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Results for “FOLIC ACID ANTAGONISTS”

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PubMed1975

[The kinetics of accumulation and elimination of the antitumor preparation tomizine-35 S].

On rats with sarcoma M-1 the peculiarities of accumulation and elimination of the folic acid antagonist-pyrimido (4,5-b), (1,4) thiazinon-35S, called "thomizine", have been studied. In travenous injection of thomizine-35S with the activity of 5 muc per animal the highest initial concentration of radioactivity was observed 5-15 minutes after the injection. While decreasing, the radioactivity absorption coefficients in organs were distributed as follows: the kidneys, pancreas, organs of the endocrinous system, lymph nodes, the stomach, liver, small intestine, brain. Thomizine-35S accumulation in rat organs proceeded not only on account of its intake with blood but also due to penetration and subsequent deposition in structural tissue elements. Lessening of radioactivity in the organism of rats was dependent exponentially. Elimination of the drug was realized mainly via the kidneys. 89 per cent of the absorbed radioactivity was eliminated from the organism with a period of semielimination of 1 hour, 11 per cent - with a period of semielimination of 36 hours.

Animals↗
PubMed2001

Cross-talk between steroid-receptor-mediated and cell-membrane-receptor-mediated signalling pathways results in the in vivo modulation of c-Met and ornithine decarboxylase gene expression in mouse kidney.

The cross-talk in vivo between two signalling pathways activated by testosterone via intracellular androgen receptor, and induced by damage to renal tubules evoked by anti-folate [N(10)-propargyl-5,8-dideazafolic acid (CB 3717)] or folate is reported. We show that CB 3717/folate induces the expression of the hepatocyte growth factor (HGF)/c-Met signalling system in injured kidneys in which a significant, but transient, elevation of the HGF mRNA level occurs. It is followed by a severalfold increase in the c-Met transmembrane receptor message that persists for up to 24 h. The c-Met expression is also positively controlled by testosterone, which induces a significant increase in its mRNA level that is abolished by an anti-androgen, casodex. However, when testosterone and anti-folate/folate are administered sequentially, a substantial (3.5-4.0-fold) decrease in the increase of c-Met expression caused by CB 3717/folate alone occurs. Similarly, testosterone-induced ornithine decarboxylase (ODC) mRNA level and activity are decreased 2.8-7.7-fold when the androgen is applied together with CB 3717. Antagonism between these pathways is also visible under physiological conditions in the kidneys of male mice in which, owing to elevated endogenous testosterone levels, neither the ODC activity nor the mRNA level is induced by anti-folate/folate, whereas the c-Met message response to these drugs is significantly decreased. Our results document a substantial negative regulation of c-Met and ODC gene expression as a result of the cross-talk between testosterone-activated and HGF-activated pathways and suggest a sex-differentiated response to injury of mouse kidneys.

Androgen Antagonists↗
PubMed2007

Critical evaluation of methods to incorporate entropy loss upon binding in high-throughput docking.

Proper accounting of the positional/orientational/conformational entropy loss associated with protein-ligand binding is important to obtain reliable predictions of binding affinity. Herein, we critically examine two simplified statistical mechanics-based approaches, namely a constant penalty per rotor method, and a more rigorous method, referred to here as the partition function-based scoring (PFS) method, to account for such entropy losses in high-throughput docking calculations. Our results on the estrogen receptor beta and dihydrofolate reductase proteins demonstrate that, while the constant penalty method over-penalizes molecules for their conformational flexibility, the PFS method behaves in a more "DeltaG-like" manner by penalizing different rotors differently depending on their residual entropy in the bound state. Furthermore, in contrast to no entropic penalty or the constant penalty approximation, the PFS method does not exhibit any bias towards either rigid or flexible molecules in the hit list. Preliminary enrichment studies using a lead-like random molecular database suggest that an accurate representation of the "true" energy landscape of the protein-ligand complex is critical for reliable predictions of relative binding affinities by the PFS method.

Algorithms↗