Studies On The Cancer Chemopreventive Action And Mechanism Of Action Of A Third Generation Retinoid R8923

The cancer chemopreventive effect and the mechanism of action of R8923 was studied systematically and it was compared with that of retinoic acid (RA) in this thesis.By using three models which were established by ourselves, namely: two—stage chemical transformation model of Balb/3T3—A31 cells in vitro; 7. 12—dimethylbenz〔a〕anthracene (DMBA) induced mammary carcinogenesis in sprague—Dawley rat and DMBA/ croton oil induced mouse skin papilloma model, We have demonstrated that at a concentration of 10^-6M, R8923 significantly inhibited 3—methylcholanthrene (3—MCA, 2μg/ml) and 12—O—tetradecanoyl—phorbol 13—acetate (TPA, 100ng/ml) induced malignant transformation of Balb/3T3—A31 cells and the effect was similar to that of RA. By given orally, R8923 could effectively inhibit DMBA induced rat mammary carcinogenesis and DMBA/croton oil induced mouse skin papillomas. This effect is dose dependent. It was shown that R8923 is an effective cancer chemopreventive agent.Both R8923 and RA could inhibit cyclophosphamide (CTX) induced micronucleus formation of polychromatic erythrocytes (PCE) of bone marrow in mouse. In Ames test, R8923 and RA lowered the MMS induced TA100 and TA102 His⁺—revertants and the e-ffect was stronger in TA102 strain than in TA100 strain. The comprehensive analysis of these results suggested that the anti—initiation action of R8923 and RA may related to their protection against DNA damage and the capacity of enhancing repairment of DNA lesions in cells.R8923 and RA could effectively inhibit croton oil induced mouse ear edema which indicated that they have anti—promotion effect.At a concentration of 10^-6M, R8923 and RA markedly inhibited TPA induced〔H〕—TdR incorporation into Balb/3T3 cells and traverse of Balb/3T3 cells from G₀/G₁ to S phase, Flow cytometry indicated that the number of cells in Go/G, phase was increased significantly. These results proved that R8923 and RA can efficiently inhibit TPA induced cell proliferation.R8923 and RA obviously inhibited croton oil induced ornithine decarboxylase(ODC) activity in mouse skin cells and inhibited TPA activated PKC and the translocation of PKC from cytoplasm to cellular membrane. At the same time they inhibited the phosphorylation of membrane protein P₉₀ and inhibited the oncogene expressions of c—fos, c—myc and H—ras, but enhanced the expression of P53 antioncogene induced by TPA in Balb/3T3 cells. This results suggested that R8923 and RA can inhibit abnormal growth of cell by modulating the expression of oncogenes and antioncogenes and maintaining the balance of cell proliferat- ion and differentiation which seems to be the major mechanism of R8923 and RA anti—pro- motion.R8923 and RA can scavenge superoxide anion (O₂^-) generated by xanthine/xanthine oxidase system. They effectively inhibited TPA stimulating rat polymorphonuclear leuko- cytes (PMNs) producing O₂^- and H₂O₂. R8923 and RA exhibited pronounced inhibitory e- ffect on NADPH/Vitamin C induced lipid peroxidation (MDA formation) of rat liver micro- some. This showed R8923 and RA have profound anti—oxidation activity which could be another important action of their anti—promotion.In summary, R8923 is a third generation compound of retinoids which is very effective for cancer chemoprevention.