The goal of rational cancer chemotherapy has become therapies which are active by virtue of the molecular events involved in transformation and which target processes that sustain the transformed phenotype. One of the most common alterations during tumor cell progression is loss of the function of the p53 pathway. Not only is p53 stabilized in response to DNA damage, but it also accumulates in response to nucleotide depletion with agents that cause little if any DNA damage, specifically, the GART class of de novo purine synthesis inhibitors and the de novo pyrimidine synthesis inhibitor PALA (N-phosphonoacetyl-L-aspartate). In this proposal, we would study how nucleotide depletion causes accumulation of p53, the mechanism of the p53 response pathway subsequent to signaling of nucleotide depletion, and the role of co-activators and repressors in this response. This proposal seeks to identify the molecules and mechanisms of the p53 signaling initiated by nucleotide depletion, learn how nucleotide depletion, per se, leads to cell death, and identify if there are survival disadvantages under nucleotide depletion conditions induced by the cancer phenotype that can be used for therapeutics. These studies are a logical extension of past studies supported by this grant, but also represent new directions to therapeutics suggested by recent advances in cancer cell biology.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Forry, Suzanne L
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Virginia Commonwealth University
Schools of Medicine
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Racanelli, Alexandra C; Rothbart, Scott B; Heyer, Cortney L et al. (2009) Therapeutics by cytotoxic metabolite accumulation: pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition. Cancer Res 69:5467-74
McCarthy, Erin A; Titus, Steven A; Taylor, Shirley M et al. (2004) A mutation inactivating the mitochondrial inner membrane folate transporter creates a glycine requirement for survival of chinese hamster cells. J Biol Chem 279:33829-36
Bronder, Julie L; Moran, Richard G (2003) A defect in the p53 response pathway induced by de novo purine synthesis inhibition. J Biol Chem 278:48861-71
Andreassi 2nd, John L; Moran, Richard G (2002) Mouse folylpoly-gamma-glutamate synthetase isoforms respond differently to feedback inhibition by folylpolyglutamate cofactors. Biochemistry 41:226-35
Bronder, Julie L; Moran, Richard G (2002) Antifolates targeting purine synthesis allow entry of tumor cells into S phase regardless of p53 function. Cancer Res 62:5236-41
Roberts, J D; Poplin, E A; Tombes, M B et al. (2000) Weekly lometrexol with daily oral folic acid is appropriate for phase II evaluation. Cancer Chemother Pharmacol 45:103-10
Titus, S A; Moran, R G (2000) Retrovirally mediated complementation of the glyB phenotype. Cloning of a human gene encoding the carrier for entry of folates into mitochondria. J Biol Chem 275:36811-7
Moran, R G (1999) Roles of folylpoly-gamma-glutamate synthetase in therapeutics with tetrahydrofolate antimetabolites: an overview. Semin Oncol 26:24-32
Tse, A; Brigle, K; Taylor, S M et al. (1998) Mutations in the reduced folate carrier gene which confer dominant resistance to 5,10-dideazatetrahydrofolate. J Biol Chem 273:25953-60
Tse, A; Moran, R G (1998) Cellular folates prevent polyglutamation of 5, 10-dideazatetrahydrofolate. A novel mechanism of resistance to folate antimetabolites. J Biol Chem 273:25944-52

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