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Gastrointestinal cancer
Published in Michael JG Farthing, Anne B Ballinger, Drug Therapy for Gastrointestinal and Liver Diseases, 2019
Justin S Waters, David Cunningham
A more recently developed antimetabolite drug that is proving very useful, particularly in carcinoma of the pancreas, is gemcitabine. This is a cytidine analogue that is incorporated into DNA in its triphosphate form, after activation by deoxycytidine kinase. This results in chain termination after the addition of one further nucleotide. It also inhibits the activity of several enzymes involved in cytidine metabolism, including ribonucleotide reductase, dCMP deaminase, and CTP synthetase, and is incorporated into RNA, leading to inhibition of RNA synthesis. Cell cycle arrest occurs in the S phase followed by the induction of cell death by apoptosis.
ACTIONS OF ANTI-CANCER DRUGS
Published in James Bishop, Cancer Facts, 1999
Stephen J. Clarke, Laurent P. Rivory
Gemcitabine (2',2'-difluorodeoxycytidine) is another deoxycytidine analogue with multiple modes of action. As with ara-C, the activated diphosphate form is an inhibitor of ribonucleotide reductase which leads to a depletion of intracellular pools of dCTP and dATP. The triphosphate may be incorporated into DNA by the enzyme DNA polymerase followed by a futher deoxynucleotide. Gemcitabine, in this penultimate position, is resilient to exonucleases and this leads to 'masked' DNA chain elongation termination. Gemcitabine has other self-potentiating effects such as inhibiting CTP synthetase. Also, dCTP is a required cofactor for dCMP deaminase, which converts gemcitabine to the essentially inactive 2',2'-difluorodeoxyuridine. The depletion of the dCTP pools should reduce the inactivation of the drug.
Cellular Oncogenes as Biotherapeutic Targets for the Differentiation and Inhibition of Cancer Cells
Published in Robert I. Glazer, Developments in Cancer Chemotherapy, 2019
Robert I. Glazer, Angelo Aquino, Gang Yu
Apart from the more commonly used differentiating agents such as DMSO, TPA, l,25(OH)2D3, and retinoic acid, a diverse spectrum of other compounds elicits morphologic changes in HL-60 cells.1 In general, the more cytotoxic the drug, the less differentiation occurs, and the narrower the dose-response relationship. Antimetabolite drugs such as the nucleoside analogs 5-azacytidine37 and neplanocin A (Figure 1),38,39 which preferentially inhibit the methylation of DNA and RNA respectively, induce a partial differentiation response in HL-60 cells mainly because of their potent cytocidal activities (Figure 2). Cell cycle specificity also plays a role in differentiation. The agents DMSO and retinoic acid generally produce an accumulation of cells in the G0/G1 phase of the cell cycle,40,41 an event which accompanies or precedes differentiation. The cytidine analog cyclopentenyl cytidine (CTP) (Figure 1) produces a rapid induction of mature myeloid cells upon treatment of HL-60 cells due to its ability to inhibit CTP synthesis, rapidly inhibit DNA synthesis, and inhibit cells from traversing S phase (Figure 2).42,43 The latter effect on HL-60 cells is also expressed by other inhibitors of CTP synthetase such as carbodine42 and 3-deazauridine,44 and by pyrazofurin, an inhibitor of orotidylate decarboxylase.44 Drugs which inhibit purine synthesis de novo such as the IMP dehydrogenase inhibitors tiazofurin and mycophenolic acid appear to be less effective inducers of myeloid differentiation in HL-60 cells.44,45
Mycobacterial ethambutol responsive genes and implications in antibiotics resistance
Published in Journal of Drug Targeting, 2021
Xiaohong Xiang, Zhen Gong, Wanyan Deng, Qingyu Sun, Jianping Xie
Rv1129c is a transcriptional activator of prpC and prpD, components of the methyl citrate cycle essential for the full virulence of M. tuberculosis [58,59]. Rv1129c may be involved in EMB, INH multiple resistance. But the specific molecular mechanism remains elusive [60–62]. Rv1662 function is similar to Rv1129c, and is involved in the production of methyl branched fatty acids, which are secondary components of thiolipids and acyl trehalose [63], Rv1699 (CTP synthase PyrG) can be inhibited by 5-methyl-N- (4-nitrophenyl) thiophene-2-carboxamide) and 3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl] propanamide, prodrugs activated by EthA monooxygenase. When Rv1699 is mutated, M. tuberculosis became resistant to the two drugs [64]. Multiple site mutations present in Rv1699 for clinical strains isolates from EMB-resistant TB patients: G407D G407D, similar mutations and Rv3806c, which are A249G A249G and F140V, Rv3756c: G56D, G56D G56D G56D G56D [62].
Structure-guided design of anti-cancer ribonucleotide reductase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Tessianna A. Misko, Yi-Ting Liu, Michael E. Harris, Nancy L. Oleinick, John Pink, Hsueh-Yun Lee, Chris G. Dealwis
Due to the crucial role hRR plays in replication, it is a major target for cancer chemotherapy12–14. One of the first described hRR inhibitors was hydroxyurea, which targets the di-iron cluster of the hRRM2 subunit to block catalysis15,16. The most common approach for developing inhibitors in the past few decades has involved modifying natural nucleoside substrates, resulting in the production of the clinically used drugs such as gemcitabine, fludarabine, clofarabine, and cladrabine17–23. Gemcitabine is a billion-dollar drug used as a front line treatment of pancreatic cancer24. Gemcitabine derives its main cytotoxicity through DNA chain termination25,26, irreversible inhibition of hRR27,28 and its interactions with several phosphate-binding proteins, such as deoxycytidine deaminase (dCMP deaminase)29, thymidylate synthase30, CTP-synthase31,32, and topoisomerase-133,34. The chain termination activity and lack of specificity exhibited by gemcitabine and other nucleoside-based drugs contribute to the toxic side effects that patients endure17–22. Thus, we have proposed that the development of a selective RR-targeted inhibitor may reduce toxic side effects and expand the therapeutic window35.