Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intestinal absorption of folates has been characterized as a facilitative process with a low pH optimum. Studies with intestinal epithelial cells have suggested that this activity is mediated by the reduced folate carrier (RFC1). In this paper, we report on folate transport characteristics in an immortalized rat IEC-6 cell line that was found to exhibit the predominant influx activity for methotrexate (MTX) at pH 5.5 with a low level of activity at pH 7.4. Transfection of this cell line with an RFC1 construct resulted in clones exhibiting increased MTX uptake at both the pHs and high folic acid uptake only at the low pH. For the two clones with the highest level of transport activity, relative MTX influx at the two pHs was reversed. Moreover, the low pH MTX influx activity ([MTX](e) = 0.5 microM) was markedly inhibited by 20 microM folic acid while influx at neutral pH was not. Furthermore, in the presence and absence of glucose at low pH, MTX and folic acid influx activity was inhibited by azide, while MTX influx at pH 7.4 was stimulated by azide in the absence of glucose but was unchanged in the presence of glucose and azide. This was contrasted with the results of transfection of the same RFC1 construct into an L1210 murine leukemia cell line bearing a nonfunctional endogenous carrier. In this case, the activity expressed was only at pH 7.4. These data indicate that RFC1 can exhibit two distinct types of folate transport activities in intestinal cells that must depend on tissue-specific modulators.
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PMID:Expression of the reduced folate carrier SLC19A1 in IEC-6 cells results in two distinct transport activities. 1160 Apr 21

Although the reduced folate carrier RFC1 and the thiamine transporters THTR-1 and THTR-2 share approximately 40% of their identity in protein sequence, RFC1 does not transport thiamine and THTR-1 and THTR-2 do not transport folates. In the present study, we demonstrate that transport of thiamine monophosphate (TMP), an important thiamine metabolite present in plasma and cerebrospinal fluid, is mediated by RFC1 in L1210 murine leukemia cells. Transport of TMP was augmented by a factor of five in cells (R16) that overexpress RFC1 and was markedly inhibited by methotrexate, an RFC1 substrate, but not by thiamine. At a near-physiological concentration (50 nM), TMP influx mediated by RFC1 in wild-type L1210 cells was approximately 50% of thiamine influx mediated by thiamine transporter(s). Within 1 min, the majority of TMP transported into R16 cells was hydrolyzed to thiamine with a component metabolized to thiamine pyrophosphate, the active enzyme cofactor. These data suggest that RFC1 may be one of the alternative transport routes available for TMP in some tissues when THTR-1 is mutated in the autosomal recessive disorder thiamine-responsive megaloblastic anemia.
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PMID:Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells. 1199 66

To elucidate the mechanism(s) of methotrexate (MTX) resistance as a possible reason underlying treatment failure in high-dose MTX regimens combined with leucovorin (LV) rescue, we established MTX-resistant human T-cell leukemia cell line CCRF-CEM cells in the presence of excess LV, and characterized their properties. Continuous exposure of the cells to escalating concentrations of MTX up to 20 microM in the presence of 1000 nM LV resulted in establishment of three MTX-resistant sublines with a wide disparity of resistance degree over a 4 logarithmic range (approximately 40-, 900- and 44,000-fold, respectively). Transmembrane transport of MTX in these sublines was diminished to 52%, 35% and 12%, respectively. Intracellular retention of MTX in these sublines was not different from that of the parent cells. A cell growth study in various concentrations of LV showed that cells with higher resistance to MTX required more LV for optimal growth. In parallel with the resistance levels, there was an increase in mRNA expression of dihydrofolate reductase gene and a decrease in that of thymidylate synthase gene, but no change in that of reduced folate carrier (RFC1) gene, as assessed by northern blot analysis. Sequencing of the RFC1 gene in all 3 sublines revealed a point mutation in codon 47 (TCC-->TTC) resulting in substitution of Phe for Ser residue, and additional deletion of CTG of codon 112 in the subline with the highest resistance. In summary, MTX exposure to CCRF-CEM cells in the presence of 1000 nM LV resulted in the establishment of heterogeneous cell populations with a wide range of transport-mediated MTX resistance, which was associated with differential alterations of RFC gene. These cell lines may serve as models for investigation of the molecular mechanism(s) underlying refractory tumors in high-dose MTX regimens with LV rescue.
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PMID:Large diversity in transport-mediated methotrexate resistance in human leukemia cell line CCRF-CEM established in a high concentration of leucovorin. 1270 99

Graft-versus-host disease (GVHD) is a frequent complication after hematopoietic cell transplant (HCT). Tissue damage as a result of chemoradiation injury is the initiating event in the pathogenesis of acute GVHD. Variations in DNA repair can influence the amount of tissue damage in response to alkylating agents and ionizing radiation used as conditioning during HCT. As DNA damage caused by these agents is repaired by the base excision repair (BER) pathway, we hypothesized that single-nucleotide polymorphisms (SNPs) in BER pathway will be associated with GVHD after HCT. Hence, we analyzed 179 SNPs in BER pathway in 470 recipients of allogeneic HCT for association with acute and chronic GVHD. In multivariate analysis, one SNP (rs6844176) in RFC1 (replication factor C (activator 1)) gene was independently associated with a higher risk of grade II-IV acute GVHD (relative risk (RR): 1.39, 95% confidence interval (CI): 1.14-1.70, P=0.001), and showed a trend toward higher risk of grade III-IV acute GVHD (RR: 1.33, 95% CI: 0.95-1.85, P=0.09). One SNP in PARP1 gene (rs1805410) was associated with a higher risk of chronic GVHD (RR: 1.81, 95% CI: 1.29-2.54, P=0.001). These results show that SNPs in the BER pathway can be used as genetic biomarkers to predict those at high risk for GVHD toward whom novel prophylactic strategies could be targeted.
Leukemia 2010 Aug
PMID:Polymorphisms in the base excision repair pathway and graft-versus-host disease. 2057 54


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