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Induction of Apoptosis Using Inhibitors of Lysophosphatidic Acid Acyltransferase-ß and Anti-CD20 Monoclonal Antibodies for Treatment of Human Non-Hodgkin's Lymphomas

Authors' Affiliations: ¹ Fred Hutchinson Cancer Research Center; Departments of ² Medicine, ³ Pathology, and ⁴ Biological Structure from the University of Washington and ⁵ Cell Therapeutics Inc., Seattle, Washington

Requests for reprints: John M. Pagel, Clinical Research, Fred Hutchinson Cancer Research Center, D5-390, 1100 Fairview Avenue North, Seattle, WA 98109. Phone: 206-667-1868; Fax: 1-206-667-5454; E-mail: jpagel{at}fhcrc.org.

Purpose: Lysophosphatidic acid acyltransferase-ß (LPAAT-ß) 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-ß may be a novel target for anticancer therapy, and, thus, we examined the effects of a series of inhibitors of LPAAT-ß on multiple human non–Hodgkin's lymphoma cell lines in vitro and in vivo.

Results: We showed that five LPAAT-ß 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-ß inhibitors were evaluated either alone or in combination with the anti-CD20 antibody, Rituximab. The LPAAT-ß 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-ß inhibitor resulted in a 2-fold increase in apoptosis compared with either agent alone. To assess the combination of Rituximab and a LPAAT-ß inhibitor in vivo, groups of athymic mice bearing s.c. human Ramos lymphoma xenografts were treated with the LPAAT-ß 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-ß inhibitor, may provide enhanced therapeutic effects through apoptotic mechanisms.

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