By Godefridus J Peters
Profitable melanoma chemotherapy is predicated seriously at the software of assorted deoxynucleoside analogs. because the very starting of contemporary melanoma chemotherapy, a few antimetabolites were brought into the health center and consequently utilized commonly for the remedy of many malignancies, either good tumors and hematological problems. within the latter ailments, cytarabine has been the mainstay of remedy of acute myeloid leukemia. even if many novel compounds have been synthesized within the Nineteen Eighties and Nineteen Nineties, no genuine development used to be made. besides the fact that, novel expertise is now able to elucidating the molecular foundation of a number of inborn mistakes in addition to a few particular malignancies. This has enabled the synthesis of a number of deoxynucleoside analogs which may be utilized for particular malignancies, similar to pentostatin and for this reason chlorodeoxyadenosine (cladribine) for the therapy of bushy telephone leukemia. Already within the early level of deoxynucleoside analog improvement, it was once well-known that numerous of those compounds have been very potent within the therapy of assorted viral infections, corresponding to for the remedy of herpes infections. This shaped the root first and foremost for the layout of azidothymidine and thus many different analogs, that are presently effectively used for the therapy of HIV infections. As a spin-off of those examine traces, a few compounds now not eligible for improvement as antiviral brokers looked to be very effective anticancer brokers. The classical instance is gemcitabine, now some of the most commonly utilized deoxynucleoside analogs, used for the (combination) therapy of non-small mobile lung melanoma, pancreatic melanoma, bladder melanoma, and ovarian melanoma.
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Extra info for Deoxynucleoside Analogs in Cancer Therapy (Cancer Drug Discovery and Development)
The physiological phosphate donor for the reaction is most likely both adenosine triphosphate (ATP) and uridine triphosphate (UTP), and the nature of the phosphate donor affects the kinetics of the reaction (1–4 and references therein). There exists an interconversion pathway between dCyt and deoxythymidine (dThd) nucleotides in the cytosol. The main enzyme in the dCyt-dThd interconversion pathway is the deaminase activity (DA); in the catabolic pathway, it is the nucleotidase activity (5′-NT) presented in Fig.
Comparison of dCK activities in different tissues. another regulation step in the formation of dCTP at the level of dCK; that is, at a high level of dCTP there is no further phosphorylation of dCyt by dCK. However, this regulation will also influence the activation of the antileukemic nucleoside analog(s) arabinosyl-cytosine (ara-C). A high level of dCTP will inhibit the phosphorylation of ara-C, decreasing the effect of the drug on DNA synthesis as presented in Fig. 3. 2. THE EXPRESSION OF dCK IN DIFFERENT CELLS AND TISSUES The expression of dCK is highest in different lymphoid cells/tissues, such as thymus, spleen, lymph nodes, stimulated blood mononuclear cells, and bone marrow cells and in all malignancies of these cells as presented in Fig.
The treatment with butyrate could be a similar stress signal for the cells as the toxic treatments listed above. The mechanisms of this “protecting” effect of dCyt against the different “stress” treatments leading to increased dCK activity and DNA repair are still unknown. It might be important to supply all four deoxynucleosides by the action of dCK and by the dCyt–dThd nucleotide interconversion pathway, operating mainly in lymphoid cells (7) (Figs. 1 and 2). Protein phosphorylation is involved in the signaling pathway induced by γ-irradiation in the case of the P53R2 RR (53), and it was suggested that the dCK activation is also dependent on protein phosphorylation (31,32,52,54).
Deoxynucleoside Analogs in Cancer Therapy (Cancer Drug Discovery and Development) by Godefridus J Peters