Phase I Study of Bryostatin 1 and Fludarabine in Patients with Chronic Lymphocytic Leukemia and Indolent (Non-Hodgkin's) Lymphoma

Roberts, John D.; Smith, Mitchell R.; Feldman, Eric J.; Cragg, Louise; Millenson, Michael; Roboz, Gail J.; Honeycutt, Connie; Thune, Rose; Padavic-Shaller, Kristin; Carter, W. Hans; Ramakrishnan, Viswanathan; Murgo, Anthony J.; Grant, Steven

doi:10.1158/1078-0432.ccr-05-2730

Cited by 36 publications

(30 citation statements)

References 44 publications

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“…The recommended bryostatin phase ii dose is 50 μg/m 2 for both sequences. The combination showed moderate activity, and responses were seen in patients who had previously been treated with fludarabine 63 .…”

Section: Bryostatin-1mentioning

confidence: 99%

Development of Cell-Cycle Inhibitors for Cancer Therapy

Dickson¹,

Schwartz

2009

Current Oncology

197

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Modulation of the cell cycle also contributes to chemotherapy resistance. The cyclin-dependent kinases (cdks), the essential engines of the cell cycle, are therefore rational therapeutic targets. Over the last several years, a new class of anticancer therapy has been developed and extensively tested: inhibitors of cdks.These drugs have been tested as single agents with modest results. However, in combination with traditional cytotoxic chemotherapy, they have the potential to overcome drug resistance and to improve cytotoxic efficacy. THE CELL CYCLE AND ITS REGULATIONThe cell cycle governs the transition from quiescence (G0) to proliferation while ensuring the fidelity of the genetic transcript. The phases associated with dna synthesis (S phase) and mitosis (M phase) are separated by the gaps G1 and G2. The cdks join with regulatory proteins called cyclins to drive the cell through the cycle.Inhibitory proteins [cdk inhibitors (cdkis)] block specific interactions. The Ink4 (inhibitor of cdk4) class of cdkis (p16 Ink4a , p15 Ink4b , p18 Ink4c , and p19 Ink4 ) bind and inhibit cyclin D-associated kinases (cdk2, -4, and -6), and the kinase inhibitor protein (Kip) group of cdkis (p21 Waf1 , p27 Kip1 , and p57 Kip2 ) block the cyclin E/cdk2 and cyclin A/cdk2 complexes 1 .The pattern of cyclin expression defines the cell's progression through the cycle 2,3 . At least 9 cdks (cdk1-cdk9) and many cyclins (cyclin A-cyclin T) are known. The cdk /cyclin complexes are activated by specific phosphorylation of the cdk by cdk7/cyclin H, also called cdk-activating kinase 4 . Specific complexes regulate each step of the cycle. Cyclins D1-D3/cdk2, -4, and -6 drive progression through G1; cyclin E/cdk2 controls entry into S phase; cyclin A/cdk2 controls S-phase progression; cyclin A/ cdk1 (also known as cdc2) controls G2; and cdk1/ cyclin B facilitates mitosis.Entry into the cell cycle (G1) is governed by the restriction point, beyond which progression through the cycle is independent of stimuli such as ABSTRACTThe cell cycle governs the transition from quiescence through cell growth to proliferation. The key parts of the cell cycle machinery are the cyclin-dependent kinases (cdks) and the regulatory proteins called cyclins. The cdks are rational targets for cancer therapy because their expression in cancer cells is often aberrant and their inhibition can induce cell death. Inhibitors of cdks can also block transcription.Several drugs targeting the cell cycle have entered clinical trials. These agents include flavopiridol, indisulam, AZD5438, SNS-032, bryostatin-1, seliciclib, PD 0332991, and SCH 727965. Phase i studies have demonstrated that these drugs can generally be administered safely. Phase ii studies have shown little single-agent activity in solid tumors, but combination studies with cytotoxic chemotherapy have been more promising. In hematologic malignancies, reports have shown encouraging single-agent and combination activity. Pharmacodynamic studies show that the dose and schedule of these drugs are crucial to permit ma...

