ABCC4 p.Ser46Asn
| Predicted by SNAP2: | A: N (97%), C: N (93%), D: N (97%), E: N (97%), F: N (82%), G: N (97%), H: N (97%), I: N (93%), K: N (97%), L: N (97%), M: N (97%), N: N (97%), P: N (97%), Q: N (97%), R: N (97%), T: N (97%), V: N (97%), W: N (78%), Y: N (82%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, E: N, F: D, G: N, H: N, I: D, K: N, L: D, M: D, N: N, P: N, Q: N, R: N, T: N, V: D, W: D, Y: D, |
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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
186 Consistently, an adjacent Ser46Asn substitution in MTX-resistant mouse leukemia cells grown on leucovorin as the sole folate source, resulted in a dramatic fall in the MTX transport Vmax with a much lesser decrease in the transport Vmax for the naturally occurring folates leucovorin and 5-CH3-THF [128].
X
ABCC4 p.Ser46Asn 17333344:186:26
status: NEW196 Of interest was the finding that some of the well-characterized mutations identified in antifolate-resistant cell lines in vitro including Ser46Asn were also identified in osteosarcoma patients.
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ABCC4 p.Ser46Asn 17333344:196:139
status: NEW199 In contrast, three mutations, Ser4Pro, Ser46Asn and Gly259Trp complemented the RFC null cell line and conferred only a modest level of MTX resistance. Whereas, several other mutations complemented the RFC null cell line but failed to confer any MTX resistance.
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ABCC4 p.Ser46Asn 17333344:199:39
status: NEW