Targeted drug design and metabolic pathway flux

Abstract

Tumor cells inherently possess various mechanisms to initiate and sustain any one of the following phenotypes; 1, proliferative; 2, differentiated; 3, transformed; 4, cycle arrested; 5; necrotic; and 6, apoptotic (Boros et aL, 2002a, b). In addition to multiple drug and apoptosis resistance, advanced and therapy-resistant tumors share a common phenotype characterized by rapid proliferation, poor differentiation and increased transformation. They also exhibit increased rates of metabolism using glucose as a primary substrate (Pitot and Jost, 1967; te Boekhorst et al, 1995; Smith, 1998; Schwart et ai, 1986). As such, factors that govern a tumor cells' response (growth, differentiation, etc.) to exogenous and endogenous agents are deeply embedded in, and dependent on, the metabolic network supplying essential substrates for de novo macromolecule synthesis and energy production. Rates of cellular proliferation are closely associated with rates of de novo macromolecule synthesis, such as RNA, DNA, proteins and longchain fatty acids (Eigenbrodt et al, 1992). These complex molecules, which eventually become structural components of new and old progenies of tumor cells, are synthesized from small molecular weight substrates, such as glucose, short chain fatty acids and amino acids in an interconnected and complex metabolic network. All pathways in the network depend on one another via substrate sharing and channeling, and by regenerating shared cofactors that participate in oxidative degradation and reductive synthesis simultaneously. Such a close relationship is evident between direct glucose oxidation in the pentose cycle and de novo fatty acid synthesis, where part of the reduced NADP+ pool is regenerated allowing the irreversible glucosesphosphate dehydrogenase reaction to proceed for the synthesis of five carbon sugars (Kuhajda, 2000; Baron et all 2004). In turn, the reducing NADP+ equivalent is used during reductive de novo synthesis of fatty acids, their chain elongation and de-saturation, allowing distant metabolic network processes to proceed in a well-controlled and synchronized fashion. © 2005 Springer Science+Business Media, Inc. All rights reserved.