ABCC4 p.His35Asp
Predicted by SNAP2: | A: N (57%), C: D (53%), D: D (80%), E: D (66%), F: N (72%), G: D (53%), I: D (53%), K: N (53%), L: N (57%), M: D (63%), N: N (82%), P: D (85%), Q: N (61%), R: N (72%), S: N (78%), T: N (57%), V: N (53%), W: D (63%), Y: N (93%), |
Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: N, |
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[hide] Molecular basis of antifolate resistance. Cancer Metastasis Rev. 2007 Mar;26(1):153-81. Assaraf YG
Molecular basis of antifolate resistance.
Cancer Metastasis Rev. 2007 Mar;26(1):153-81., [PMID:17333344]
Abstract [show]
Folates play a key role in one-carbon metabolism essential for the biosynthesis of purines, thymidylate and hence DNA replication. The antifolate methotrexate has been rationally-designed nearly 60 years ago to potently block the folate-dependent enzyme dihydrofolate reductase (DHFR) thereby achieving temporary remissions in childhood acute leukemia. Recently, the novel antifolates raltitrexed and pemetrexed that target thymidylate synthase (TS) and glycineamide ribonucleotide transformylase (GARTF) were introduced for the treatment of colorectal cancer and malignant pleural mesothelioma. (Anti)folates are divalent anions which predominantly use the reduced folate carrier (RFC) for their cellular uptake. (Anti)folates are retained intracellularly via polyglutamylation catalyzed by folylpoly-gamma-glutamate synthetase (FPGS). As the intracellular concentration of antifolates is critical for their pharmacologic activity, polyglutamylation is a key determinant of antifolate cytotoxicity. However, anticancer drug resistance phenomena pose major obstacles towards curative cancer chemotherapy. Pre-clinical and clinical studies have identified a plethora of mechanisms of antifolate-resistance; these are frequently associated with qualitative and/or quantitative alterations in influx and/or efflux transporters of (anti)folates as well as in folate-dependent enzymes. These include inactivating mutations and/or down-regulation of the RFC and various alterations in the target enzymes DHFR, TS and FPGS. Furthermore, it has been recently shown that members of the ATP-binding cassette (ABC) superfamily including multidrug resistance proteins (MRP/ABCC) and breast cancer resistance protein (BCRP/ABCG2) are low affinity, high capacity ATP-driven (anti)folate efflux transporters. This transport activity is in addition to their established facility to extrude multiple cytotoxic agents. Hence, by actively extruding antifolates, overexpressed MRPs and/or BCRP confer antifolate resistance. Moreover, down-regulation of MRPs and/or BCRP results in decreased folate efflux thereby leading to expansion of the intracellular folate pool and antifolate resistance. This chapter reviews and discusses the panoply of molecular modalities of antifolate-resistance in pre-clinical tumor cell systems in vitro and in vivo as well as in cancer patients. Currently emerging novel strategies for the overcoming of antifolate-resistance are presented. Finally, experimental evidence is provided that the identification and characterization of the molecular mechanisms of antifolate-resistance may prove instrumental in the future development of rationally-based novel antifolates and strategies that could conceivably overcome drug-resistance phenomena.
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No. Sentence Comment
331 In this respect, perhaps the best characterized antifolate-resistant cell line with enhanced GGH activity is H35D rat hepatoma cells [205].
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ABCC4 p.His35Asp 17333344:331:109
status: NEW333 H35D cells also exhibited a 90% decrease in the formation of MTX polyglutamates in the absence of alterations in FPGS activity; the parent monoglutamate form of MTX was the predominant intracellular species [206].
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ABCC4 p.His35Asp 17333344:333:0
status: NEW334 Unlike antifolates, the total cellular folate pool was identical in both parental H35 and H35D cells grown in medium containing folic acid concentrations at the range of 2.3-10 μM. Therefore, the impact of enhanced GGH activity on cellular THF cofactor polyglutamates is much less prominent than that on antifolates.
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ABCC4 p.His35Asp 17333344:334:90
status: NEW335 However, the antifolate-resistance phenotype in H35D cells should be regarded as multifactorial since these drug-resistant cells also displayed a marked impairment of antifolate uptake.
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ABCC4 p.His35Asp 17333344:335:48
status: NEW