Antifolate targets

Curtin NJ, Hughes AN. Pemetrexed disodium, a novel antifolate with multiple targets. Lancet Oncol 2001 2 298-306. 

The RFC must actively transport sufficient levels of unbound drug to provide intracellular drug concentrations adequate to sustain inhibition of the target enzyme dihydrofolate reductase (DHFR) and for the synthesis of polyglutamated antifolates, the storage form of these drugs. Indeed, antifolate resistance due to decreased RFC expression has been cited in the literature since 1962 and has since emerged as an important mechanism of resistance to classical antifolates. 

Antifolates with clinically important activity include the sulfa drugs, which target DHPS, as well as pyrimethamine and proguanil, which target DHFR. The most commonly used clinical formulation of the antifolates is to use a combination of a sulfa drug such as sulfadox-ine and pyrimethamine to inhibit both enzymes involved in folate metabolism. The primary goal of this combination is to inhibit DNA synthesis when the parasite begins DNA synthesis for cell replication. 

Surprisingly, a method of antifolate resistance commonly cited in tumor cells is gene amplification resulting in increased target protein and decreased anti-folate efficacy, which has yet to be identified in any clinically relevant isolate. A further difference in antifolate resistance between mammalian cells and the parasitic cell is altered polyglutamation of die antifolate drugs. In mammalian cells, folates are taken up by a folate transport system and once inside the cell are poly-glutamated to trap the folates intracellularly. A reported mechanism of resistance in the cancer cell is the loss of... 

A CEM cell subline with 75-fold resistance to lAHQ was developed [160] and found to be as sensitive as the parent CEM line to MTX. This was consistent with the biochemical studies and strengthened the view that therapeutic strategies with TS-targeted antifolates were a viable alternative to the use of classical DHFR-targeted drugs. 

Garg and Achenie also demonstrated a reasonable approach to the solution of the I-QSAR problem in 2001. " ° Taking a target scaffold of an antifolate molecule for dihydrofolate reductase inhibition, these authors generated a QSAR for both activity and selectivity. They solved the I-QSAR problem to maximize selectivity through changing substitutents on the scaffold, subject to a constraint of a threshold activity. Finally, a work by Skvortsova, et al. " from 2003 demonstrated that the I-QSAR problem could be solved for the Hosoya index plus constraints on the number of carbon atoms for a system of 78 hydrocarbons. 

More knowledge of pterinoids means renewed hope of solving such old clinical problems as the pathogenesis of sprue. Increased interest, too, attaches to the unconjugated pterins in the body Are they increased or diminished in some diseases The effectiveness of antifolics in the palliative treatment of leukemia is halted by toxic symptoms and, eventually, by drug fastness this emphasizes the need to explore pteridine metabolism to find new opportunities for chemotherapy aimed at pterinoid targets. 

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