Document Detail

Induction of apoptosis using inhibitors of lysophosphatidic acid acyltransferase-beta and anti-CD20 monoclonal antibodies for treatment of human non-Hodgkin's lymphomas.
MedLine Citation:
PMID:  16000584     Owner:  NLM     Status:  MEDLINE    
PURPOSE: Lysophosphatidic acid acyltransferase-beta (LPAAT-beta) is a transmembrane enzyme critical for the biosynthesis of phosphoglycerides whose product, phosphatidic acid, plays a key role in raf and AKT/mTor-mediated signal transduction. EXPERIMENTAL DESIGN: LPAAT-beta may be a novel target for anticancer therapy, and, thus, we examined the effects of a series of inhibitors of LPAAT-beta on multiple human non-Hodgkin's lymphoma cell lines in vitro and in vivo. RESULTS: We showed that five LPAAT-beta inhibitors at doses of 500 nmol/L routinely inhibited growth in a panel of human lymphoma cell lines in vitro by >90%, as measured by [3H]thymidine incorporation. Apoptotic effects of the LPAAT-beta inhibitors were evaluated either alone or in combination with the anti-CD20 antibody, Rituximab. The LPAAT-beta inhibitors induced caspase-mediated apoptosis at 50 to 100 nmol/L in up to 90% of non-Hodgkin's lymphoma cells. The combination of Rituximab and an LPAAT-beta inhibitor resulted in a 2-fold increase in apoptosis compared with either agent alone. To assess the combination of Rituximab and a LPAAT-beta inhibitor in vivo, groups of athymic mice bearing s.c. human Ramos lymphoma xenografts were treated with the LPAAT-beta inhibitor CT-32228 i.p. (75 mg/kg) daily for 5 d/wk x 4 weeks (total 20 doses), Rituximab i.p. (10 mg/kg) weekly x 4 weeks (4 doses total), or CT-32228 plus Rituximab combined. Treatment with either CT-32228 or Rituximab alone showed an approximate 50% xenograft growth delay; however, complete responses were only observed when the two agents were delivered together. CONCLUSIONS: These data suggest that Rituximab, combined with a LPAAT-beta inhibitor, may provide enhanced therapeutic effects through apoptotic mechanisms.
John M Pagel; Christian Laugen; Lynn Bonham; Robert C Hackman; David M Hockenbery; Rama Bhatt; David Hollenback; Heather Carew; Jack W Singer; Oliver W Press
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  11     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2005 Jul 
Date Detail:
Created Date:  2005-07-07     Completed Date:  2005-12-07     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4857-66     Citation Subset:  IM    
Fred Hutchinson Cancer Research Center; Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
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MeSH Terms
Acyltransferases / antagonists & inhibitors*,  metabolism
Alanine Transaminase / blood
Antibodies, Monoclonal / administration & dosage,  adverse effects,  pharmacology*
Antigens, CD20 / immunology
Antineoplastic Combined Chemotherapy Protocols / adverse effects,  therapeutic use*
Apoptosis / drug effects*
Aspartate Aminotransferases / blood
Caspases / metabolism
Cell Line, Tumor
Dose-Response Relationship, Drug
Enzyme Inhibitors / administration & dosage,  adverse effects,  pharmacology*
Hydrocarbons, Halogenated / administration & dosage,  pharmacology*
Injections, Intraperitoneal
Lymphoma, Non-Hodgkin / drug therapy*,  pathology
Mice, Nude
Mice, SCID
Specific Pathogen-Free Organisms
Survival Analysis
Thymidine / metabolism
Time Factors
Treatment Outcome
Triazines / administration & dosage,  pharmacology*
Xenograft Model Antitumor Assays
Grant Support
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antigens, CD20; 0/CT-32228; 0/Enzyme Inhibitors; 0/Hydrocarbons, Halogenated; 0/Triazines; 0/rituximab; 10028-17-8/Tritium; 50-89-5/Thymidine; EC 2.3.-/Acyltransferases; EC acyltransferase; EC Aminotransferases; EC Transaminase; EC 3.4.22.-/Caspases

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