azaserine and Liver-Neoplasms

Topics: Adenocarcinoma; Amino Sugars; Animals; Antibiotics, Antineoplastic; Azaserine; Benzazepines; Bleomycin; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Cricetinae; Dactinomycin; Daunorubicin; DNA; Dogs; Glycosides; Haplorhini; Humans; Leukemia L1210; Liver Neoplasms; Lymphoma; Mice; Mitomycins; Naphthacenes; Plicamycin; Pyrroles; Rats; RNA; Sarcoma 180; Streptonigrin; Streptozocin

Cancer was hypothesized to be driven by cancer stem cells (CSCs), but the metabolic determinants of CSC-like phenotype still remain elusive. Here, we present that hexosamine biosynthetic pathway (HBP) at least in part rescues cancer cell fate with inactivation of glycolysis. Firstly, metabolomic analysis profiled cellular metabolome in CSCs of hepatocellular carcinoma using CD133 cell-surface marker. The metabolic signatures of CD133-positive subpopulation compared to CD133-negative cells highlighted HBP as one of the distinct metabolic pathways, prompting us to uncover the role of HBP in maintenance of CSC-like phenotype. To address this, CSC-like phenotypes and cell survival were investigated in cancer cells under low glucose conditions. As a result, HBP inhibitor azaserine reduced CD133-positive subpopulation and CD133 expression under high glucose condition. Furthermore, treatment of N-Acetylglucosamine in part restores CD133-positive subpopulation when either 2.5 mM glucose in culture media or glycolytic inhibitor 2-deoxy-D-glucose in HCC cell lines was applied, enhancing CD133 expression as well as promoting cancer cell survival. Together, HBP might be a key metabolic determinant in the functions of hepatic CSC marker CD133.

Topics: AC133 Antigen; Azaserine; Biomarkers; Biosynthetic Pathways; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Survival; Glucose; Glycolysis; Hexosamines; Humans; Liver Neoplasms; Metabolomics; Neoplastic Stem Cells; Phenotype

Dietary administration of dehydroepiandrosterone (DHEA) (0.6%) or butylated hydroxytoluene (BHT) (1%) during or subsequent to two i.p. injections of azaserine (30 mg/kg body wt) resulted in significant alteration of yield of preneoplastic lesions in both pancreas and liver. While concomitant application appeared not to have any effect on subsequent development of glutathione S-transferase P form (GST-P) positive hepatocellular lesions in either case, BHT and to a lesser extent also DHEA reduced initiation of pancreatic acinar carcinogenesis. Both BHT and DHEA were associated with significant increase in GST-A form positive pancreatic foci when administered after cessation of carcinogen treatment while clearly inhibiting liver lesion development. The results point to a marked differential in the response of the liver and pancreas to external stimulus with regard to preneoplastic focal lesions while demonstrating significant second stage promotion of pancreatic acinar carcinogenesis by BHT and DHEA.

Topics: Animals; Azaserine; Butylated Hydroxytoluene; Dehydroepiandrosterone; Liver Neoplasms; Male; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Strains

Chemoprevention by synthetic retinoids of the progression of carcinomas of the pancreas induced in rats by azaserine was evaluated. Lewis rats were given five weekly injections of azaserine, 30 mg/kg, while being fed a chow diet. Two weeks after completion of carcinogen treatment, groups of rats were fed the chow diet supplemented with four different retinoids at the level of 0.5 to 2 mmol/kg of diet for 1 year. The incidence of pancreatic and other neoplasms was determined by autopsy and histological study. The incidence of localized pancreatic carcinoma among male and female non-retinoid-treated controls was 25 and 17%, respectively. No invasive or metastatic carcinomas were found in the control group. The combined incidence of localized and invasive pancreatic carcinomas among male and female rats treated with retinoids was: N-(4-pivaloyloxyphenyl)retinamide, 4 and 0%; N-(2-hydroxypropyl)retinamide, 14 and 6%; N-(3-hydroxypropyl)retinamide, 16 and 4%; and N-(2,3-dihydroxypropyl)retinamide, 12 and 6%. High- and low-dose groups are combined in this summary of data. Thus, there was a trend towards fewer pancreatic carcinomas among all retinoid-treated groups. The reduction in incidence was significant in both male and female rat groups given N-(4-pivaloyloxyphenyl)retinamide and N-(2,3-dihydroxypropyl)retinamide. The principal evidence of retinoid toxicity was growth failure, which was most severe in animals treated with N-(4-pivaloyloxyphenyl)retinamide, and testicular atrophy, which was most severe among male animals treated with N-(3-hydroxypropyl)retinamide. Among the females, groups treated with three of the four retinoids showed a dose-related increase in incidence of hepatocellular carcinomas. Since the retinoids were fed after the completion of exposure to the carcinogen, the effects on both pancreatic and liver carcinogenesis were exerted during the postinitiation phase of carcinogenesis.

