Synthesis of DNA, inhibition

The antitumor activity of geldanamycin and its derivatives appears to result from inhibition of DNA synthesis whereas RNA synthesis is not affected (261). The antitumor activity of the maytansinoids also appears to result from the inhibition of DNA synthesis. The mechanism of action of maytansine (104) has been hypothesized to be the acid catalyzed loss of water from the C-9 hydroxyl group of the carbinolamide to form a reactive acyl imine intermediate, which reacts rapidly with nucleophiles on the bases of DNA (262). 

Mitomycin C was found to have broad activity against a range of tumors and has been used clinically since the early 1960s [14, 15]. It causes many specific cellular effects, including inhibition of DNA synthesis, recombination, chromosome breakage, sister chromatid exchange, induction of DNA repair, and induction of... 

In 1985, it was reported by Hsiang et al. [43] that the cytotoxic activity of 20-(S)-camptothecin (CPT III) was attributed to a novel mechanism of action involving the nuclear enzyme topo I, and this discovery of unique mechanism of action revived the interest in CPT and its analogues as anticancer agents. CPT stabilizes the covalent, reversible topo I-DNA complex leading to the inhibition of DNA synthesis in mammalian cells and interferes with the topo I breakage-reunion reaction [44]. Clinical trials and structure-activity relationships have demonstrated the requirement of the a-hydroxy group, the... 

Bidentate sites may be available in DNA itself. In the binding of Hg2+ and Ag+ we surmise that the binding is to amino-groups of cytidine and adenine and possibly the N(7) of guanine as all these positions are accessable in DNA. The introduction of a more kinetically permanent group such at [Pt(NH3)2]2+ attached to two such groups, e.g. two amino groups could lead to the formation of an inter-strand cross-link and an inhibition of DNA synthesis (90). 

Yarbro JW, Kennedy BJ, Barnum CP. Hydroxyurea inhibition of DNA synthesis in ascites tumor. Proc Natl Acad Sci USA 1965 53 1033-1035. 

The mechanism of action of nalidixic acid against E. coli. was found to be inhibition of DNA synthesis.(25) No selective effect on purines or pyrimidines was found and no inhibition of initiator synthesis was demonstrated. In addition the nalidixic acid could be removed from cultures after exposures up to 75 minutes by rinsings and cells would recover from the block. 

Fritzsche H, Wahnert U, Chaires JB, Dattagupta N, Schlessinger IT5, Crothers DM (1987) Anthracycline antibiotics. Interaction with DNA and nucleosomes and inhibition of DNA synthesis. Biochemistry 26(7) 1996-2000... 

Let s start with three examples of antitumor drugs that work by the inhibition of DNA synthesis methotrexate (MTX, Methopterin), 5-fluorouracil (Fluril), and 6-mercaptopurine (Purinethol). These are all old cancer drags, marketed under numerous trade names, including those indicated above. Although the mechanism of action of each one is different, at the end of the day they all inhibit DNA synthesis. 

D-Arabinofuranosyladenine, presumably as the triphosphate, inhibits the incorporation of precursors into DNA [154], and the triphosphate inhibits non-competitively the incorporation of thymidine triphosphate into DNA in extracts of ascites cells, suggesting a direct interaction with DNA polymerase, possibly at an allosteric site [155]. Other studies have confirmed the inhibition of DNA synthesis catalyzed by DNA polymerase [335, 335a]. 

Tetrahydrofolate is in turn converted to N, N °-methylenetetrahydrofolate, which is an essential cofactor for the synthesis of thymidylate, purines, methionine, and glycine. The major mechanism by which methotrexate brings about cell death appears to be inhibition of DNA synthesis through a blockage of the biosynthesis of thymidylate and purines. 

Doxorubicin binds tightly to DNA by its ability to intercalate between base pairs and therefore is preferentially concentrated in nuclear structures. Intercalation results in steric hindrance, hence production of single-strand breaks in DNA and inhibition of DNA synthesis and DNA-dependent RNA synthesis. The enzyme topoisomerase II is thought to be involved in the generation of DNA strand breaks by the anthracydines. Cells in S-phase are most sensitive to doxorubicin, although cytotoxicity also occurs in other phases of the cell cycle. 

Cisplatin (Platinol) is an inorganic coordination complex with a broad range of antitumor activity. It is especially useful in the treatment of testicular and ovarian cancer. It binds to DNA at nucleophilic sites, such as the N7 and 06 of guanine, producing alterations in DNA structure and inhibition of DNA synthesis. Adjacent guanine residues on the same DNA strand are preferentially cross-linked. This platinating activity is analogous... 

Tenofovir is an acyclic nucleoside phosphonate (ie, nucleotide) analog of adenosine (Figure 49-2). Like the nucleoside analogs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA. However, only two rather than three intracellular phosphorylations are required for active inhibition of DNA synthesis. 

Mechlorethamine Forms DNA cross-links, resulting in inhibition of DNA synthesis and function Hodgkin s and non-Hodgkin s lymphoma Nausea and vomiting Moderate depression of peripheral blood count excessive doses produce severe bone marrow depression with leukopenia, thrombocytopenia, and bleeding alopecia and hemorrhagic cystitis occasionally occur with cyclophosphamide cystitis can be prevented with adequate hydration busulfan is associated with skin pigmentation, pulmonary fibrosis, and adrenal... 

Capecitabine Inhibits TS incorporation of FUTP into RNA resulting in alteration in RNA processing incorporation of FdUTP into DNA resulting in inhibition of DNA synthesis and function Breast cancer, colorectal cancer, gastroesophageal cancer, hepatocellular cancer, pancreatic cancer Diarrhea, hand-foot syndrome, myelosuppression, nausea and vomiting... 

Gemcitabine Inhibits DNA synthesis and repair inhibits ribonucleotide reductase with reduced formation of dNTPs incorporation of gemcitabine triphosphate into DNA resulting in inhibition of DNA synthesis and function Pancreatic cancer, bladder cancer, breast cancer, non-small cell lung cancer, ovarian cancer, non-Hodgkin s lymphoma, soft tissue sarcoma Nausea, vomiting, diarrhea, myelosuppression... 

Fluorouracil (5-FU) is inactive in its parent form and requires activation via a complex series of enzymatic reactions to ribosyl and deoxyribosyl nucleotide metabolites. One of these metabolites, 5-fluoro-2 -deoxyuridine-5 -monophosphate (FdUMP), forms a covalently ternary complex with the enzyme thymidylate synthase and the reduced folate 5,10-methylenetetrahydrofolate, a reaction critical for the de novo synthesis of thymidylate. This results in inhibition of DNA synthesis through "thymineless death." 5-FU is converted to 5-fluorouridine-5 -triphosphate (FUTP), which is then incorporated into RNA, where it interferes with RNA processing and mRNA translation. 5-FU is also converted to 5-fluorodeoxyuridine-5 -triphosphate (FdUTP), which can be incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function. Thus, the cytotoxicity of 5-FU is thought to be the result of combined effects on both DNA- and RNA-mediated events. 

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