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Modulation of diethylnitrosamine carcinogenesis in rat liver and oesophagus
R M Balansky1, P M Blagoeva, Z I Mircheva
1National Centre of Oncology, Sofia, Bulgaria.
Abstract:
A series of 16 experiments, using a total of 2,000 BD6 rats, was designed in order to assess the ability of 8 individual agents or their combinations to modulate the liver and oesophageal carcinogenesis induced by multiple doses of diethylnitrosamine (DEN). Of the antioxidants tested, sodium selenite, ascorbic acid, and butylated hydroxytoluene generally exhibited protective effects on both types of tumors. In contrast, retinoic acid behaved as a promoter of DEN hepatocarcinogenesis, but this effect could be eliminated by its combination with either selenite or butylated hydroxytoluene. Caffeine and theophylline, when individually assayed, were devoid of significant protective effects, and the latter methylxanthine stimulated oesophageal tumorigenesis when administered after exposure to the carcinogen. Caffeine tended to decrease the multiplicity of liver tumors and potentiated the inhibitory effect of selenite in the liver. Irrespective of combination with caffeine, treatment with phenobarbital before each DEN injection tended to reduce the multiplicity of both liver and oesophageal tumors. On the other hand, the metabolic inhibitor diethyldithiocarbamate, given after each DEN injection, dramatically enhanced the incidence and multiplicity of oesophageal tumors. Thus, on the whole, modulation of DEN carcinogenesis varied depending on test agents, their combinations, dosages, treatment schedules, and target organ.
Insights
Certain antioxidants like sodium selenite and ascorbic acid protected against diethylnitrosamine-induced liver and esophageal tumors in rats. However, retinoic acid promoted tumors, while diethyldithiocarbamate enhanced esophageal cancer incidence.
Area of Science:
- Toxicology
- Carcinogenesis Research
- Chemoprevention Studies
Background:
- Diethylnitrosamine (DEN) is a known carcinogen that induces liver and esophageal tumors.
- Understanding agents that can modulate chemical carcinogenesis is crucial for developing preventative strategies.
Purpose of the Study:
- To evaluate the chemomodulatory effects of eight agents and their combinations on diethylnitrosamine (DEN)-induced liver and esophageal carcinogenesis in rats.
- To identify potential protective or promoting agents against DEN-induced cancer.
Main Methods:
- Conducted 16 experiments with 2,000 BD6 rats.
- Administered multiple doses of diethylnitrosamine (DEN) to induce carcinogenesis.
- Tested individual agents and combinations including antioxidants, retinoic acid, methylxanthines, phenobarbital, and a metabolic inhibitor.
Main Results:
- Antioxidants (sodium selenite, ascorbic acid, butylated hydroxytoluene) generally showed protective effects against both tumor types.
- Retinoic acid promoted DEN-induced hepatocarcinogenesis, but this was counteracted by selenite or butylated hydroxytoluene.
- Caffeine showed some protective effect on liver tumors and potentiated selenite's effect; theophylline stimulated esophageal tumors.
- Phenobarbital reduced tumor multiplicity in both organs, while diethyldithiocarbamate significantly enhanced esophageal tumor incidence and multiplicity.
Conclusions:
- Modulation of DEN-induced carcinogenesis is complex and depends on the specific agent, combination, dosage, timing, and target organ.
- Certain antioxidants and phenobarbital demonstrate chemopreventive potential, whereas retinoic acid and diethyldithiocarbamate can act as promoters or enhancers.