Antifolates resistance

Roy, K., et al. Chromosomal localization of the murine RFC-1 gene encoding a folate transporter and its amplification in an antifolate resistant variant overproducing the transporter. Cancer Genet. Cytogenet. 1998, 305, 29-38. 

Hooijberg, J.H., Broxterman, H.J., Kool, M., et al. (1999) Antifolate resistance mediated by the multidrug resistance proteins MRPl and MRP2. Cancer Research. 59, 2532-2535. 

Rothem, L., Aronheim, A., and Assaraf, Y.G. (2003) Alterations in the expression of transcription factors and the reduced folate carrier as a novel mechanism of antifolate resistance in human leukemia cells. Journal of Biological Chemistry. 278, 8935-8941. 

JF Cortese, CV Plowe. Antifolate resistance due to new and known Plasmodium falciparum dihydrofolate reductase mutations expressed in yeast. Mol Biochem Parasitol 94 205-214, 1998. 

Rothem L, Stark M, Kaufman Y, Mayo L, Assaraf YG (2004) Reduced folate carrier gene silencing in multiple antifolate-resistant tumor cell lines is due to a simultaneous loss of function of multiple transcription factors but not promoter methylation. J Biol Chem 279 374-384... 

Assaraf, Y.G. (2007) Molecular basis of antifolate resistance. Cancer Metastasis Rev. 26, 153-181. 

Yuthavong, Y., Yuvaniyama, J., Chitnumsub, P., Vanichtanankul, J., Chusacultanachai, S., Tarnchompoo, B., Vilaivan, T., and Kamchonwongpaisan, S. (2005). Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase Structural basis for antifolate resistance and development of effective inhibitors. Parasitology 130,249-259. 

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. 

Loss of RFC function can occur by decreased expression of the protein and thus decreased levels of membrane-bound RFC. Once the RFC was cloned it became evident that profound losses of RFC transport and antifolate resistance were associated with... 

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... 

As mentioned above, the quinazoline aspartates are potent inhibitors of DHFR, and in fact, may be more tightly bound to the enzyme than either MTX or AMT. Albrecht et al. [268] observed essentially stoichiometric inhibition of DHFR s from two lines of Chinese hamster cells, and also noted that, depending on the enzyme studied, dihydrofolate was much less successful in reversing the inhibitory effect of methasquin than of MTX or AMT. This was especially true when the dose-response for inhibition of enzyme activity by MTX and AMT displayed a curvilinear pattern indicative of a relatively high off-rate . Since this property was perceived as a likely basis for acquired antifolate resistance via enzyme mutation, the quinazoline aspartates were seen as possessing a distinct advantage over MTX and AMT. 

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