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PubMed2003

Nucleoside and nucleotide analogue reverse transcriptase inhibitors: a clinical review of antiretroviral resistance.

Although advances in highly active antiretroviral therapy (HAART) have made long-term suppression of HIV an achievable goal of therapy, a substantial proportion of first-line regimens will eventually fail. Successful longterm treatment requires consideration of downstream treatment options at the time of initiating or changing regimens. An understanding of the patterns and interactions of resistance mutations, and the appropriate use of genotypic and phenotypic testing is an important component of successful drug sequencing. Resistance to multiple nucleoside reverse transcriptase inhibitors (NRTIs) may result from several genotypically distinct pathways, including the Q151M (151 complex), the 69 insertion complex, two distinct thymidine analogue mutational pathways and the K65R mutation. Knowledge of the clinical implications of these and other resistance pathways, as well as the antagonism or synergy between mutations, helps guide individualized treatment choices from initial therapy in the treatment-naive patient to salvage therapy in the highly treatment-experienced individual. The development of effective sequencing strategies will depend upon the continued understanding of drug resistance mutation patterns and their associations with specific HAART combinations. This review summarizes research advances that further the understanding of nucleoside and nucleotide analogue resistance mutations, and their interplay.

Antiretroviral Therapy, Highly Active↗
PubMed2001

Effects of extracellular nucleotides and nucleosides on prostate carcinoma cells.

1. The purpose of this work was to characterize the receptors involved in the action of nucleotides on the human prostate carcinoma cell lines LNCaP, PC-3 and DU145. 2. Northern blotting revealed the presence of P2Y(2), P2Y(6) and P2Y(11) messengers in the three cell lines. P2Y(1) mRNA was only observed in the DU145 cells. In both PC-3 and DU145 cells, ATP and UTP stimulated inositol phosphate accumulation in an equipotent, equiactive and non-additive way, suggesting the involvement of P2Y(2) receptors. ATP also increased cyclic AMP, but this effect is likely to result from degradation into adenosine and activation of A(2) receptor. A(2) receptor activation led to a synergistic enhancement of prostate-specific antigen secretion induced by vasoactive intestinal peptide. 3. RT - PCR experiments detected the expression of the P2X(4) and P2X(5) receptors in the DU145 cells and the P2X(4), P2X(5) and P2X(7) receptors in the PC-3 cells. The calcium influx induced by BzATP confirmed the functional expression of P2X receptors. 4. ATP inhibited the growth of PC-3 and DU145 cells. This effect was mimicked neither by UTP nor by adenosine, indicating that it does not result from phospholipase C or adenylyl cyclase activation. On the contrary, in PC-3 cells, BzATP reproduced the effect of ATP, which was associated to a moderate decrease of proliferation and an increase of apoptosis. In DU145 cells, ATP was more potent than BzATP and growth inhibition was mainly associated with necrosis. We suggest that P2X receptors might be involved in the inhibition by nucleotides of prostate carcinoma cell growth.

Adenosine Triphosphate↗
PubMed1989

Nucleoside and nucleotide modulation of genetic expression--a new approach to chemotherapy.

Unlike conventional enzymes, receptors that activate G proteins do not catalyze the direct formation or cleavage of covalent bonds but act instead as a catalyst for the exchange of GTP vs GDP, which results in major conformational changes in the alpha subunit of G proteins and dissociation and selective binding of the alpha subunit which provokes direct enzyme activation eventually resulting in stimulation of protein kinase A, B or C. Each of these kinases can phosphorylate specific DNA binding proteins which allow new portions of DNA to be read and expressed. Such a series of events can act as switches to control cellular genetic expression resulting in cellular proliferation, differentiation or hormonal secretion of growth factors (Scheme I). Examples of nucleosides and nucleotides which appear to exert their therapeutic effects via G protein control of cellular proliferation resulting in differentiation are tiazofurin, selenazofurin, and 8-chloro-cAMP which have been synthesized and studied in our laboratories. The clinical application of these nucleosides in cancer treatment is presently underway and offers a viable alternative to chemotherapy with highly cytotoxic agents. The use of these derivatives result in down-regulation of the G protein regulatory pathways responsible for rapid cell division. Alternatively, a series of guanosine analogs prepared in our laboratories, 8-bromoguanosine, 8-mercaptoguanosine, 7-methyl-8-oxoguanosine and 7-thia-8-oxoguanosine, all activate various aspects of the immune response by up-regulation of G protein regulatory pathways in various lymphocyte derived cells. Guanosine-like nucleosides which function in this manner could have major clinical application as antitumor, antiviral and antimetastatic agents providing the desired specificity can be achieved. Specific immune enhancement of the aged might be an attainable goal if suitable orally active guanosine derivatives with high specificity can be achieved. The G protein regulatory pathways for modulation of genetic expression in specific cell types provide a major modern approach to new chemotherapeutic agents.

Animals↗