sirolimus and pyrimidine

An increasing number of immunosuppressive drugs became available for clinical use over the past few decades. These include substances with recently recognized immunosuppressive properties, which needed careful evaluation in various trials before they could be approved for use in different diseases. The effectiveness of other agents was already established, but knowledge about their modes of action or the mechanisms that lead to side effects was acquired much later. This understanding also contributed to the development of new drugs that display synergistic effects or lack certain adverse effects. The greater choice afforded by such research endeavours allows us to select the best therapeutic strategy for an individual patient; however, this requires a comprehensive knowledge of the available options. The present review provides an update of current knowledge of the most important substances (including calcineurin and target of rapamycin inhibitors, regulators of gene expression, and inhibitors of purine and pyrimidine synthesis) and surveys some of the novel agents that are expected to play an important role in the future.

Topics: Adrenal Cortex Hormones; Alkylating Agents; Calcineurin Inhibitors; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Kidney Transplantation; Propylene Glycols; Purines; Pyrimidines; Sirolimus; Sphingosine; Vitamin D

The urea cycle (UC) is the main pathway by which mammals dispose of waste nitrogen. We find that specific alterations in the expression of most UC enzymes occur in many tumors, leading to a general metabolic hallmark termed "UC dysregulation" (UCD). UCD elicits nitrogen diversion toward carbamoyl-phosphate synthetase2, aspartate transcarbamylase, and dihydrooratase (CAD) activation and enhances pyrimidine synthesis, resulting in detectable changes in nitrogen metabolites in both patient tumors and their bio-fluids. The accompanying excess of pyrimidine versus purine nucleotides results in a genomic signature consisting of transversion mutations at the DNA, RNA, and protein levels. This mutational bias is associated with increased numbers of hydrophobic tumor antigens and a better response to immune checkpoint inhibitors independent of mutational load. Taken together, our findings demonstrate that UCD is a common feature of tumors that profoundly affects carcinogenesis, mutagenesis, and immunotherapy response.

Topics: Amino Acid Transport Systems, Basic; Animals; Aspartate Carbamoyltransferase; Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); Cell Line, Tumor; Dihydroorotase; Female; Genomics; Humans; Metabolomics; Mice; Mice, Inbred C57BL; Mice, SCID; Mitochondrial Membrane Transport Proteins; Neoplasms; Ornithine Carbamoyltransferase; Phosphorylation; Pyrimidines; RNA Interference; RNA, Small Interfering; Sirolimus; TOR Serine-Threonine Kinases; Urea

Treatment of mammalian cells with the immunosuppressant rapamycin, a bacterial macrolide, selectively suppresses mitogen-induced translation of an essential class of mRNAs which contain an oligopyrimidine tract at their transcriptional start (5'TOP), most notably mRNAs encoding ribosomal proteins and elongation factors. In parallel, rapamycin blocks mitogen-induced p70 ribosomal protein S6 kinase (p70s6k) phosphorylation and activation. Utilizing chimeric mRNA constructs containing either a wild-type or disrupted 5'TOP, we demonstrate that an intact polypyrimidine tract is required for rapamycin to elicit an inhibitory effect on the translation of these transcripts. In turn, a dominant-interfering p70s6k, which selectively prevents p70s6k activation by blocking phosphorylation of the rapamycin-sensitive sites, suppresses the translation of the chimeric mRNA containing the wild-type but not the disrupted 5'TOP. Conversion of the principal rapamycin-sensitive p70s6k phosphorylation site, T389, to an acidic residue confers rapamycin resistance on the kinase and negates the inhibitory effects of the macrolide on 5'TOP mRNA translation in cells expressing this mutant. The results demonstrate that the rapamycin block of mitogen-induced 5'TOP mRNA translation is mediated through inhibition of p70s6k activation.

Topics: 3T3 Cells; Animals; Cell Line, Transformed; Drug Resistance; Enzyme Activation; Enzyme Inhibitors; Human Growth Hormone; Humans; Mice; Mutagenesis; Polyenes; Protein Biosynthesis; Protein Serine-Threonine Kinases; Pyrimidines; Recombinant Fusion Proteins; Ribosomal Protein S6 Kinases; RNA, Messenger; Sirolimus