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Section: Bryostatin-1mentioning

confidence: 99%

Development of Cell-Cycle Inhibitors for Cancer Therapy

Dickson¹,

Schwartz

2009

Current Oncology

197

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“…12,13,22 Mechanistically this may be related to the fact that bryostatin 1 acts as a mixed antagonist/agonist of PKC. Bryostatin 1 has been shown to induce Mcl-1 expression in CLL cells, thus enhancing apoptosis resistance.…”

Section: Bl22 Overcomes Bryostatin 1-induced Upregulation Of Mcl-1 Anmentioning

confidence: 99%

“…11 However, after phase I/II evaluation, it is now evident that bryostatin 1 has minimal single agent activity and, therefore, combined treatments of bryostatin 1 and chemotherapeutics were investigated in clinical trials. 12,13 The ability of bryostatin 1 to induce a 'hairy cell phenotype' in CLL cells, including the marked upregulation of CD22, prompted us to investigate whether it could enhance the cytotoxicity of BL22. By using dose-response evaluation of bryostatin 1 we demonstrate that the combination of BL22 and bryostatin 1 increases the cytotoxicity of the immunotoxin not only through upregulation of CD22, but also through modulation of PKC-βII.…”

Section: Introductionmentioning

confidence: 99%

The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC- II depletion

Biberacher¹,

Decker²,

Oelsner³

et al. 2011

Haematologica

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BackgroundIn spite of potent first-line therapies for chronic lymphocytic leukemia, treatment remains palliative and all patients frequently relapse. Treatment options for these patients are more limited. BL22 is a recombinant protein composed of the variable region of a monoclonal antibody that binds to CD22 and of PE38, a truncated Pseudomonas exotoxin. BL22 is a very potent drug already used in patients with hairy cell leukemia, whereas in chronic lymphocytic leukemia its cytotoxicity is limited by a lower expression of CD22. Here we demonstrate that this limitation can be overcome by pre-activation of chronic lymphocytic leukemia cells with bryostatin 1. Design and MethodsPrimary malignant B cells from chronic lymphocytic leukemia and mantle cell lymphoma patients were used in vitro to assess the therapeutic impact of drug combinations using BL22 and bryostatin 1. ResultsWe demonstrate that bryostatin 1 sensitizes chronic lymphocytic leukemia cells for the cytotoxic effects of BL22 through activation of protein kinase C and subsequently increased CD22 surface expression. Dose and time response analysis reveals that activation of protein kinase C further activates an autocrine feedback loop degrading protein kinase C-βII protein. Depletion of protein kinase C-βII and upregulation of CD22 persist for several days following pre-stimulation with bryostatin 1. Therefore, our data provide a rationale for the sequential administration of BL22 following bryostatin 1 treatment. In addition to primary chronic lymphocytic leukemia cells, bryostatin 1 also sensitizes diffuse large B-cell lymphoma and mantle cell lymphoma cells to BL22 induced apoptosis. ConclusionsOur data suggest that the combination of bryostatin 1 with antibodies directed against CD22 is a potent drug combination for the treatment of low-and high-grade B-cell lymphoma.Key words: CLL, bryostatin 1, CD22, immunotoxin, B-cell lymphoma. CD22 upregulation and PKC-βII depletion. Haematologica 2012;97(5):771-779. doi:10.3324/haematol.2011 This is an open-access paper. Citation: Biberacher V, Decker T, Oelsner M, Wagner M, Bogner C, Schmidt B, Kreitman RJ, Peschel C, Pastan I, Meyer zum Büschenfelde C and Ringshausen I. The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC-βII depletion

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“…Bryostatin 1, a PKD activator, has been used in several clinical trials for cancers including prostate with limited success (Roberts et al, 2006;Ku et al, 2008). Further understanding of PKD1 mechanism of PKD1 activity will provide newer approaches to improve efficacy of activators and inhibitors.…”

Section: Hsp27 Mediates Repression Of Ar By Pkd1 In Pc Cellsmentioning

confidence: 99%

Heat shock protein 27 mediates repression of androgen receptor function by protein kinase D1 in prostate cancer cells

et al. 2009

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We have previously shown that protein kinase D1 (PKD1), charter member of PKD protein family, is downregulated in advanced prostate cancer (PC) and influences androgen receptor (AR) function in PC cells. Other independent studies showed that serine 82 residue in heat shock protein 27 (Hsp27) undergoes substrate phosphorylation by PKD1 and is associated with nuclear transport of AR resulting in increased AR transcriptional activity. In this study, we show that PKD1 interacts and phosphorylates Hsp27 at Ser82 in PC cells, which is mediated by p38-dependent mitogen-activated protein kinase pathway and is necessary for PKD1 repression of AR transcriptional activity and androgen-dependent proliferation of PC cells. The study provides first in vivo evidence that Hsp27 is a mediator of repression of AR function by PKD1 in PC cells, thereby linking the data in the published literature.

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Phase I Study of Bryostatin 1 and Fludarabine in Patients with Chronic Lymphocytic Leukemia and Indolent (Non-Hodgkin's) Lymphoma

Cited by 36 publications

References 44 publications

Development of Cell-Cycle Inhibitors for Cancer Therapy

Development of Cell-Cycle Inhibitors for Cancer Therapy

The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC- II depletion

Heat shock protein 27 mediates repression of androgen receptor function by protein kinase D1 in prostate cancer cells

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