创新抗癌药物20（S）-人参皂苷Rg3的研究
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摘要
本论文对具有很强抗癌生物活性的20(S)-人参皂苷Rg3进行了深入开发研究,按照《新药审评办法》分别进行了部分药效学试验、长期毒性试验和Ⅰ期临床研究,取得了以下创新性成果:
(1)首次对国内外三萜类化合物抗癌研究进展进行了综述。
(2)首次进行了20(S)-人参皂苷Rg3体内、体外抗癌活性的研究
1)首次研究了20(S)-人参皂苷Rg3对人前列腺癌PC-3M细胞生长的抑制作用。结果表明20(S)-人参皂苷Rg3可明显抑制PC-3M细胞的生长[IC50=(248.5±0.58)mg.L-1];细胞生长周期中S期细胞数增加,G2/M期细胞数明显减少,在G1峰前出现明显的凋亡峰;20(S)-人参皂苷Rg3作用后PC-3M细胞呈现明显的凋亡改变,细胞caspase-8 mRNA含量增加、表达明显增强。说明20(S)- Rg3能诱导PC-3M细胞发生凋亡,机制可能与其活化caspase-8作用有关。
2)首次进行了20(S)-人参皂苷Rg3对非小细胞肺癌的抑制作用的研究
选取人非小细胞肺癌瘤株(NCI-H460人大细胞肺癌、A549人肺腺癌及LTEP-78人肺鳞癌)荷瘤裸鼠模型,分别给与环磷酰胺(40mg/kg)、20(S)-人参皂苷Rg3(3.0mg/kg、1.0mg/kg、0.3mg/kg)及联合用药[环磷酰胺20mg/kg + 20(S)-人参皂苷Rg3 0.5mg/kg]。结果表明20(S)-人参皂苷Rg3具有明显抑制人非小细胞肺癌肿瘤生长的作用,其作用与其抑制血管生成和促进细胞凋亡有关。
(3)首次应用Wistar大鼠对20(S)-人参皂苷Rg3进行二十六周肌肉注射给药的长期毒性试验,该受试药品对Wistar大鼠无延迟性毒性反应。
(4)首次对20(S)-人参皂苷Rg3进行Ⅰ期临床研究。
在中国健康受试者中进行的20(S)-人参皂苷Rg3注射液的单剂药代动力学研究,结果表明各剂量组AUC0-t、AUC0-inf和Cmax在不同性别受试者间不具有显著性差异;受试者在单次肌肉注射20(S)-Rg3注射液的情况下,安全性良好。
20(S)-ginsenoside Rg3 is a kind of effective anti-cancer triterpene compound. Further investigations on the pharmacodynamic action, long-term toxicity tests and phaseⅠclinical trial of 20(S)-ginsenoside Rg3 were reported in this thesis. The innovative results were as follows:
First, a review about triterpenes compound anti-cancer activities researches in all over the world were reported for the first time.
Second, the anti-cancer activities of 20(S)-ginsendoside Rg3 were studied in vitro and in vivo. The apoptosis effect of 20(S)-ginsendoside Rg3 on human prostate carcinoma PC-3M cell and the possible mechanism were studied for the first time. MTT assay method was adopted to observe the inhibition of PC-3M cell by 20(S)-ginsendoside Rg3 and the IC50 was calculated. The change of cell phase was determined by flow cytometry. The apoptosis of cell in morphology was observed by AO/EB fluorescence double dye technology. The apoptosis was investigated by immuno cellular chemistry and the changes of apoptotic gene caspase-8 were investigated by RT-PCR. The results showed that 20(S)-ginsendoside Rg3 inhibited the proliferation of PC-3M cell IC50 was 248·5±0·58 mg/L, significantly lower than that of the control group. Cell number increased in S phase and decreased in G2/M phase in treatment group. Meanwhile, there was an apoptotic apex before G1 apex. 20(S)-Rg3 promoted PC-3M cell apoptosis and the caspase-8 mRNA level was significantly increased. So it can supposed that 20(S)-ginsenoside Rg3 can induce PC-3M cell apoptosis, which may be closely related to the activation of caspase-8.
