Molecular therapy for obesity and diabetes based on a long-term increase in hepatic fatty-acid oxidation.

UNLABELLED: Obesity-induced insulin resistance is associated with both ectopic lipid deposition and chronic, low-grade adipose tissue inflammation. Despite their excess fat, obese individuals show lower fatty-acid oxidation (FAO) rates. This has raised the question of whether burning off the excess fat could improve the obese metabolic phenotype. Here we used human-safe nonimmunoreactive adeno-associated viruses (AAV) to mediate long-term hepatic gene transfer of carnitine palmitoyltransferase 1A (CPT1A), the key enzyme in fatty-acid ß-oxidation, or its permanently active mutant form CPT1AM, to high-fat diet-treated and genetically obese mice. High-fat diet CPT1A- and, to a greater extent, CPT1AM-expressing mice showed an enhanced hepatic FAO which resulted in increased production of CO(2) , adenosine triphosphate, and ketone bodies. Notably, the increase in hepatic FAO not only reduced liver triacylglyceride content, inflammation, and reactive oxygen species levels but also systemically affected a decrease in epididymal adipose tissue weight and inflammation and improved insulin signaling in liver, adipose tissue, and muscle. Obesity-induced weight gain, increase in fasting blood glucose and insulin levels, and augmented expression of gluconeogenic genes were restored to normal only 3 months after AAV treatment. Thus, CPT1A- and, to a greater extent, CPT1AM-expressing mice were protected against obesity-induced weight gain, hepatic steatosis, diabetes, and obesity-induced insulin resistance. In addition, genetically obese db/db mice that expressed CPT1AM showed reduced glucose and insulin levels and liver steatosis. CONCLUSION: A chronic increase in liver FAO improves the obese metabolic phenotype, which indicates that AAV-mediated CPT1A expression could be a potential molecular therapy for obesity and diabetes.

[Improvement in the regimen for combined CDDP and CPT-11 chemotherapy].

UNLABELLED: Combination therapy with cisplatin (CDDP) and irinotecan hydrochloride (CPT-11) is expected to be effective against refractory tumors. The antitumor effect of CPT-11 is believed to depend on the area under the concentration-time curve (AUC) of SN 38, which is a metabolite of the prodrug CPT-11. Of the major adverse effects of CPT-11, leukopenia is dependent on the AUC of CPT-11 and severe diarrhea is believed to be dependent on the peak concentration (Cmax) of SN 38. Considering these properties of CPT-11, we investigated the administration of a new regimen. METHOD: The subjects were patients with gynecological cancer who consented to intra-arterial [IA] infusion. The patients received CDDP (30 mg/m2 over 2 hours) concurrently with CPT-11 (40 mg/m2 over 24 hours) at 2-week intervals. Plasma concentrations of platinum and CPT-11 were measured before and after administration. To prevent binding of SN 38 to the large intestinal mucosa, we performed 1) alkalization, 2) detoxification of SN 38, and 3) clearance of the large intestine. RESULT: 1) A decrease in tumor diameter or negative conversion on cytology and reduced tumor marker levels were observed in patients receiving IA infusion. 2) No serious adverse reactions occurred, except grade 3 diarrhea in one patient given infusion at the initial dose. 3) The rate of conversion from CPT-11 to SN 38 was about 10%, which was higher than the 3% rate after standard 90-minute intra-venous [i.v.] infusion. 4) In the patients treated with IA infusion, CPT-11 levels in venous blood were one thirty-third of those in arterial blood. 5) Regarding the venous blood concentration of platinum when CDDP (30 mg/m2) was administered, the AUC of free platinum in patients given IA infusion was about 2.5 times that after i.v. infusion. CONCLUSION: The IA infusion treatment produced a good clinical response with good compliance.