in recurrent epithelial ovarian carcinoma

et al. 2003

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“…but. when the same or higher doses were Diven over 1 h. no tumour responses were observed (Prendiville et al 1993). In this latter studv.…”

Section: Resultsmentioning

confidence: 63%

“…In the first. brvostatin was administered as a 1 infusion in 60% ethanol evenr 2 weeks for three cycles (Prendiville et al 1993 Immunological mechanisms are implicated in melanoma regression. In viexx of the responses observed in two patients with melanoma in our phase I trial (Philip et al 1993) …”

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confidence: 99%

A phase II study of bryostatin 1 in metastatic malignant melanoma

Propper

Macaulay²,

O’Byrne³

et al. 1998

Br J Cancer

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Summary 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 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 gg m-2 weekly for three courses followed by a rest week. The drug was given in PET diluent (10 gg bryostatin ml-of 60% polyethylene glycol, 30% ethanol, 10°h 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.

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“…Bryostatin 1 is a potent activator of protein kinase C (Kraft et al, 1986), as are the phorbol esters (Prendiville et al, 1993). Phorbol esterinduced activation of protein kinase C has been reported to affect intracellular calcium, although both elevation and reduction in cytosolic calcium have been reported (Dosemeci et al, 1988;Tseng and Boyden, 1991;Lacerda et al, 1988 (1995).…”

Section: Discussionmentioning

confidence: 99%

“…It has dose-limiting toxicity manifesting as myalgia about 48 h after administration (Philip et al, 1993;Prendiville et al, 1993). The muscle pain is generalised and frequently starts in the calf muscles.…”

mentioning

confidence: 99%

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

Thompson

Macaulay²,

O’Byrne³

et al. 1996

Br J Cancer

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Summary 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 ,ug 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 mitochondial metabolism and nifedipine did not reduce the clinical toxicity of bryostatin 1, which cannot therefore be due to vasoconstriction.Keywords: bryostatin 1; energy metabolism; nifedipine; mitochondria; myalgia; near infrared spectroscopy; 31p nuclear magnetic resonance; protein kinase C; vasoconstriction Bryostatin 1, a protein kinase C activator (Kraft et al., 1986), is used as an anti-neoplastic agent. It has dose-limiting toxicity manifesting as myalgia about 48 h after administration (Philip et al., 1993;Prendiville et al., 1993). The muscle pain is generalised and frequently starts in the calf muscles. The symptoms become increasingly severe and prolonged with each course of bryostatin. The aetiology of this toxicity is unknown. 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).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,...

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A phase I study of intravenous bryostatin 1 in patients with advanced cancer

Cited by 132 publications

References 22 publications

A phase II trial of bryostatin-1 administered by weekly 24-hour infusion in recurrent epithelial ovarian carcinoma

A phase II trial of bryostatin-1 administered by weekly 24-hour infusion in recurrent epithelial ovarian carcinoma

A phase II study of bryostatin 1 in metastatic malignant melanoma

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

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