Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor.

No approved therapy exists for cancer-associated cachexia. The colon-26 mouse model of cancer cachexia mimics recent late-stage clinical failures of anabolic anti-cachexia therapy and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx-024. The histone deacetylase inhibitor (HDACi) AR-42 exhibited anti-cachectic activity in this model. We explored combined SARM/AR-42 therapy as an improved anti-cachectic treatment paradigm. A reduced dose of AR-42 provided limited anti-cachectic benefits, but, in combination with GTx-024, significantly improved body weight, hindlimb muscle mass, and grip strength versus controls. AR-42 suppressed the IL-6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx-024-mediated ß-catenin target gene regulation was apparent in cachectic mice only when combined with AR-42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx-024 therapy and a blockade of GTx-024-mediated anabolic signaling. AR-42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx-024. Combining GTx-024, a clinically established anabolic therapy, with AR-42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients.

Discovery of Anticancer Agents of Diverse Natural Origin.

Recent progress is described in an ongoing collaborative multidisciplinary research project directed towards the purification, structural characterization, chemical modification, and biological evaluation of new potential natural product anticancer agents obtained from a diverse group of organisms, comprising tropical plants, aquatic and terrestrial cyanobacteria, and filamentous fungi. Information is provided on how these organisms are collected and processed. The types of bioassays are indicated in which initial extracts, chromatographic fractions, and purified isolated compounds of these acquisitions are tested. Several promising biologically active lead compounds from each major organism class investigated are described, and these may be seen to be representative of a very wide chemical diversity.

Comparison of high-dose intermittent and low-dose continuous oral artemisinin in dogs with naturally occurring tumors.

To evaluate the clinical toxicity and activity of orally administered artemisinin in dogs with spontaneous tumors, 24 client-owned dogs were randomly divided into two groups and received either low-continuous dose (3 mg/kg q 24 hr) or high-dose intermittent (three doses of 45 mg/kg q 6 hr repeated q 1 wk) of artemisinin per os. Treatment was continued for 21 days. Dogs were evaluated weekly for clinical effect and at the end of the treatment for hematologic and biochemical adverse events. Whole blood concentrations of artemisinin and dihydroartemisinin were measured by liquid chromatography/tandem mass spectrometry after the first dose of artemisinin in three dogs in each group. Blood concentrations of artemisinin and dihydroartemisinin were <0.1 µM at all time points, and there was no difference in blood concentration between the two dosing groups. The most frequent adverse event was anorexia, which was observed in 11% of the low-dose group and 29% of the high-dose group. Oral artemisinin, both in low-dose continuous and high-dose intermittent, is well tolerated in dogs but results in low bioavailability. Parenteral administration should be considered for future studies.

CYP3A4/5 combined genotype analysis for predicting statin dose requirement for optimal lipid control.

BACKGROUND: Statins are indicated for prevention of atherosclerotic cardiovascular disease. Metabolism of certain statins involves the cytochrome P450 3A (CYP3A) enzymes, and CYP3A4*22 significantly influences the dose needed for achieving optimal lipid control for atorvastatin, simvastatin, and lovastatin. CYP3A4/5 combined genotype approaches have proved useful in some studies involving CYP3A substrates. We intend to compare a combined genotype analysis to our previously reported single gene CYP3A4 analysis. METHODS: A total of 235 patients receiving stable statin doses were genotyped and grouped by CYP3A4/5 status. RESULTS: The number and demographic composition of the patients categorized into the combined genotype groups were consistent with those reported for other cohorts. Dose requirement was significantly associated with the ordered combined-genotype grouping; median daily doses were nearly 40% greater for CYP3A4/5 intermediate metabolizers compared with poor metabolizers, and median daily doses were nearly double for extensive metabolizers compared with poor metabolizers. The combined-genotype approach, however, did not improve the genotype-dosage correlation p-values when compared with the previously-reported analysis; values changed from 0.129 to 0.166, 0.036 to 0.185, and 0.014 to 0.044 for atorvastatin, simvastatin, and the combined statin analysis, respectively. CONCLUSIONS: The previously-reported single-gene approach was superior for predicting statin dose requirement in this cohort.