At the same time, growth-inhibitory effect of 20(S)-ginsenoside Rg3 on BALB/C-nu mice bearing human non-small cell lung cancer were studied. BALB/C-nu mice bearing human non-small cell lung cancer (NCI-H460, A549 and LTEP-78) were randomized into six groups: control group, cyclophosphamide (CTX) group intraperitoneal injection administered at dose of 40mg/kg once a day for 5 days, 20(S)-ginsenoside Rg3 groups intraperitoneal injection administered at doses of 3.0mg/kg, 1.0mg/kg and 0.3mg/kg to the animals once a day for 4 or 5 weeks and CTX combined with ginsenoside Rg3 group (20mg/kg+ 0.5mg/kg). Results showed 20(S)-ginsenoside Rg3 significantly inhibited tumor grew, tumor inhibition rate higher than 30% respectively (A549: 62.80%, 59.53%, 48.41%; NCI-H460: 74.61%, 62.32%, 51.27%; LTEP-78: 69.20%, 65.19%, 50.62%). In addition, the 20(S)-ginsenoside Rg3 groups tumor microvascular density (MVD) lower than the control group, while the apoptosis rate was significantly higher than control group. There were no significant different anti-tumor effects between 20(S)-ginsenoside Rg3 combined with CTX group and the CTX group. The synergies effect of 20(S)-ginsenoside Rg3 and CTX was not obvious. In conclusion, 20(S)-ginsenoside Rg3 significantly inhibited the growth of non-small cell lung cancer tumor. These effects might be partially attributed to it could inhibit angiogenesis and promote apoptosis.
Third, the Wistar rats long time toxicity test of 20(S)-ginsenoside Rg3 intramuscular administrated for 26 weeks were performed for the first time.
20(S)-Ginsenoside Rg3 at the doses of 4.2 mg/(kg?d) (11.6-fold of clinical human body surface area equivalent daily dose), 10mg/(kg?d) (27.6-fold of clinical human body surface area equivalent daily dose) and 20mg/(kg?d) (55.5-fold of clinical human body surface area equivalent daily dose). Two control groups were injection water control group and injection solvent control group respectively. The test doses were designed base on the mice MTD of intramuscular injection and intraperitoneal injection, mice pharmacodynamic dose, clinical human daily dose, clinic dosage regimen, human body surface area equivalent dosage conversion method.
Test results were as follows: in 4.2mg/(kg?d) dose group and two control groups, the injection site of the rats become indurascent. The phenomenon gradually release and recovered after drug withdrawal. There were no other abnormal changes about blood and biochemical indexes, organ coefficient and organ pathology. In 10mg/(kg?d) dose group, the injection site of the rats became indurascent. The phenomenon gradually release and recovered after drug withdrawal. The quantity of heterophil granulocyte increased and achroacyte decrease in male rats. There were no other abnormal changes about blood and biochemical indexes, organ coefficient and organ pathology. In 20mg/(kg?d) dose group, the injection site of the rats became indurascent obviously. The phenomenon gradually release after drug withdrawal but there were little induration after 8 weeks. The quantity of total white blood cells, heterophil granulocyte, neutrophilic myelocyte, eosinophilic granulocyte band form, eosinophilic granulocyte segmented form, the ratio of granular cell to rhodocyt were increased. And achroacyte, early erythroblast, ntermediate erythroblast and late erythroblast were decreased. There were no other abnormal changes about blood and biochemical indexes, organ coefficient and organ pathology.
Therefore, the changes induced by 20(S)-ginsenoside Rg3 intramuscular administrated 4.2 mg/(kg?d), 10.0 mg/(kg?d) and 20.0 mg/(kg?d) for 26 weeks were caused by the drug concentration higher than absorbability and induced inflammation, not caused by 20(S)-ginsenoside Rg3 toxic reaction. There were no target organ and sensitive blood index of 20(S)-ginsenoside Rg3 on Wistar rats. And also no tardive toxic reaction could be observed.
Fourth, PhaseⅠclinical trial on 20(S)-ginsenoside Rg3 were performed for the first time.
