BACKGROUNDOur previous studies have demonstrated potent oncolysis efficacy of the E1A, E1B double-restricted replication-competent oncolytic adenovirus AxdAdB-3 for treatment of bladder cancer. Here, we reported the feasibility and efficacy of AxdAdB-3 alone, or in combination with gemcitabine for treating renal cell carcinoma.

METHODSCytopathic effects of AxdAdB-3 were evaluated in human renal cell carcinoma cell lines TOS-1, TOS-2, TOS-3, TOS-3LN, SMKT-R3, SMKT-R4 and ACHN, and in normal human renal proximal tubule epithelial cells (RPTEC). AxdAdB-3 induced down-regulation of the cell cycle was determined by flow cytometry. Combination therapies of AxdAdB-3 with gemcitabine were evaluated in vitro and in vivo on subcutaneous TOS-3LN tumors in a severe combined immunodeficiency disease (SCID) mouse model.

RESULTSAxdAdB-3 was potently cytopathic against the tested most renal cell carcinoma cell lines including TOS-2, TOS-3, TOS-3LN, SMKT-R3 and SMKT-R4, while normal human RPTEC were not destroyed. AxdAdB-3 effectively induced cell cycle S-phase entry. Combined therapy of AxdAdB-3 with gemcitabine demonstrated stronger antitumor effects in vitro and in vivo compared with either AxdAdB-3 or gemcitabine alone.

CONCLUSIONAxdAdB-3 alone, or in combination with gemcitabine may be a promising strategy against renal cell carcinoma.

Adenoviridae ; genetics ; metabolism ; physiology ; Adenovirus E1A Proteins ; genetics ; Adenovirus E1B Proteins ; genetics ; Animals ; Antimetabolites, Antineoplastic ; pharmacology ; therapeutic use ; Carcinoma, Renal Cell ; drug therapy ; therapy ; Cell Cycle ; drug effects ; genetics ; Cell Line ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Coxsackie and Adenovirus Receptor-Like Membrane Protein ; Deoxycytidine ; analogs & derivatives ; pharmacology ; therapeutic use ; Flow Cytometry ; Humans ; Immunohistochemistry ; Male ; Mice ; Mice, Inbred BALB C ; Mice, SCID ; Oncolytic Virotherapy ; Receptors, Virus ; genetics ; metabolism ; Xenograft Model Antitumor Assays

Protamine has been widely used as a pharmaceutical product and natural food preservative. However, few studies have been conducted to assess the beneficial function of dietary protamine. This study examined the effects of dietary salmon protamine on serum and liver lipid levels and the expression levels of genes encoding proteins involved in lipid homeostasis in the liver of rats. Groups of male Wistar rats were fed AIN93G diet containing 2% or 5% protamine. After 4 weeks of feeding these diets, markedly decreased serum and liver cholesterol (CHOL) and triacylglycerol levels were noted. Increased activity of liver carnitine palmitoyltransferase-2 and acyl-CoA oxidase, which are key enzymes of fatty acid beta-oxidation in the mitochondria and peroxisomes, was found in rats fed on protamine. Furthermore, rats fed protamine showed enhanced fecal excretion of CHOL and bile acid and increased liver mRNA expression levels of ATP-binding cassette (ABC) G5 and ABCG8, which form heterodimers and play a major role in the secretion of CHOL into bile. The decrease in triacylglycerol levels in protamine-fed rats was due to the enhancement of liver beta-oxidation. Furthermore, rats fed protamine exhibited decreased CHOL levels through the suppression of CHOL and bile acid absorption and the enhancement of CHOL secretion into bile. These results suggest that dietary protamine has beneficial effects that may aid in the prevention of lifestyle-related diseases such as hyperlipidemia and atherosclerosis.
Absorption ; Acyl-CoA Oxidase ; Animals ; Atherosclerosis ; Bile ; Carnitine ; Cholesterol ; Diet ; Homeostasis ; Humans ; Hyperlipidemias ; Lipid Metabolism ; Liver ; Male ; Mitochondria ; Peroxisomes ; Proteins ; Rats ; Rats, Wistar ; RNA, Messenger ; Salmon ; Triglycerides