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Abstract

Grant Number:	1R41CA102842-01
PI Name:	MAURER, BARRY J.
PI Email:	bmaurer@chla.usc.edu
PI Title:
Project Title:	PPMP as a Ceramide Catabolism Inhibitor for Chemotherapy

Abstract: DESCRIPTION (provided by applicant): Our goal is to develop 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) as a clinical inhibitor of ceremide catabolism, in order to enhance the anti-cancer activity of the cytotoxic retinoid, fenretinide (4-HPR). We have reported that 4-HPR increased ceramide in numerous pediatric and adult solid cancer and leukemia cell lines in vitro. We have also reported that PPMP, an inhibitor of glucosylceramide synthase and l-O-acylceramide synthase, further increased ceramide and synergized 4-HPR cytotoxicity. We hypothesize that intravenous or oral formulations of PPMP can achieve plasma and tissue levels that inhibit ceramide catabolism in vitro. We hypothesize that PPMP will enhance the anti-cancer effect of 4-HPR with tolerable systemic toxicity in vivo. We will: AIM 1. Identify the stereoisomer of PPMP that most effectively inhibits ceramide catabolism and increases 4-HPR cytotoxicity. AIM 2. Develop a cGMP process, and produce PPMP for pre-IND studies. AIM 3. Formulate PPMP for intravenous and/or oral delivery. AIM 4. Perform small animal pharmacokinetic and toxicology studies to support a Phase II STTR application to support IND-directed toxicology studies and cGMP PPMP manufacture for Phase I clinical trial. 4-HPR+PPMP represents a novel, p53-independent chemotherapy that is based upon the generation and manipulation of ceramide in vivo.

Thesaurus Terms:
ceramide, chemoprevention, drug design /synthesis /production, drug interaction, fenretinide, lipid metabolism, morpholine, neoplasm /cancer chemotherapy
cytotoxicity, high throughput technology, intravenous administration, oral administration, pharmacokinetics, stereoisomer, tritium
SCID mouse, cell line, laboratory rat, radiotracer, thin layer chromatography

Institution:	AVANTI POLAR LIPIDS, INC.
	700 INDUSTRIAL PARK DR
	ALABASTER, AL 35007
Fiscal Year:	2003
Department:
Project Start:	11-JUL-2003
Project End:	30-JUN-2004
ICD:	NATIONAL CANCER INSTITUTE
IRG:	ZCA1

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