OBJECTIVES: Bryostatin-1 is a macrocyclic lactone that has been shown to regulate protein kinase C (PKC) activity and thereby potentially inhibit tumor invasion, angiogenesis, cell adhesion, and multidrug resistance. In preclinical experiments, bryostatin-1 induces tumor growth inhibition and enhances cytotoxicity when combined with other agents including cisplatin in cervical cancer cells. It was therefore anticipated that combination bryostatin-1-cisplatin therapy would be effective in patients with cervical cancer. The current study was conducted to evaluate this therapeutic approach in patients with recurrent or advanced-stage cervical carcinoma. METHODS: An IRB-approved New York Gynecologic Oncology Group (NYGOG) trial was activated for patients with a histological diagnosis of metastatic cervical cancer or in patients with recurrent disease not eligible for surgery or radiation. Enrolled patients received bryostatin-1 (50-65 microg/m(2)) as a 1-h infusion followed by cisplatin (50 mg/m(2)). The combined treatment was administered every 21 days. RESULTS: Fourteen patients were enrolled. The majority of patients had squamous cell carcinoma. Ten out of fourteen patients had recurrent disease. Fifty percent of the patients received bryostatin at 50 microg/m(2) and 50% received bryostatin at 65 microg/m(2). Seventy-one percent completed two cycles of treatment. The most common grade II-III toxicities were myalgia, anemia, and nausea or vomiting. One patient developed a hypersensitivity reaction and one developed grade III nephrotoxicity. Seventy-one percent (10/14) of patients were evaluated for tumor response. Eight out of ten (80%) of patients had progressive disease and 2/10 (20%) had stable disease. There were no treatment responses. CONCLUSIONS: Despite promising preclinical data, this clinical trial indicates that the combination of cisplatin and bryostatin-1 at the doses and schedule used is not effective in patients with advanced-stage or recurrent cervical cancer. There is even the possibility of therapeutic antagonism. The development of a serum assay for bryostatin-1 and additional mechanistic studies would be useful for future bryostatin clinical trials.
OBJECTIVES:Bryostatin-1 is a macrocyclic lactone that has been shown to regulate protein kinase C (PKC) activity and thereby potentially inhibit tumor invasion, angiogenesis, cell adhesion, and multidrug resistance. In preclinical experiments, bryostatin-1 induces tumor growth inhibition and enhances cytotoxicity when combined with other agents including cisplatin in cervical cancer cells. It was therefore anticipated that combination bryostatin-1-cisplatin therapy would be effective in patients with cervical cancer. The current study was conducted to evaluate this therapeutic approach in patients with recurrent or advanced-stage cervical carcinoma. METHODS: An IRB-approved New York Gynecologic Oncology Group (NYGOG) trial was activated for patients with a histological diagnosis of metastatic cervical cancer or in patients with recurrent disease not eligible for surgery or radiation. Enrolled patients received bryostatin-1 (50-65 microg/m(2)) as a 1-h infusion followed by cisplatin (50 mg/m(2)). The combined treatment was administered every 21 days. RESULTS: Fourteen patients were enrolled. The majority of patients had squamous cell carcinoma. Ten out of fourteen patients had recurrent disease. Fifty percent of the patients received bryostatin at 50 microg/m(2) and 50% received bryostatin at 65 microg/m(2). Seventy-one percent completed two cycles of treatment. The most common grade II-III toxicities were myalgia, anemia, and nausea or vomiting. One patient developed a hypersensitivity reaction and one developed grade III nephrotoxicity. Seventy-one percent (10/14) of patients were evaluated for tumor response. Eight out of ten (80%) of patients had progressive disease and 2/10 (20%) had stable disease. There were no treatment responses. CONCLUSIONS: Despite promising preclinical data, this clinical trial indicates that the combination of cisplatin and bryostatin-1 at the doses and schedule used is not effective in patients with advanced-stage or recurrent cervical cancer. There is even the possibility of therapeutic antagonism. The development of a serum assay for bryostatin-1 and additional mechanistic studies would be useful for future bryostatin clinical trials.
Authors: Liwei Bao; Michael A Gorin; Manchao Zhang; Alejandra C Ventura; William C Pomerantz; Sofia D Merajver; Theodoros N Teknos; Anna K Mapp; Quintin Pan Journal: Cancer Res Date: 2009-06-30 Impact factor: 12.701
Authors: Corina E Antal; Andrew M Hudson; Emily Kang; Ciro Zanca; Christopher Wirth; Natalie L Stephenson; Eleanor W Trotter; Lisa L Gallegos; Crispin J Miller; Frank B Furnari; Tony Hunter; John Brognard; Alexandra C Newton Journal: Cell Date: 2015-01-22 Impact factor: 41.582
Authors: Anna C Pavlick; Jennifer Wu; John Roberts; Mark A Rosenthal; Anne Hamilton; Scott Wadler; Kathleen Farrell; Michelle Carr; David Fry; Anthony J Murgo; Ruth Oratz; Howard Hochster; Leonard Liebes; Franco Muggia Journal: Cancer Chemother Pharmacol Date: 2009-02-17 Impact factor: 3.333
Authors: Catríona M Dowling; James Phelan; Julia A Callender; Mary Clare Cathcart; Brian Mehigan; Paul McCormick; Tara Dalton; John C Coffey; Alexandra C Newton; Jacintha O'Sullivan; Patrick A Kiely Journal: Oncotarget Date: 2016-04-12