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DNA and RNA synthesis: antifolates

Soros VB, Yonemoto W and Greene WC: Newlysynthesized APOBEC3G is incorporated into HIV virions, inhibited byHIV RNA and subsequently activated by RNase H. PLoS Pathog.3:e152007. :

Backus JW, Schock D and Smith HC: Onlycytidines 5′ of the apolipoprotein B mRNA mooring sequence areedited. Biochim Biophys Acta. 1219:1–14. 1994. : :

Alkylated bases prevent DNA synthesis and RNA transcription from the affected DNA.

GGH Gene - GeneCards | GGH Protein | GGH Antibody

Consequently antifolates inhibit cell division, DNA/RNA synthesis and repair and protein synthesis.

A second mechanism by which alkylating agents cause DNA damage is the formation of cross-bridges, bonds between atoms in the DNA (pink linkages below). In this process, two bases are linked together by an alkylating agent that has two DNA binding sites. Bridges can be formed within a single molecule of DNA (as shown below) or a cross-bridge may connect two different DNA molecules. Cross-linking prevents DNA from being separated for synthesis or transcription.

In the first mechanism an (represented in the figure below as a pink star) attaches alkyl groups (small carbon compounds-depicted as pink triangles) to DNA bases. This alteration results in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases (frame 3 of the diagram below). Alkylated bases prevent DNA synthesis and RNA transcription from the affected DNA.

Pharmacogenetic and Pharmacodynamic Testing - …

All members of the AID/APOBEC family possess one ortwo catalytic domains that deaminate cytidine in RNA and DNA. Thedeaminases mediate the hydrolytic removal of an amino group at theC4 position of a cytidine (C) or deoxycytidine (dC) generating auridine (U) or deoxyuridine (dU), respectively (). The presence of the enzyme in cellsproducing RNA virus results in C-to-U conversion of minus strandreverse transcripts and G-to-A in plus strand DNA. The binding tothe target DNA creates a U-G mismatch, which generates a C-to-Ttransition in minus strand DNA and a G-to-A transition in plusstrand DNA during general DNA replication without repair pathways() (). In humans, the family comprises 11members with distinct functions, including AID, APOBEC1 (A1),APOBEC2 (A2), APOBEC4 (A4) and APOBEC3 (A3) subgroups. The A3 groupconsists of seven proteins: A3A, A3B, A3C, A3DE, A3F, A3G and A3H(–). The seven A3 genes are arranged in atandem gene cluster on chromosome 22 in humans (). The presence of the AID/APOBECfamily is restricted to vertebrates. AID and A2 are likely to bethe ancestral members, while A1 and A3 are later evolutionaryarrivals (), A3s are restrictedto placental mammals, and their gene copy number isspecies-specific. For example, mice only possess a single A3 gene,pigs have two, sheep and cattle have three, cats have four, horseshave six and primates have at least seven A3 genes (). The rapid expansion of the A3 locusin humans indicates an important role in the host genome defenseagainst exogenous viruses and endogenous retroelements (–).The role of the AID/APOBEC family in the inhibition of viralinfection was initially described for HIV-1. Various studies haveshown that the genome of hepadnaviruses is hyperedited by cytidinedeaminases (–). Recent reports demonstrated that HBVDNA replication is restricted by A1, AID, A3A, A3B, A3C, A3G, A3F,but not A3DE (,,,–),specifically via the degradation of HBV cccDNA (), which was investigated in anexperimental setting through deaminase-independent and -dependentmechanisms (,).

The antineoplastic effect of nucleoside analogs depends on their inhibition of DNA and RNA synthesis

N2 - Thymidylate synthase (TS) is an essential enzyme for the de novo synthesis of thymidylate and subsequently DNA synthesis. TS has been used as a target for cancer chemotherapy in the development of fluoropyrimidines such as 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine and of novel folate-based TS inhibitors such as ZD1694 (Tomudex, Raltitrexed), ZD9331, LY231514 (ALIMTA, Pemetrexed), AG337 (Thymitaq, Nolatrexed) and AG331. Although TS has been considered as a target for chemotherapy, the precise mechanism by which TS inhibition leads to cell death is still not completely resolved. TS inhibition results in depletion of dTTP, an essential precursor for DNA, and an increase in dUTP. This results in the so-called thymine-less death due to misincorporation of dUTP into DNA; its excision, catalysed by uracil-DNA glycosylase, results in DNA damage. Both this imbalance in dTTP/dUTP and DNA damage can result in induction of downstream events, leading to apoptosis. On the other hand a specific interaction exists between oncogenes and TS, by binding of TS protein to the p53 and c-myc RNA, while wt p53 can also inhibit TS promotor activity. TS inhibition by either 5-FU or antifolates can also result in a depression of TS protein mediated inhibition of TS mRNA translation leading to induction of more TS protein synthesis, and p53 protein may further deregulate this process. These complex indirect and direct interactions between oncogenes and TS may have as yet unclear clinical implications, since most data are based on in vitro or in vivo studies and some results are contradictive. In some preliminary clinical studies evidence was postulated for a combined prognostic role for TS and p53. This knowledge should be used to design clinical studies with the aim to deliver effective treatment to potentially sensitive patients both in the adjuvant setting and in advanced stage disease.