Pharmacokinetic parameters of intramuscular injection 20(S)-Ginsenoside Rg3 in single-dose 10 mg, 30mg and 60mg were calculated by WinNonlin(Pharsight 4.0.1) process standards for non-compartmental model, the data were as follows: Tmax for 2 h, 4 h and 4 h (median) respectively, Cmax were 135.4±35.3, 162.1±47.2 and 399.8±217.0 ng/Ml, AUC0 -t were 3297.4±1318.1, 7694.9±1908.9 and 23798.6±9007.8 h?ng/mL, AUC0-inf were 3474.1±1312.3, 8156.5±1782.7 and 25666.8±9401.1 h? ng/mL, t1/2 were 32.0±26.7, 51.7±15.4 and 53.9±25.7 h, Cl/F were 3176.3±939.4, 3812.1±713.1 and 2719.4±1267.7 mL/h, Vd/F were 152369.0±155966.4, 290811.4±121121.1 and 230322.2±196756.8 mL; Excretion72h% were 0.53±0.14%, 0.44±0.09% and 0.37±0.17% respectively.
The pharmacokinetic parameters were analyzed by SPSS (v11.0) statistical analysis software. Coefficients correlation between doses and pharmacokinetic parameters (AUC0-t, AUC0-inf, Cmax) were 0.851, 0.859 and 0.665, P<0.05, indicated that AUC0-t, AUC0-inf and Cmax of 20(S)-ginsenoside Rg3 were dose-dependent pharmacokinetic parameters. No signifcant difference were showed between t1/2 and Cl/F by one-factor analysis of variance on three groups (P>0.05). t1/2 were signifcant difference between male and female (P<0.05). No signifcant difference in Cl/F, AUC0-t, AUC0-inf and Cmax between male and female (P>0.05).
No serious adverse events happened during the trial, and no subject withdrawn before the trial finished. Only one adverse event (head trauma, midrange) on Day-1 was not concerned with the test drug.
(1)首次对国内外三萜类化合物抗癌研究进展进行了综述。
(2)首次进行了20(S)-人参皂苷Rg3体内、体外抗癌活性的研究
1)首次研究了20(S)-人参皂苷Rg3对人前列腺癌PC-3M细胞生长的抑制作用。结果表明20(S)-人参皂苷Rg3可明显抑制PC-3M细胞的生长[IC50=(248.5±0.58)mg.L-1];细胞生长周期中S期细胞数增加,G2/M期细胞数明显减少,在G1峰前出现明显的凋亡峰;20(S)-人参皂苷Rg3作用后PC-3M细胞呈现明显的凋亡改变,细胞caspase-8 mRNA含量增加、表达明显增强。说明20(S)- Rg3能诱导PC-3M细胞发生凋亡,机制可能与其活化caspase-8作用有关。
2)首次进行了20(S)-人参皂苷Rg3对非小细胞肺癌的抑制作用的研究
选取人非小细胞肺癌瘤株(NCI-H460人大细胞肺癌、A549人肺腺癌及LTEP-78人肺鳞癌)荷瘤裸鼠模型,分别给与环磷酰胺(40mg/kg)、20(S)-人参皂苷Rg3(3.0mg/kg、1.0mg/kg、0.3mg/kg)及联合用药[环磷酰胺20mg/kg + 20(S)-人参皂苷Rg3 0.5mg/kg]。结果表明20(S)-人参皂苷Rg3具有明显抑制人非小细胞肺癌肿瘤生长的作用,其作用与其抑制血管生成和促进细胞凋亡有关。
(3)首次应用Wistar大鼠对20(S)-人参皂苷Rg3进行二十六周肌肉注射给药的长期毒性试验,该受试药品对Wistar大鼠无延迟性毒性反应。
(4)首次对20(S)-人参皂苷Rg3进行Ⅰ期临床研究。
在中国健康受试者中进行的20(S)-人参皂苷Rg3注射液的单剂药代动力学研究,结果表明各剂量组AUC0-t、AUC0-inf和Cmax在不同性别受试者间不具有显著性差异;受试者在单次肌肉注射20(S)-Rg3注射液的情况下,安全性良好。
20(S)-ginsenoside Rg3 is a kind of effective anti-cancer triterpene compound. Further investigations on the pharmacodynamic action, long-term toxicity tests and phaseⅠclinical trial of 20(S)-ginsenoside Rg3 were reported in this thesis. The innovative results were as follows:
First, a review about triterpenes compound anti-cancer activities researches in all over the world were reported for the first time.
