Deoxyribonucleic acid synthesis inhibition

Howie JA. Gale GR. Cis-dichlorodiammineplatinum (II). Persistent and selective inhibition of deoxyribonucleic acid synthesis in vivo. Biochem Pharmacol 1970 19(10) 2757-2762. 

Howie JA, Gale GR. CIs-dIchlorodlammlne platinum II persistent and selective Inhibition of deoxyribonucleic acid synthesis in vitro. Blochem Pharmacol 1970 19 2757-62. 

Johnson LR, Guthrie PD. Secretin inhibition of gastrin-stimulated deoxyribonucleic acid synthesis. Gastroenterology 61 601-601, 1974. 

Ensminger, W. D., and Tamm, I., 1970, Inhibition of synchronized cellular deoxyribonucleic acid synthesis during Newcastle disease virus, mengovirus or reovirus infection, J. Virol. 5 672. 

A single oral dose of 1 mg CN /kg as potassium cyanide did not inhibit testicular deoxyribonucleic acid (DNA)-synthesis in mice (Friedman and Staub 1976). Other genotoxicity studies are discussed in Section 2.5. 

Deoxyribonucleic acid (DNA) serves as a template for the synthesis of nucleic acids. Ribonucleic acid (RNA) executes protein synthesis and thus permits cell growth. Synthesis of new DNA is a prerequisite for cell division. Substances that inhibit reading of genetic information at the DNA template damage the regulatory center of cell metabolism. The substances listed below are useful as antibacterial drugs because they do not affect human cells. 

Molecular basis of macrocytosis Abnormal proliferation of erythroid precursors in the bone marrow, since folate deficiency encumbers the maturation of these cells by inhibition of deoxyribonucleic acid (DNA) synthesis. 

Floxuridine is a pyrimidine antimetabolite with its primary effect to interfere with the synthesis of deoxyribonucleic acid (DNA) and to a lesser extent inhibit the formation of ribonucleic acid (RNA). It is indicated in palliative management of GI adenocarcinoma metastatic to the liver administered by continuous regional intra-arterial infusion as long as cancer does not extend beyond the area perfused by a single artery. Floxuridine, an antimetabolite and anti-neoplastic agent (0.1 to 0.6 mg/kg daily by intra-arterial infusion), is used to treat brain, breast, head, neck, liver, gallbladder, and bile duct cancer (see also Figure 15). 

A number of workers have shown that novobiocin inhibits protein synthesis in bacteria. For example, it inhibits /S-galactosidase synthesis in both Staph, aureus and E. coli [48, 64]. Although M-protein synthesis in a Group A streptococcus is not inhibited by novobiocin [70], the inhibition of protein synthesis in Strept. faecium has been attributed to the inhibition of tRNA synthesis [23]. Novobiocin inhibits protein synthesis in Staph, aureus [26], but as the inhibition of other macro-molecules also occurs to a similar extent, this effect may not be the primary action of the antibiotic. The antibiotic also inhibits protein synthesis in E. coli [33, 71] but this inhibition appears much later than the observed inhibition of deoxyribonucleic acid (DNA) synthesis. 

The antimetabolite, raltitrexed, is a folate analogue and is a potent and specific inhibitor of the enzyme thymidylate synthase. Inhibition of this enzyme ultimately interferes with the synthesis of deoxyribonucleic acid (DNA) leading to cell death. The intracellular polyglutamation of raltitrexed leads to the formation within cells of even more potent inhibitors of thymidylate synthase. Folate (methylene tetrahydrofolate) is a co-faetor required by thymidylate synthase and therefore theoretically folinic acid or folic acid may interfere with the aetion of raltitrexed. Clinieal interaction studies have not yet been undertaken to confirm these predieted inter-aetions. ... 

Azo dyes are known for their medicinal importance and are widely recognised for their use in several therapeutic areas including antineoplastics [42], antidiabetics [43], antiseptics [44], antibacterial [45] and antitumour [18]. They are known to be involved in a number of biological reactions such as the inhibition of deoxyribonucleic acid (DNA), ribonucleic acid, protein synthesis, carcinogenesis and nitrogen fixation... 

The information which specifies the amino-acid sequence of a protein is stored in the nucleotide sequence of the double helix of deoxyribonucleic acid (DNA). The transcription of sections of this information into ribonucleic acid (RNA) is catalysed by RNA polymerases. These enzymes not only control the synthesis of RNA but also recognize stop and start signals on the DNA. The start signals are complex and may be blocked by repressor molecules which inhibit the transcription process. Once synthesized, the (messenger) RNA is processed and exported to ribosomes where its nucleotide sequence is translated into protein. Triplets of three nucleotides (codons) in the messenger RNA each specify (encode) one amino acid. The linear sequence of nucleotides in the messenger RNA thus specifies the sequence of amino acids in the protein whose primary structure will therefore correspond directly to the sequence of nucleotides in the DNA. 

It is now believed that much of the pharmacological activity of these drugs derives from their direct interaction with double-helical deoxyribonucleic acids (Gale et al, 1972 Lown, 1977). By perturbing DNA structure, these drugs may inhibit the synthesis of nucleic acids and interfere with cellular mitosis. The antitumor activity of many of these drugs likely involves this inhibition of DNA synthesis. 

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