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Retinoids prevent epithelial carcinogenesis induced by N-nitroso compounds
1Cancer Institute, Sun Yat-Sen University of Medical Sciences, Guangzhou, China.
Abstract:
Two new retinoic acid esters and retinamides synthesized in China, N-(4-ethoxycarbophenyl)retinamide (RI) and N-(4-carboxyphenyl)retinamide (RII), significantly inhibited carcinogenesis induced in the epithelium of the forestomach of mice by N-nitrososarcosine ethyl ester. RI also markedly inhibited carcinogenesis induced in the epithelium of the oesophagus and forestomach in rats by this ester. No sign of hypervitaminosis was noticed with doses as high as six times the therapeutic dose. RI also inhibited precancerous and cancerous lesions in the nasal cavity and nasopharynx and oesophagus of rats induced by dinitrosopiperazine. In a malignant oesophageal epithelial cell line from rats, RE25-3, established in our laboratory, RI and RII inhibited mitosis, proliferation rate, chromosomal aberrations and incorporation of 3H-thymidine into DNA. The ability to form colonies on agar plates was also inhibited by these two compounds.
Insights
Two novel retinamides, RI and RII, effectively inhibited chemical-induced carcinogenesis in mouse and rat models. These compounds also demonstrated anti-cancer effects in vitro without signs of toxicity, suggesting therapeutic potential.
Area of Science:
- Oncology
- Medicinal Chemistry
- Carcinogenesis Research
Background:
- Chemical carcinogens like N-nitrososarcosine ethyl ester and dinitrosopiperazine induce precancerous and cancerous lesions in various organs.
- Retinoids are known for their role in cell differentiation and cancer prevention, necessitating the development of novel analogs.
Purpose of the Study:
- To synthesize and evaluate the anti-cancer properties of two new retinamides, N-(4-ethoxycarbophenyl)retinamide (RI) and N-(4-carboxyphenyl)retinamide (RII).
- To assess the efficacy of RI and RII in inhibiting chemically induced carcinogenesis in animal models and their effects on cancer cell lines.
Main Methods:
- Synthesis of novel retinamides RI and RII.
- Administration of RI and RII to mice and rats exposed to chemical carcinogens (N-nitrososarcosine ethyl ester, dinitrosopiperazine).
- In vitro studies using a rat malignant oesophageal epithelial cell line (RE25-3) to assess effects on cell division, DNA synthesis, and colony formation.
Main Results:
- RI and RII significantly inhibited forestomach carcinogenesis in mice induced by N-nitrososarcosine ethyl ester.
- RI markedly inhibited oesophageal and forestomach carcinogenesis in rats induced by the same ester.
- RI also inhibited precancerous and cancerous lesions in the nasal cavity, nasopharynx, and oesophagus of rats induced by dinitrosopiperazine.
- Both RI and RII inhibited mitosis, proliferation, chromosomal aberrations, and DNA synthesis in the RE25-3 cell line.
- Colony formation ability was also inhibited by RI and RII in vitro.
- No signs of hypervitaminosis were observed even at doses six times the therapeutic level.
Conclusions:
- N-(4-ethoxycarbophenyl)retinamide (RI) and N-(4-carboxyphenyl)retinamide (RII) are potent inhibitors of chemical carcinogenesis in vivo.
- These novel retinamides exhibit anti-proliferative and anti-clastogenic effects on cancer cells in vitro.
- RI and RII show promise as chemopreventive or therapeutic agents against various cancers with a favorable safety profile.