Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas.

Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3 lysine 79 (H3K79). Mutations in IDH1 or IDH2 were associated with longer overall survival (P=0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (P=0.021). IDH1 and IDH2 mutations were significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation. We identified 2309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors.

Effect of auranofin on DNA and protein synthesis in human lymphocytes.

The effect of auranofin-a new oral gold compound for the treatment of rheumatoid arthritis-and gold sodium thiosulphate on DNA and protein synthesis, as well as their effect on membrane transport in stimulated lymphocytes was studied. It was found that only auranofin in the given concentrations inhibits the incorporation of 3H thymidine and 14C amino acids. The studies on membrane transport present evidence that the pharmacological action of auranofin might be mediated through its action at the cellular membrane level.

Auranofin. New oral gold compound for treatment of rheumatoid arthritis.

Eight patients with rheumatoid arthritis were treated with SK & F D-39162 (auranofin), a new oral gold compound which was effective in suppressing adjuvant-induced arthritis in rats. Clinical and humoral parameters were studied during a 3-month period of drug administration followed by a 3-month period under placebo. The drug was absorbed, well tolerated, and its action was manifested by a drop in the mean IgG blood levels in the third week of treatment accompanied by clinical improvement after 5 weeks of oral gold intake. Together with IgG changes, an increase of the albumin ratio was observed, as well as a decrease of alpha2-globulin and rheumatoid factor titres. From a total number of 60 swollen joints found initially in the 8 patients only 17 were swollen at week 12 and 9 at week 15. Although the number of patients treated was too small to allow definite conclusions, a follow-up study under placebo of clinical and laboratory changes in the same patients during another 3-month period showed that IgG serum levels rapidly reverted preceding a flare up of disease activity after withdrawal of the drug. This confirmed a direct role in cause-effect relation played by the new oral gold compound.

Antiarthritic properties and unique pharmacologic profile of a potential chrysotherapeutic agent: S K & F D-30162.

SK&F D-39162, a potential chrysotherapeutic agent, on oral administration was effective in suppressing the development of inflammatory lesions and 7S anti-sheep red blood cell antibody formation in adjuvant arthritic rats. Oral absorption of SK&F D-39162 was indicated by the presence of serum gold levels. In contrast to orally administered SK&F D-39162, gold sodium thiomalate administered intramuscularly at equivalent gold doses, appeared to be less effective in suppressing the primary and secondary lesions of adjuvant arthritis, produced relatively higher levels of gold in both serum and kidneys and produced marked toxicity. Other pharmacologic properties of SK&F D-39162 distinguishing it from gold sodium thiomalate which may have clinical significance include potent inhibitory activity on antibody-forming cells, immediate hypersensitivity reactions and extracellular release of lysosomal enzymes. In further contrast to gold sodium thiomalate, SK&F D-39162 is not a potent inhibitor of sulfhydryl group reactivity. In pharmacokinetic studies, the daily oral administration of SK&F D-39162 to normal rats produced greater stability of blood gold levels and less kidney gold accumulation than parenterally administered gold sodium thiomalate.