第三代维甲类化合物R8923的癌化学预防作用及其作用机理的研究
摘要
本文系统地研究了第三代维甲类化合物R8923的癌化学预防作用；探讨了R8923的抗致突变、抗促癌作用及其作用机理，并与全反式维甲酸(RA)进行了比较。
通过应用自己建立的Balb／3T3—A31细胞体外二阶段化学转化模型、二甲基苯蒽(DMBA)诱发Sprague-Dawley大白鼠乳腺癌模型以及DMBA／巴豆油诱发昆明种小白鼠皮肤乳头状瘤模型，证明：R8923(10~(-6)M浓度)可显著抑制3-甲基胆蒽(3-MCA，2μg／ml)和TPA(100ng／ml)联合转化Balb／3T3—A31细胞，抑制作用与RA接近。R8923口服(1mg／Kg)可有效抑制DMBA诱发大白鼠乳腺癌，R8923口服还能有效地抑制DMBA／巴豆油诱发小白鼠皮肤乳头状瘤，增加剂量，则抑制作用更强，其抑制作用以抗促癌为主。
R8923和RA均对环磷酰胺(CTX)引起的小白鼠骨髓嗜多染红细胞微核形成有抑制作用。在Ames实验中，R8923和RA均抑制基磺酸甲酯(MMS)诱发沙门氏菌TA100和TA102回复突变，而对TA102回复突变的抑制作用更强。综合分析表明，R8923和RA可能影响致癌剂与DNA结合和／或提高细胞DNA损伤修复能力，从而发挥抗致突变作用。
R8923和RA口服均能有效地抑制巴豆油引起的小白鼠耳肿胀，提示它们具有抗促癌作用。
R8923和RA在10~(-6)M浓度时，能显著抑制TPA促进~3[H]—TdR参入Balb／3T3细胞，显著抑制TPA促进Balb／3T3细胞由G_0／G_1期向S期移行，证明R8923和RA具有抑制TPA引起的细胞增殖作用，这是它们抗促癌的主要作用途径。
R8923和RA均抑制TPA对Balb／3T3细胞内PKC的激活和抑制PKC由胞浆向胞膜转移；抑制TPA促进Balb／3T3细胞的膜蛋白P_(90)磷酸化；抑制由PKC介导的TPA促进的Balb／3T3细胞c—fos、c—myc、H—ras等癌基因的mRNA表达，进一步增强抗癌基因P53的mRNA表达。可以认为R8923和RA抗促癌的主要作用机制在于通过调控细胞癌基因、抗癌基因表达水平，维持细胞增殖、分化的调控机制的平衡，起着抗细胞异常增殖作用。
R8923和RA口服均明显抑制巴豆油诱导的小白鼠表皮细胞鸟氨酸脱羧酶(ODC)活性，这是它们抗促癌作用机制的一个重要方面。
研究还证明，R8923和RA具有清除黄嘌呤／黄嘌呤氧化酶系统产生O_2~-的作用；具有抑制TPA刺激大白鼠多核白细胞(PMNs)产生O_2~-及H_2O_2的作用；能明显抑制NADPH／Vitamin C诱导大白鼠肝细胞微粒体脂质过氧化，表明，R8923和RA均有较强的抗氧化作用，这可能是R8923和RA的另一重要的抗促癌作用机制。应用MTT法研究R8923和RA的细胞毒性作用表明：对于HCT—8细胞株(人结肠癌细胞)，R8923和RA的细胞半数杀伤浓度分别为IC_(50(R8923))=3.128×10~(-5)M、IC_(50(RA))=3.118×10~(-5)M；对于KB细胞(人口腔上皮癌细胞)，两者细胞半数杀伤浓度分别为IC_(50(R8923))=4.303×10~(-4)M和IC_(50(RA))=8.331×10~(-4)M。R8923和RA均为低细胞毒性化合物，且两者细胞毒性非常接近。
R8923是新一代的有效的癌化学预防化合物，其癌预防活性可与RA相媲美，细胞毒性作用与RA非常接近。相信在进一步研究其代谢动力学及急性、亚急性毒性基础上，适当改造其分子结构的某些基团，将会显示出良好的应用前景。
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~(-6)M, 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~(-6)M, R8923 and RA markedly inhibited TPA induced〔H〕—TdR incorporation into Balb/3T3 cells and traverse of Balb/3T3 cells from G_0/G_1 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 P_(90) 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 (O_2~-) generated by xanthine/xanthine oxidase system. They effectively inhibited TPA stimulating rat polymorphonuclear leuko- cytes (PMNs) producing O_2~- and H_2O_2. 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.