Topics: Animals; Atrophy; Azaserine; Body Weight; Cocarcinogenesis; Diet; Female; Liver Neoplasms; Male; Neoplasms, Experimental; Pancreatic Neoplasms; Rats; Rats, Inbred Lew; Sex Factors; Testis; Vitamin A

Chemoprevention by retinoids of the progression of carcinomas induced in rats by azaserine was evaluated. Wistar/Lewis rats were given 15 weekly injections of azaserine, 10 mg/kg, while fed a chow diet; after the completion of carcinogen treatment, they were fed a chow diet supplemented with four different retinoids at the level of 0.5 to 2 mmol/kg diet for 1 year. The incidence of neoplasms was determined by autopsy and histological study. The incidence of pancreatic carcinoma among a male positive control group (azaserine treated, but not retinoid treated) was 42%. The incidence of pancreatic carcinoma among male rats treated with retinoids was: N-2-hydroxyethylretinamide, 6%; N-4-propionyloxyphenylretinamide, 17%; and retinylidene dimedone, 12%. The incidence in rats fed these three retinoids was significantly (p less than 0.05) below the control group incidence. Thus, these three retinoids appeared to be effective in inhibiting the progression of pancreatic carcinomas in the azaserine-induced model. A similar trend was demonstrated in females, but statistical significance was shown only in rats fed N-2-hydroxyethylretinamide. A fourth retinoid, N-4-carboxyphenylretinamide, was more toxic and less effective in chemoprevention. Since retinoids were fed after exposure to carcinogen, the effect was exerted during the postinitiation phase of carcinogenesis. The ratio of invasive pancreatic carcinomas to localized carcinomas (carcinoma in situ) was clearly higher among non-retinoid-treated rats than among those treated with retinoids. This is consistent with retarded progression in the retinoid-treated groups.

Topics: Animals; Azaserine; Female; Liver Neoplasms; Male; Neoplasm Metastasis; Neoplasms, Experimental; Pancreas; Pancreatic Neoplasms; Rats; Vitamin A

Inbred W/LEW rats and noninbred CD-1 mice were compared for responsiveness to induction of pancreatic adenocarcinomas by azaserine. At 1 year following the first of 15 weekly ip injections of 10 mg azaserine/kg body weight, the rats had a pancreatic adenoma incidence of 71% (12/17) and a pancreatic adenocarcinoma incidence of 35% (6/17), with 1 invasive adenocarcinoma. The mice showed none of these advanced lesions, although numerous pancreatic atypical acinar cell nodules (AACN) were present. An examination of the number and size of the AACN showed the rats to hve more and larger AACN thatn did the mice. The concentration of [14C]azaserine and/or its metabolites was greater in rat pancreas than in mouse pancreas. Alkaline sucrose gradients were used to compare azaserine-induced pancrewtic and liver DNA damage in W/LEW and F344 rats, the CD-1 mouse, the Syrian golden hamster, and the strain 13 guinea pig. DNA damage was detected 1 hour following azaserine administration in both pancreata and livers of all animals tested and persisted for at least 1 week in the pancreata of all animals except the CD-1 mouse; however, neither the degree nor persistence of DNA damage accurately reflected the differing responsiveness of these species to induction of pancreatic AACN or neoplasms by azaserine.

Topics: Adenocarcinoma; Adenoma; Animals; Azaserine; Carcinogens; DNA; Liver; Liver Neoplasms; Lung Neoplasms; Mice; Neoplasms, Experimental; Pancreas; Pancreatic Neoplasms; Rats; Rats, Inbred Strains

Topics: Animals; Azaserine; Body Weight; Carcinogens; Carcinoma, Hepatocellular; Choline; Diet; Liver; Liver Neoplasms; Male; Neoplasms, Experimental; Organ Size; Pancreas; Pancreatic Neoplasms; Rats

Topics: Animals; Azaserine; Carcinoma, Ehrlich Tumor; Cell Adhesion; Cell Aggregation; Cells, Cultured; Chick Embryo; Culture Media; Cytological Techniques; Glutamine; Indicators and Reagents; Liver Neoplasms; Mice; Norleucine; Retina; Sarcoma 180; Time Factors; Trypsin

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Azaguanine; Azaserine; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; DNA; DNA, Neoplasm; Fluorouracil; Idoxuridine; Liver Neoplasms; Lymphoma; Lymphoma, Non-Hodgkin; Mercaptopurine; Mice; Neoplasms, Experimental; Nitrogen Mustard Compounds; Nucleosides; Nucleotides; Purines; Research; RNA; RNA, Neoplasm; Sarcoma 180; Thioguanine; Uracil Mustard

Topics: Animals; Antineoplastic Agents; Azaserine; Carcinoma, Hepatocellular; Liver Neoplasms; Neoplasms; Purines; Sarcoma; Sarcoma 180