1989
DOI: 10.1002/ajh.2830310103
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In vitro DNA synthesis by megaloblastic bone marrow: Effect of folates and cobalamins on thymidine incorporation and de novo thymidylate synthesis

Abstract: The de novo pathway of thymidylate synthesis (i.e., methylation of dUMP to dTMP) is directly folate dependent and indirectly vitamin B12 (cobalamins) dependent. In deficiency of these vitamins, this pathway is impaired, and exogenous deoxyuridine (dU) fails to suppress adequately in vitro incorporation of [3H]thymidine (3H-TdR) into DNA via the salvage pathway (i.e., abnormal dU suppression). This abnormality is corrected by the addition of folate compounds (analogues) and/or vitamin B12 depending on the natur… Show more

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Cited by 23 publications
(9 citation statements)
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References 33 publications
(19 reference statements)
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“…The forgetfulness, irritability, and paranoia often seen in folate deficiency reverse within days of starting folate therapy [ 1 1,131. B , , deficiency produces blockade of folate utilization 11 1, 27,39]. The neuropsychiatric stigmata of B deficiency may relate to methyl group deficiency [42].…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…The forgetfulness, irritability, and paranoia often seen in folate deficiency reverse within days of starting folate therapy [ 1 1,131. B , , deficiency produces blockade of folate utilization 11 1, 27,39]. The neuropsychiatric stigmata of B deficiency may relate to methyl group deficiency [42].…”
Section: Discussionmentioning
confidence: 99%
“…100 pg B,,/month by injection was considered marginally adequate therapy for pernicious anemia and most other B,, deficiencies due to poor B,, absorption, with only a few exceptions, such as in certain malignancies [26]. However, we are now seeing AIDS patients whose negative B , , balance, manifested by holotranscobalamin I1 < 20 pg/ml, abnormal ddUST (diagnostic dU suppression test) [39], and elevated granulocyte segmentation were corrected by 1 mg B,, parenterally, but quickly became again abnormal a few weeks later. This suggests they have an AIDS-related (possibly infection-related and/or chronic systemic disease-related) defect in transport and/or delivery of B,, to cells with cell surface receptors for holo-TC 11, and/or a defect in getting B,, into these cells and/or storing it in them and/or delivering it to its apoenzymes and/or a defect in the apoenzymes themselves or in their pathways.…”
Section: Discussionmentioning
confidence: 99%
“…Low cytosolic levels of N 5 ,N 10 -methylenetetrahydrofolate (the folate cofactor for thymidylate synthase) decreases synthesis of thymidylate (dTMP; ref. 21), increasing the cellular dUMP͞dTMP ratio and DNA polymerase-mediated dUTP misincorporation into DNA (20,(22)(23)(24). Uracil is excised from DNA by uracil-DNA glycosylase and apyrimidinic endonuclease, generating transient singlestrand breaks (nicks) that could result in a less repairable and more hazardous double-strand break if two opposing nicks are formed (25).…”
mentioning
confidence: 99%
“…A portion of the aspirated bone marrow was collected aseptically in cold heparinized 0.06 M Tris-buffered Hank's balanced salt solution, pH 7.4, and processed into a monolayered suspension for short-term culture; DNA synthesis was monitored by measuring incorporation of 3 H-thymidine ( 3 H-TdR) into DNA, and dU suppression test was done as described by us previously [16,17] . The dU suppression values were calculated as follows: H-TdR incorporation into cellular DNA is a sensitive radionucleoside marker of DNA synthesis.…”
Section: Dna Synthesis and Du Suppression Testmentioning
confidence: 99%