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Induction of apoptosis using inhibitors of lysophosphatidic acid acyltransferase-beta and anti-CD20 monoclonal antibodies for treatment of human non-Hodgkin's lymphomas.

AbstractPURPOSE:
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.
AuthorsJohn M Pagel, Christian Laugen, Lynn Bonham, Robert C Hackman, David M Hockenbery, Rama Bhatt, David Hollenback, Heather Carew, Jack W Singer, Oliver W Press
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 13 Pg. 4857-66 (Jul 01 2005) ISSN: 1078-0432 [Print] United States
PMID16000584 (Publication 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.)
Chemical References
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, CD20
  • CT-32228
  • Enzyme Inhibitors
  • Hydrocarbons, Halogenated
  • Triazines
  • Tritium
  • Rituximab
  • Acyltransferases
  • 2-acylglycerophosphate acyltransferase
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Caspases
  • Thymidine
Topics
  • Acyltransferases (antagonists & inhibitors, metabolism)
  • Alanine Transaminase (blood)
  • Animals
  • Antibodies, Monoclonal (administration & dosage, adverse effects, pharmacology)
  • Antibodies, Monoclonal, Murine-Derived
  • 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)
  • Humans
  • Hydrocarbons, Halogenated (administration & dosage, pharmacology)
  • Injections, Intraperitoneal
  • Lymphoma, Non-Hodgkin (drug therapy, pathology)
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Rituximab
  • Specific Pathogen-Free Organisms
  • Survival Analysis
  • Thymidine (metabolism)
  • Time Factors
  • Treatment Outcome
  • Triazines (administration & dosage, pharmacology)
  • Tritium
  • Xenograft Model Antitumor Assays

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