We have established 51 solid tumor and 10 ALL in vivo models. The models identify vincristine and cyclophosphamide as having broad-spectrum activity. The PPTP tumor panels appear to generally recapitulate the activity of these agents against specific childhood cancers and to have the potential for identifying novel agents having significant clinical activity.

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Belinostat is a hydroxamate class HDAC inhibitor that has demonstrated activity in peripheral T-cell lymphoma and is undergoing clinical trials for non-hematologic malignancies. We studied the pharmacokinetics of belinostat in hepatocellular carcinoma patients to determine the main pathway of metabolism of belinostat. The pharmacokinetics of belinostat in liver cancer patients were characterized by rapid plasma clearance of belinostat with extensive metabolism with more than 4-fold greater relative systemic exposure of major metabolite, belinostat glucuronide than that of belinostat. There was significant interindividual variability of belinostat glucuronidation. The major pathway of metabolism involves UGT1A1-mediated glucuronidation and a good correlation has been identified between belinostat glucuronide formation and glucuronidation of known UGT1A1 substrates. In addition, liver microsomes harboring UGT1A1*28 alleles have lower glucuronidation activity for belinostat compared to those with wildtype UGT1A1. The main metabolic pathway of belinostat is through glucuronidation mediated primarily by UGT1A1, a highly polymorphic enzyme. The clinical significance of this finding remains to be determined.Trial RegistrationClinicalTrials.gov NCT00321594

Administration of tert-butyl-4-hydroxyanisole or of two dithiolthiones to female CD-1 mice protected against the acute toxic effects of two hepatotoxic agents, acetaminophen and carbon tetrachloride. Reduced mortality of mice was observed following pretreatment with tert-butyl-4-hydroxyanisole or dithiolthiones. Pretreatment reduced or prevented hepatic glutathione depletion produced by these two hepatotoxic agents. Liver damage, i.e., as determined by serum transaminase and sorbitol dehydrogenase activities, was less after pretreatment with tert-butyl-4-hydroxyanisole or dithiolthiones. Administration of dithiolthiones resulted in increased (from four-to over six-fold) activities of liver glutathione-S-transferases.The anticarcinogenic (1) and antimutagenic (2) properties of the antioxidant butylated hydroxyanisole (BHA) are associated with many biochemical effects (2-4). For example, oral administration of BHA increased glutathione (GSH) levels and enhanced the activities of GSH-S-transferases and other enzymes in many rodent tissues. By contrast, reduction in hepatic acid-soluble GSH levels was observed after administration of two hepatotoxic agents, acetaminophen (5) and carbon tetrachloride (CC1,) (See below).Recently, we noted that administration of two dithiolthiones produced many biochemical effects similar to those observed with BHA. The two dithiolthiones used in the present study were oltipraz (5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione) and anethol dithiolthione (3-(p-methoxyphenyl)-l,2-dithiol-3-thione; ADT).Oltipraz ADT If hepatic GSH depletion was related to the toxic effects of acetaminophen (5) and CC14, pretreatment with

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