The use of chemotherapy to treat cancer began at the start of the 20th century with attempts

Thymidylate synthase (TS; 5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1.45) is essential for the de novo synthesis of thymidylate, a precursor of DNA. Previous studies have shown that the cellular level of this protein is regulated at both the transcriptional and posttranscriptional levels. The regulation of human TS mRNA translation was studied in vitro with a rabbit reticulocyte lysate system. The addition of purified human recombinant TS protein to in vitro translation reactions inhibited translation of TS mRNA. This inhibition was specific in that recombinant TS protein had no effect on the in vitro translation of mRNA for human chromogranin A, human folate receptor, preplacental lactogen, or total yeast RNA. The inclusion of dUMP, 5-fluorodUMP, or 5,10-methylene-tetrahydrofolate in in vitro translation reactions completely relieved the inhibition of TS mRNA translation by TS protein. Gel retardation assays confirmed a specific interaction between TS protein and its corresponding mRNA but not with unrelated mRNAs, including human placenta, human .8-actin, and yeast tRNA. These studies suggest that translation of TS mRNA is controlled by its own protein end product, TS, in an autoregulatory manner.Thymidylate synthase (TS; 5,10-methylenetetrahydrofolate: dUMP C-methyltransferase, EC 2.1.1.45) catalyzes the conversion of 2'-deoxyuridine 5'-monophosphate (dUMP) and 5,10-methylenetetrahydrofolate (5,10-methylene-H4PteGlu, where H4PteGlu is tetrahydropteroylglutamic acid) to thymidine monophosphate (dTMP) and dihydrofolate (H2PteGlu) (1). This enzymatic reaction provides the sole intracellular de novo source of dTMP, and because of its central role in the synthesis of DNA precursors, TS remains an important target enzyme in cancer chemotherapy (2).Both the cDNA and corresponding mRNA clones for mouse (3) and human (4) TS have been isolated and sequenced, and these probes have facilitated the analysis of TS structure and expression and the study of the molecular basis of TS regulation. This enzyme has been purified and well characterized from various sources, including bacteria, bacteriophage, yeast, viruses, parasites, and mammals (5-9). TS is a dimeric protein with identical subunits, each =35 kDa, and comparison of the predicted primary amino acid sequence ofthe protein from eight different sources reveals that it is one of the most highly conserved proteins.Previous studies examining regulation of TS expression have concentrated on cell-cycle-directed events. Various investigators have shown that maximal TS activity occurs during periods of active DNA synthesis (10-12). Moreover, this increase in TS enzyme levels that arises as cells enter S phase appears to be regulated at both the transcriptional and posttranscriptional levels (13-15). Takeishi et al. (4) also suggested the possibility of translational regulation of TS expression given the theoretical potential of three interconvertible secondary structures, each containing a stem-loop structure in the 5' untranslated region (5' U...

This phase I study evaluated the safety, tolerability, and pharmacokinetics of copanlisib, an intravenously administered pan-phosphatidylinositol 3-kinase inhibitor in patients with advanced solid tumors or non-Hodgkin's lymphoma. Copanlisib was well tolerated with a manageable safety profile, with anti-tumor activity in both advanced solid tumors and hematological malignancies.