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Research and development of cancer chemopreventive agents in China
1Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
Abstract:
Since the late 1970s, a comprehensive search for cancer chemopreventive agents has been established in our Institute. A series of new retinoids have been synthesized and screened on the basis of established methodologies of experimental chemoprevention in vitro as well as in vivo. Pharmacological studies demonstrated that N-4-(carboxyphenyl)retinamide (RII) induces cell differentiation of HL-60 cells and inhibits dimethylnitrosamine-induced carcinogenesis of the forestomach in mice, 7,12-dimethylbenz[a]anthracene (DMBA)-induced papilloma in mouse skin, and DMBA-induced carcinogenesis of the buccal pouch in Syrian golden hamsters. It significantly promoted lymphoblastic transformation and activated macrophages. In further studies, RII significantly inhibited ornithine decarboxylase activity. After 6 months of chronic toxicological studies in rats and dogs, RII was recommended for clinical trial. Phase II studies found that RII is effective in treating oral and vulvar leukoplakia. It is also effective in treating myelodysplastic syndrome and dysplasia of uterine cervix. The chalcone retinoidal compounds were discovered when the search for new retinoids with less toxicity and higher potency led to third-generation retinoids, which were synthesized and screened. Structure-activity relationship studies found that 3,5-di-tert-butyl-4-methoxy-4-carboxyl chalcone (R9158) is the most active inhibitor of a variety of cancer cells. It has no effect on the Colony Forming Unit-Granulocyte/Macrophage (CFU-GM) of bone marrow in mice. In in vivo studies, R9158 showed a remarkable inhibition of chondrosarcoma in rats. It had no cross-resistance to vincristine, but was cross-resistant to all-trans retinoic acid. Red ginseng, a processed Panax ginseng, is considered a typical tonic in traditional Chinese medicine. Our studies demonstrated that red ginseng extract inhibited DMBA-induced skin papilloma significantly. Experiments showed that glycyrrhetinic acid inhibited croton oil-induced ear edema in mice. It also inhibited epidermal ornithine decarboxylase as well as the rapid DNA damage induced by the carcinogen benzo[a]pyrene (B[a]P). Our pharmacological studies demonstrated that Chinese gallotannin inhibited the malignant transformation of B[a]P-induced V79 cells in vitro and B[a]P-induced pulmonary adenoma in A/J mice in vivo significantly.
Insights
This study explored novel cancer chemopreventive agents, including retinoids like RII and R9158, alongside natural compounds such as red ginseng, glycyrrhetinic acid, and Chinese gallotannin. Several agents demonstrated significant efficacy in preclinical models and some in clinical trials for various cancers and pre-cancerous conditions.
Area of Science:
- Chemoprevention Research
- Drug Discovery and Development
- Oncology
Background:
- A comprehensive search for cancer chemopreventive agents has been ongoing since the late 1970s.
- This research focuses on synthesizing and screening novel retinoids and other compounds for cancer prevention.
- Established methodologies for in vitro and in vivo experimental chemoprevention guide the screening process.
Purpose of the Study:
- To identify and evaluate novel chemopreventive agents with reduced toxicity and enhanced potency.
- To investigate the efficacy of synthesized retinoids and natural compounds against various cancers and pre-cancerous lesions.
- To establish structure-activity relationships for new retinoid compounds.
Main Methods:
- Synthesis and screening of novel retinoids, including N-4-(carboxyphenyl)retinamide (RII) and chalcone retinoidal compounds like R9158.
- In vitro assays using HL-60 cells and V79 cells, and in vivo studies in mice and hamsters involving carcinogen-induced models (DMBA, N-nitrosamine, benzo[a]pyrene).
- Pharmacological evaluations including cell differentiation, inhibition of carcinogenesis, ornithine decarboxylase activity, and toxicological studies.
Main Results:
- N-4-(carboxyphenyl)retinamide (RII) showed efficacy in inhibiting various cancers and was effective in Phase II trials for oral/vulvar leukoplakia, myelodysplastic syndrome, and cervical dysplasia.
- 3,5-di-tert-butyl-4-methoxy-4-carboxyl chalcone (R9158) demonstrated potent inhibition of cancer cells and chondrosarcoma in rats, with no cross-resistance to vincristine.
- Red ginseng extract, glycyrrhetinic acid, and Chinese gallotannin exhibited significant chemopreventive effects in preclinical models against skin papilloma, edema, and pulmonary adenoma, respectively.
Conclusions:
- Novel retinoids and natural compounds show significant promise as cancer chemopreventive agents.
- RII and R9158 represent potential therapeutic candidates for various neoplastic conditions.
- Further investigation into these agents could lead to new strategies for cancer prevention and treatment.