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Combination Chemotherapy as an Adjuvant Treatment …


19/02/1976 · Original Article

AB - Thymidylate synthase (TS) is an essential enzyme for the de novo synthesis of thymidylate and subsequently DNA synthesis. TS has been used as a target for cancer chemotherapy in the development of fluoropyrimidines such as 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine and of novel folate-based TS inhibitors such as ZD1694 (Tomudex, Raltitrexed), ZD9331, LY231514 (ALIMTA, Pemetrexed), AG337 (Thymitaq, Nolatrexed) and AG331. Although TS has been considered as a target for chemotherapy, the precise mechanism by which TS inhibition leads to cell death is still not completely resolved. TS inhibition results in depletion of dTTP, an essential precursor for DNA, and an increase in dUTP. This results in the so-called thymine-less death due to misincorporation of dUTP into DNA; its excision, catalysed by uracil-DNA glycosylase, results in DNA damage. Both this imbalance in dTTP/dUTP and DNA damage can result in induction of downstream events, leading to apoptosis. On the other hand a specific interaction exists between oncogenes and TS, by binding of TS protein to the p53 and c-myc RNA, while wt p53 can also inhibit TS promotor activity. TS inhibition by either 5-FU or antifolates can also result in a depression of TS protein mediated inhibition of TS mRNA translation leading to induction of more TS protein synthesis, and p53 protein may further deregulate this process. These complex indirect and direct interactions between oncogenes and TS may have as yet unclear clinical implications, since most data are based on in vitro or in vivo studies and some results are contradictive. In some preliminary clinical studies evidence was postulated for a combined prognostic role for TS and p53. This knowledge should be used to design clinical studies with the aim to deliver effective treatment to potentially sensitive patients both in the adjuvant setting and in advanced stage disease.

Antimetabolites as Chemotherapy Agents

Folic acid is a growth( )factor that provides single carbons to the precursors used to form the nucleotides used in the synthesis of DNA and RNA. Folate antagonists, also known as antifolates, act by blocking the active site of dihydrofolate reductase (DHFR), an enzyme that reduces folic acid to its active form. Active folates are co-enzymes necessary for methylation in various metabolic processes, in which they deliver methyl groups (one-carbon units) to specific target molecules. The inhibition of the dihydrofolate reductase keeps the folic acid in an inactive state. A decrease in the amount of activated folates is thought to cause a decrease in methylation, inhibiting a necessary step in purine and thymidylate formation. When nucleic( )acid formation is compromised because of a lack of nucleotides, cell growth is disrupted. Methotrexate is the most commonly used folate antagonist.

Nelarabine - an overview | ScienceDirect Topics

The pyrimidine antagonists act to block the synthesis of pyrimidine containing nucleotides (C and T in DNA; C and U in RNA). The drugs used to block the construction of these nucleotides have structures that are similar to the natural compound. By acting as 'decoys', these drugs can prevent the production of the finished nucleotides. They may exert their effects at different steps in that pathway and may directly inhibit crucial enzymes. The pyrimidine antagonist may also be incorporated into a growing DNA chain and lead to termination of the process.

Evidence for distinct DNA- and RNA-based mechanisms …

The activation-induced cytidine deaminase(AID)/apolipoprotein B mRNA editing enzyme, catalyticpolypeptide-like (APOBEC) family, which was first described forinhibition of human immunodeficiency virus type 1 (HIV-1), isimportant in the innate immune system, as it defends againstviruses, including HBV through hypermutation-dependent and-independent mechanisms. Nine of 11 APOBEC3 family members havebeen identified to exert varying levels of activity against HBVunder experimental conditions (). APOBEC-3A and APOBEC-3B are essential for cccDNAdegradation by IFN-α or the lymphotoxin-β receptor-agonist withoutdamaging the infected host cells (). Thus, targeting the formation andsubsequent processing of viral cccDNA may be more rationalapproaches.

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