Treatment of patients with metastatic melanoma with bryostatin-1 - phase II study

González, Rodrigo; Ebbinghaus, S.; Henthorn, T. K.; Miller, D. M.; Kraft, Andrew S.

doi:10.1097/00008390-199912000-00010

Cited by 41 publications

(12 citation statements)

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“…We find that mutation of RUNX1/ AML1c serine 94, comparable with RUNX2/AML3 serine 104, has little or no effect on RUNX1/AML1c activity. 2 Mutation of the other RUNX2/AML3 amino-terminal phosphorylation site, serine 14, had no detectable effect on RUNX2/ AML3 activity (40). Likewise, we find that mutation of RUNX1/ AML1c threonine 41 and serine 48 eliminates phosphorylation of the amino terminus but has little effect on RUNX1/AML1c activity.…”

Section: Discussionmentioning

confidence: 49%

“…2 However, mutation of all 11 AML1c Ser-Pro or Thr-Pro sites results in a protein with less transcriptional activity than the 4M protein, at least on some promoters. This suggests that the four PMA-induced Ser-Pro/Thr-Pro sites in the AML1c activation domain may be the strongest regulators of activity, but the remaining sites may have subtle effects on activity, perhaps through different mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, mutation of RUNX1/AML1c serine 424 had little or no effect on transcriptional activity. 2 This difference may be either protein-specific or cell type-specific.…”

Section: Discussionmentioning

confidence: 99%

“…1). The ability of phorbol esters to induce differentiation of leukemic cells has suggested that additional compounds that activate protein kinase C might be used as treatments for human leukemia (2). It is possible that PMA-induced differentiation occurs through the regulation of a limited number of key proteins, for example transcription factors, that are essential for hematopoiesis.…”

mentioning

confidence: 99%

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Phorbol Ester Treatment of K562 Cells Regulates the Transcriptional Activity of AML1c through Phosphorylation

Zhang

Biggs

Kraft

2004

Journal of Biological Chemistry

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We find that phorbol ester (PE) treatment of K562 cells greatly stimulates promoters (T cell receptor ␤, myeloperoxidase, macrophage colony-stimulating factor receptor, and granulocyte macrophage colony-stimulating factor receptor) containing AML1 transcription factor binding sites. This stimulation of AML1c transcriptional activity is mediated by direct phosphorylation of the AML1c molecule on multiple phosphorylation sites. Eleven AML1c (S/T)P sites in the transcriptional activating domain are phosphorylated at a basal level in untreated K562 cells; treatment of the K562 cells with PE results in increased phosphorylation at five of these sites (serines 276, 293, 303, 462, and threonine 300). Mutation of these five sites to alanine inhibits PE-induced transcriptional activity; mutation of the sites to an acidic amino acid, aspartic acid, stimulates constitutive activity. Single mutations in four amino acids or double mutations (serines 276 and 293 or threonine 300 and serine 303) have little effect on AML1c transcriptional activity. Inhibitor assays suggest that the ERK family of protein kinases is activated by PEs to phosphorylate the (S/T)P sites within the AML1c molecule and markedly enhance the transcriptional activity of AML1c.

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Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 99%

“…In contrast, mutation of RUNX1/AML1c serine 424 had little or no effect on transcriptional activity. 2 This difference may be either protein-specific or cell type-specific.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Phorbol Ester Treatment of K562 Cells Regulates the Transcriptional Activity of AML1c through Phosphorylation

Zhang

Biggs

Kraft

2004

Journal of Biological Chemistry

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“…Phase II studies of bryostatin 1 given at the same dose but with a one hour infusion in patients with malignant melanoma have also failed to demonstrate significant antitumour activity (Propper et al, 1998;Gonzalez et al, 1999). In contrast, in a phase I trial Varterasian et al (1998) achieved a higher MTD, again limited by myalgia, of 120 µg/m 2 bryostatin 1, infused over 72 hours every 2 weeks.…”

Section: Discussionmentioning

confidence: 99%

A phase II trial of bryostatin 1 in patients with non-Hodgkin's lymphoma

et al. 2001

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Summary Bryostatin 1 is a naturally occurring macrocyclic lactone with promising antitumour and immunomodulatory function in preclinical and phase I clinical investigations. In this phase II study, 17 patients with progressive non-Hodgkin's lymphoma of indolent type (NHL), previously treated with chemotherapy, received a median of 6 (range 1-9) intravenous infusions of 25 µg/m 2 bryostatin 1 given once weekly over 24 hours. In 14 evaluable patients no responses were seen. Stable disease was attained in one patient for 9 months. The principal toxicities were myalgia and phlebitis. Treatment was discontinued early because of toxicity alone (phlebitis) in 2 patients, toxicity in addition to progressive disease in 3 patients (myalgia and phlebitis n = 2; thrombocytopenia n = 1) and progressive disease in 5 patients. The results fail to demonstrate efficacy of this regimen of bryostatin 1 in the treatment of NHL. In light of preclinical data that demonstrate synergy between bryostatin 1 and several cytotoxic agents and cytokines, clinical studies to investigate bryostatin 1 in combination are warranted. We also present data to demonstrate that central venous lines may be used in future studies to avoid phlebitis.

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Bryostatin and Their Analogues

Diederichsen¹

2003

Organic Synthesis Highlights V

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Treatment of patients with metastatic melanoma with bryostatin-1 - phase II study

Cited by 41 publications

References 0 publications

Phorbol Ester Treatment of K562 Cells Regulates the Transcriptional Activity of AML1c through Phosphorylation

Phorbol Ester Treatment of K562 Cells Regulates the Transcriptional Activity of AML1c through Phosphorylation

A phase II trial of bryostatin 1 in patients with non-Hodgkin's lymphoma

Bryostatin and Their Analogues

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