通过应用自己建立的Balb／3T3—A31细胞体外二阶段化学转化模型、二甲基苯蒽(DMBA)诱发Sprague-Dawley大白鼠乳腺癌模型以及DMBA／巴豆油诱发昆明种小白鼠皮肤乳头状瘤模型，证明：R8923(10~(-6)M浓度)可显著抑制3-甲基胆蒽(3-MCA，2μg／ml)和TPA(100ng／ml)联合转化Balb／3T3—A31细胞，抑制作用与RA接近。R8923口服(1mg／Kg)可有效抑制DMBA诱发大白鼠乳腺癌，R8923口服还能有效地抑制DMBA／巴豆油诱发小白鼠皮肤乳头状瘤，增加剂量，则抑制作用更强，其抑制作用以抗促癌为主。
R8923和RA均对环磷酰胺(CTX)引起的小白鼠骨髓嗜多染红细胞微核形成有抑制作用。在Ames实验中，R8923和RA均抑制基磺酸甲酯(MMS)诱发沙门氏菌TA100和TA102回复突变，而对TA102回复突变的抑制作用更强。综合分析表明，R8923和RA可能影响致癌剂与DNA结合和／或提高细胞DNA损伤修复能力，从而发挥抗致突变作用。
R8923和RA口服均能有效地抑制巴豆油引起的小白鼠耳肿胀，提示它们具有抗促癌作用。
R8923和RA在10~(-6)M浓度时，能显著抑制TPA促进~3[H]—TdR参入Balb／3T3细胞，显著抑制TPA促进Balb／3T3细胞由G_0／G_1期向S期移行，证明R8923和RA具有抑制TPA引起的细胞增殖作用，这是它们抗促癌的主要作用途径。
R8923和RA均抑制TPA对Balb／3T3细胞内PKC的激活和抑制PKC由胞浆向胞膜转移；抑制TPA促进Balb／3T3细胞的膜蛋白P_(90)磷酸化；抑制由PKC介导的TPA促进的Balb／3T3细胞c—fos、c—myc、H—ras等癌基因的mRNA表达，进一步增强抗癌基因P53的mRNA表达。可以认为R8923和RA抗促癌的主要作用机制在于通过调控细胞癌基因、抗癌基因表达水平，维持细胞增殖、分化的调控机制的平衡，起着抗细胞异常增殖作用。
R8923和RA口服均明显抑制巴豆油诱导的小白鼠表皮细胞鸟氨酸脱羧酶(ODC)活性，这是它们抗促癌作用机制的一个重要方面。
研究还证明，R8923和RA具有清除黄嘌呤／黄嘌呤氧化酶系统产生O_2~-的作用；具有抑制TPA刺激大白鼠多核白细胞(PMNs)产生O_2~-及H_2O_2的作用；能明显抑制NADPH／Vitamin C诱导大白鼠肝细胞微粒体脂质过氧化，表明，R8923和RA均有较强的抗氧化作用，这可能是R8923和RA的另一重要的抗促癌作用机制。应用MTT法研究R8923和RA的细胞毒性作用表明：对于HCT—8细胞株(人结肠癌细胞)，R8923和RA的细胞半数杀伤浓度分别为IC_(50(R8923))=3.128×10~(-5)M、IC_(50(RA))=3.118×10~(-5)M；对于KB细胞(人口腔上皮癌细胞)，两者细胞半数杀伤浓度分别为IC_(50(R8923))=4.303×10~(-4)M和IC_(50(RA))=8.331×10~(-4)M。R8923和RA均为低细胞毒性化合物，且两者细胞毒性非常接近。
R8923是新一代的有效的癌化学预防化合物，其癌预防活性可与RA相媲美，细胞毒性作用与RA非常接近。相信在进一步研究其代谢动力学及急性、亚急性毒性基础上，适当改造其分子结构的某些基团，将会显示出良好的应用前景。
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~(-6)M, 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~(-6)M, R8923 and RA markedly inhibited TPA induced〔H〕—TdR incorporation into Balb/3T3 cells and traverse of Balb/3T3 cells from G_0/G_1 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 P_(90) 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 (O_2~-) generated by xanthine/xanthine oxidase system. They effectively inhibited TPA stimulating rat polymorphonuclear leuko- cytes (PMNs) producing O_2~- and H_2O_2. 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.
引文
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