Selective RET kinase inhibition for patients with RET-altered cancers.

Background: Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET fusions, activating mutations and acquired resistance mutations.

A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors.

Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs.

Antibody-mediated inhibition of fibroblast growth factor 19 results in increased bile acids synthesis and ileal malabsorption of bile acids in cynomolgus monkeys.

Fibroblast growth factor 19 (FGF19) represses cholesterol 7α-hydroxylase (Cyp7α1) and inhibits bile acid synthesis in vitro and in vivo. Previous studies have shown that anti-FGF19 antibody treatment reduces growth of colon tumor xenografts and prevents hepatocellular carcinomas in FGF19 transgenic mice and thus may be a useful cancer target. In a repeat dose safety study in cynomolgus monkeys, anti-FGF19 treatment (3-100 mg/kg) demonstrated dose-related liver toxicity accompanied by severe diarrhea and low food consumption.

Hepatocyte cytotoxicity induced by various hepatotoxins mediated by cytochrome P-450IIE1: protection with diethyldithiocarbamate administration.

The objective of this study was to determine whether the thiol drug, diethyldithiocarbamate (DEDC) and its two metabolites, disulfiram (DS) and carbon disulfide (CS2) could be used as inhibitors of cytochrome P-450IIE1 to protect hepatocytes from cytotoxic xenobiotics. (1) Hepatocytes isolated from rats following pyrazole administration to induce cytochrome P-450IIE1 were much more susceptible to carbon tetrachloride (CCl4) and dimethylnitrosamine (DMN) than hepatocytes from untreated rats. Microsomes isolated from P-450IIE1-induced liver were also much more effective at catalysing a NADPH-dependent metabolism of CCl4 and DMN.

Molecular mechanism for prevention of N-acetyl-p-benzoquinoneimine cytotoxicity by the permeable thiol drugs diethyldithiocarbamate and dithiothreitol.

The present study was carried out to elucidate the mechanism by which the permeable thiol drug diethyldithiocarbamate (DEDC) exhibited an antidotal effect against acetaminophen-induced hepatotoxicity in vivo. DEDC was found to act as an antidote against acetaminophen-induced cytotoxicity in hepatocytes isolated from a pyrazole-pretreated rat without affecting cytochrome P-450 levels. The mechanism of protection exhibited against reactive intermediate N-acetyl-p-benzoquinoneimine (NAPQI)-induced cytotoxicity by DEDC was then investigated and compared with that exhibited by the permeable thiol-reductant dithiothreitol (DTT).

Disulfiram may mediate erythrocyte hemolysis induced by diethyldithiocarbamate and 1,4-naphthoquinone-2-sulfonate.

The increase in 1,4-naphthoquinone-2-sulfonate (NQS)-induced hemolysis by the superoxide dismutase inhibitor diethyldithiocarbamate (DEDC) was formerly attributed to increased superoxide anion levels in the erythrocyte. Our results show that removal of DEDC after preincubation and prior to the addition of NQS did not produce a significant increase in hemolysis, which suggests that hemolysis is primarily caused by the reaction products of DEDC with NQS and not to the inactivation of superoxide dismutase. Disulfiram, the oxidized product of DEDC, was found to be the main product formed when excess DEDC was reacted with NQS.

Butylated hydroxyanisole (BHA) does not cause forestomach hyperplasia by inhibiting the release of gastric mucus.

High doses of BHA cause hyperplasia and subsequent neoplasia in the rodent forestomach and can inhibit gastric prostaglandin (PG) synthesis in vitro. This paper examines the hypothesis that BHA induced forestomach hyperplasia occurs in response to a reduction of gastric mucus, with consequent irritation of the forestomach. This could result from inhibition of the formation of the PG's which mediate the synthesis and release of protective mucus.

Modulation of benzoquinone-induced cytotoxicity by diethyldithiocarbamate in isolated hepatocytes.

The copper-chelating thiol drug diethyldithiocarbamate protected isolated hepatocytes from benzoquinone-induced alkylation cytotoxicity by reacting with benzoquinone and forming a conjugate which was identified by fast atom bombardment mass spectrometry as 2-(diethyldithiocarbamate-S-yl) hydroquinone. In contrast to benzoquinone, the conjugate was not cytotoxic to isolated hepatocytes. The thiol reductant dithiothreitol had no effect on benzoquinone-induced alkylation cytotoxicity.

Molecular mechanisms for bromotrichloromethane cytotoxicity in isolated rat hepatocytes.

1. Bromotrichloromethane added to isolated rat hepatocytes resulted in increased cell death as determined by trypan blue uptake. Toxicity increased in a concentration-dependent fashion between 2.

Diethyldithiocarbamate (DEDC) enhances quinone mediated oxidative stress cytotoxicity in isolated hepatocytes by forming toxic quinone conjugates.

The copper-chelating thiol drug, diethyldithiocarbamate (DEDC) had previously been used to inhibit superoxide dismutase (SOD) and enhance oxidative stress mediated cytotoxicity. Using isolated rat hepatocytes, it was confirmed that DEDC enhances oxidative stress cytotoxicity induced by 1,4-naphthoquinone (1,4-NQ) and 1,4-naphthoquinone-2-sulphonate (1,4-NQ-2S). However, equimolar concentrations of DEDC also enhances cytotoxicity induced by benzoquinone, previously shown to cause cytotoxicity as a result of alkylation and not oxidative stress.

The toxicity of disulphides to isolated hepatocytes and mitochondria.

The disulfide metabolites of thiono-sulfur drugs were found to be about 50 to 100 times more toxic to isolated rat hepatocytes than the corresponding parent drugs. The order of decreasing cytotoxicity for the disulfide metabolites was disulfiram greater than propylthiouracil disulfide greater than formamidine disulfide greater than phenylthiourea disulfide greater than thiobenzamide disulfide greater than cystamine. Depletion of intracellular GSH levels preceded cytotoxicity.