Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To test the relationship between DMs and drug resistance in newly established AML cell lines, KY821, and its clone KY821A3, the latter had lost DMs during cloning, were cultured in increasing concentrations of MTX. KY821 became resistant against 2 x 10(-4) M MTX, whereas KY821A3 did against 2 x 10(-5) M MTX in a same period. Enhanced enzyme activities of DHFR were correspondent to the increased DMs numbers and DHFR gene amplification in both resistant clones. The amplified DHFR gene was located on DMs by in situ hybridization. These data indicated that the presence of DMs in KY821 would facilitate the acquisition of drug resistance.
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PMID:A new myeloblastic leukemia cell line with double minute chromosomes. Induction of methotrexate resistance and dihydrofolate reductase gene amplification. 156 Jun 71

The mechanisms of action of MTX and 5-FU have been further elucidated. Such studies will be important for the design of drug combinations and for the development of novel antifolate and fluoropyrimidine analogs. A greater understanding of MTX and ara-C transport and drug levels required to optimize transport may also aid in these endeavors. Pharmacokinetic parameters have been found to be predictors of relapse in children with acute leukemia, particularly with respect to MTX, 6-MP and ara-C. The intracellular terminal half-life of ara-C was correlated with remission duration in AML. Assay systems aimed at uncovering response predictors through biochemical analysis of patient tumor samples are being developed, including an interesting use of NMR spectroscopy to study the pharmacokinetics of fluorine-19-labeled 5-FU in vivo. Such an approach may yield valuable information on 5-FU anabolism in tumors in situ. A high frequency of resistance to MTX apparently may be generated within a single cell cycle by transient exposures to DNA synthesis inhibitors. The resistance may be based on either target enzyme amplification or altered membrane transport. These important studies provided bases for the rapid emergence of clinical resistance. Further, the multidrug-resistant phenotype appears to be a much broader based phenomenon as MTX resistance was found to be a frequent event in cells selected for multidrug resistance. A variety of novel approaches have been proposed to overcome antimetabolite resistance and to improve the selectivity of these agents, including the use of guanosine nucleotides, leucovorin and allopurines as biochemical modulators of 5-FU. Efficient techniques for the transfection of resistant DHFR into tissues using retroviruses have been reported. These studies serve as starting point for the ultimate development of more effective strategies for the treatment of human malignancies.
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PMID:Antimetabolites. 307 79

The fluorescence signal intensity of the DHFR gene was analysed in lymphocytes from 15 normal donors, in MTX-resistant HeLa cells (carrying DHFR gene amplification) and in bone marrow blasts from 16 patients with acute leukaemia (AL) by in situ hybridisation. Our aim was to verify if DHFR gene amplification may be responsible for increased enzyme activity in leukemic cells. The results obtained with a fluorescence in situ hybridisation method were quantified using the Scion image software program and compared with cytochemical and cytophotometric data relating to DHFR activity. In AL a heterogeneous hybridisation pattern was generally observed at the single cell level. However, leukemic lymphoblasts showed higher fluorescence signal intensity of the DHFR gene as compared with normal lymphocytes, and leukemic myeloblasts a much higher signal than lymphoblasts. HeLa cells showed the highest fluorescence signal intensity. In all samples enzyme activity behaved in parallel. These results indicate that the increased expression of DHFR in leukemic blasts is due to a gene amplification. The high levels in AML can explain the MTX natural resistance.
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PMID:Quantification of the DHFR gene in blast cells of leukaemia patients by fluorescence in situ hybridisation. 1466 92