A multi-center phase II study of sequential paclitaxel and bryostatin-1 (NSC 339555) in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma

Ajani, Jaffer A.; Jiang, Yixing; Faust, Josephine; Chang, Baochong B.; Ho, Linus; Yao, James C.; Rousey, Steven R.; Dakhil, Shaker R.; Cherny, R C; Craig, Catherine; Bleyer, Archie

doi:10.1007/s10637-006-6452-1

Cited by 67 publications

(53 citation statements)

References 9 publications

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“…First, paclitaxel is considered an effective drug for gastric cancer, with response rates ranging from 20 to 28% in single-agent phase II studies (Ajani et al, 1998;Ohtsu et al, 1998;Yamada et al, 2001;Yamaguchi et al, 2002). Furthermore, Ajani et al (2006a) reported that sequential treatment with paclitaxel and bryostatin-1 is effective, with a response rate of 29%. Paclitaxel is a good candidate for combined treatment because of it lacks crossresistance to fluoropyrimidine derivatives.…”

Section: Discussionmentioning

confidence: 99%

Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer

et al. 2006

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Both paclitaxel and S-1 are effective against gastric cancer, but the optimal regimen for combined chemotherapy with these drugs remains unclear. This phase I/II study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD), dose-limiting toxicity (DLT), and objective response rate of paclitaxel in combination with S-1. S-1 was administered orally at a fixed dose of 80 mg m À2 day À1 from days 1 to 14 of a 28-day cycle. Paclitaxel was given intravenously on days 1, 8, and 15, starting with a dose of 40 mg m À2 day À1 . The dose was increased in a stepwise manner to 70 mg m À2 . Treatment was repeated every 4 weeks unless disease progression was confirmed. In the phase I portion, 17 patients were enrolled. The MTD of paclitaxel was estimated to be 70 mg m À2 because 40% of the patients given this dose level (two of five) had DLT. The RD was determined to be 60 mg m À2 . In the phase II portion, 24 patients, including five with assessable disease who received the RD in the phase I portion, were evaluated. The median number of treatment courses was six (range: 1 -17). The incidence of the worst-grade toxicity in patients given the RD was 28 and 8%, respectively. All toxic effects were manageable. The response rate was 54.1%, and the median survival time was 15.5 months. Our phase I/II trial showed that S-1 combined with paclitaxel is effective and well tolerated in patients with advanced gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer

et al. 2006

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“…However, several phase II studies using bryo-1 alone were disappointing in melanoma, 33 colorectal cancer, 34 and gastric carcinoma. 35 As the application of paclitaxel followed by bryo-1 significantly reduced tumor growth in mice, 36 phase II studies of bryo-1, in combination with other cytotoxic agents, were tried in pancreatic and prostate cancer, and renal cell and gastric carcinoma. 8,10,35 As a result, an enhanced response to paclitaxel by bryo-1 was observed in advanced gastric or gastroesophageal junction adenocarcinoma in phase II studies.…”

Section: Biology and Chemistry Of Bryostatin-1mentioning

confidence: 99%

“…35 As the application of paclitaxel followed by bryo-1 significantly reduced tumor growth in mice, 36 phase II studies of bryo-1, in combination with other cytotoxic agents, were tried in pancreatic and prostate cancer, and renal cell and gastric carcinoma. 8,10,35 As a result, an enhanced response to paclitaxel by bryo-1 was observed in advanced gastric or gastroesophageal junction adenocarcinoma in phase II studies. 35 Similar results were obtained for advanced esophageal and gastroesophageal junction cancer.…”

Section: Biology and Chemistry Of Bryostatin-1mentioning

confidence: 99%

Challenges to the development of bryostatin‐type anticancer drugs based on the activation mechanism of protein kinase Cδ

Irie

Yanagita

Nakagawa

2010

Medicinal Research Reviews

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Protein kinase C (PKC) isozymes are widely recognized as targets for anticancer therapy, and recent investigations demonstrated that PKC activators are potential therapeutic candidates for Alzheimer's disease and acquired immune deficiency syndrome. However, concerns exist about their therapeutic uses because most PKC activators are potent tumor promoters. Bryostatin 1 (bryo-1) is a unique PKC activator with little tumor-promoting activities. Bryo-1 is currently undergoing clinical trials for the treatment of cancer. However, its limited availability from natural sources and difficulty in the synthesis hamper further studies on its mode of action and structural optimization. Although excellent practical methods for synthesizing several bryo-1-related compounds have been developed, the identification of synthetically more accessible compounds with bryo-1-like activity also provides a promising way to circumvent the problem of supply. The authors focused on the bryo-1's unique mechanism of activating PKCδ that plays a tumor suppressor role, and found that a simple and less lipophilic analogue (aplog-1) of the tumor-promoting aplysiatoxin showed PKCδ-activating behavior similar to bryo-1. Aplog-1 was easily synthesized in only 22 steps using standard reactions. Moreover, its tumor-promoting activity in vitro was very weak, and its cell growth-inhibitory activities were comparable to those of bryo-1. These data suggest that aplog-1 could become another therapeutic lead for cancer.

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“…Its efficacy as a single agent has varied as a function of cancer type. More recently, studies have shown that it can enhance the clinical efficacy of known oncolytics in several cases (28)(29)(30). Additionally, bryostatin or its tunable analogs provide a starting point for promising immunotherapeutic approaches to cancer treatment (31).…”

mentioning

confidence: 99%

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

Wender

Baryza

Brenner

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Modern methods for the identification of therapeutic leads include chemical or virtual screening of compound libraries. Nature's library represents a vast and diverse source of leads, often exhibiting exquisite biological activities. However, the advancement of natural product leads into the clinic is often impeded by their scarcity, complexity, and nonoptimal properties or efficacy as well as the challenges associated with their synthesis or modification. Function-oriented synthesis represents a strategy to address these issues through the design of simpler and therefore synthetically more accessible analogs that incorporate the activity-determining features of the natural product leads. This study illustrates the application of this strategy to the design and synthesis of functional analogs of the bryostatin marine natural products. It is specifically directed at exploring the activity-determining role of bryostatin A-ring functionality on PKC affinity and selectivity. The resultant functional analogs, which were prepared by a flexible, modular synthetic strategy, exhibit excellent affinity to PKC and differential isoform selectivity. These and related studies provide the basic information needed for the design of simplified and thus synthetically more accessible functional analogs that target PKC isoforms, major targets of therapeutic interest.

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A multi-center phase II study of sequential paclitaxel and bryostatin-1 (NSC 339555) in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma

Cited by 67 publications

References 9 publications

Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer

Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer

Challenges to the development of bryostatin‐type anticancer drugs based on the activation mechanism of protein kinase Cδ

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

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