Second, the anti-cancer activities of 20(S)-ginsendoside Rg3 were studied in vitro and in vivo. The apoptosis effect of 20(S)-ginsendoside Rg3 on human prostate carcinoma PC-3M cell and the possible mechanism were studied for the first time. MTT assay method was adopted to observe the inhibition of PC-3M cell by 20(S)-ginsendoside Rg3 and the IC50 was calculated. The change of cell phase was determined by flow cytometry. The apoptosis of cell in morphology was observed by AO/EB fluorescence double dye technology. The apoptosis was investigated by immuno cellular chemistry and the changes of apoptotic gene caspase-8 were investigated by RT-PCR. The results showed that 20(S)-ginsendoside Rg3 inhibited the proliferation of PC-3M cell IC50 was 248·5±0·58 mg/L, significantly lower than that of the control group. Cell number increased in S phase and decreased in G2/M phase in treatment group. Meanwhile, there was an apoptotic apex before G1 apex. 20(S)-Rg3 promoted PC-3M cell apoptosis and the caspase-8 mRNA level was significantly increased. So it can supposed that 20(S)-ginsenoside Rg3 can induce PC-3M cell apoptosis, which may be closely related to the activation of caspase-8.
At the same time, growth-inhibitory effect of 20(S)-ginsenoside Rg3 on BALB/C-nu mice bearing human non-small cell lung cancer were studied. BALB/C-nu mice bearing human non-small cell lung cancer (NCI-H460, A549 and LTEP-78) were randomized into six groups: control group, cyclophosphamide (CTX) group intraperitoneal injection administered at dose of 40mg/kg once a day for 5 days, 20(S)-ginsenoside Rg3 groups intraperitoneal injection administered at doses of 3.0mg/kg, 1.0mg/kg and 0.3mg/kg to the animals once a day for 4 or 5 weeks and CTX combined with ginsenoside Rg3 group (20mg/kg+ 0.5mg/kg). Results showed 20(S)-ginsenoside Rg3 significantly inhibited tumor grew, tumor inhibition rate higher than 30% respectively (A549: 62.80%, 59.53%, 48.41%; NCI-H460: 74.61%, 62.32%, 51.27%; LTEP-78: 69.20%, 65.19%, 50.62%). In addition, the 20(S)-ginsenoside Rg3 groups tumor microvascular density (MVD) lower than the control group, while the apoptosis rate was significantly higher than control group. There were no significant different anti-tumor effects between 20(S)-ginsenoside Rg3 combined with CTX group and the CTX group. The synergies effect of 20(S)-ginsenoside Rg3 and CTX was not obvious. In conclusion, 20(S)-ginsenoside Rg3 significantly inhibited the growth of non-small cell lung cancer tumor. These effects might be partially attributed to it could inhibit angiogenesis and promote apoptosis.
Third, the Wistar rats long time toxicity test of 20(S)-ginsenoside Rg3 intramuscular administrated for 26 weeks were performed for the first time.
20(S)-Ginsenoside Rg3 at the doses of 4.2 mg/(kg?d) (11.6-fold of clinical human body surface area equivalent daily dose), 10mg/(kg?d) (27.6-fold of clinical human body surface area equivalent daily dose) and 20mg/(kg?d) (55.5-fold of clinical human body surface area equivalent daily dose). Two control groups were injection water control group and injection solvent control group respectively. The test doses were designed base on the mice MTD of intramuscular injection and intraperitoneal injection, mice pharmacodynamic dose, clinical human daily dose, clinic dosage regimen, human body surface area equivalent dosage conversion method.
Test results were as follows: in 4.2mg/(kg?d) dose group and two control groups, the injection site of the rats become indurascent. The phenomenon gradually release and recovered after drug withdrawal. There were no other abnormal changes about blood and biochemical indexes, organ coefficient and organ pathology. In 10mg/(kg?d) dose group, the injection site of the rats became indurascent. The phenomenon gradually release and recovered after drug withdrawal. The quantity of heterophil granulocyte increased and achroacyte decrease in male rats. There were no other abnormal changes about blood and biochemical indexes, organ coefficient and organ pathology. In 20mg/(kg?d) dose group, the injection site of the rats became indurascent obviously. The phenomenon gradually release after drug withdrawal but there were little induration after 8 weeks. The quantity of total white blood cells, heterophil granulocyte, neutrophilic myelocyte, eosinophilic granulocyte band form, eosinophilic granulocyte segmented form, the ratio of granular cell to rhodocyt were increased. And achroacyte, early erythroblast, ntermediate erythroblast and late erythroblast were decreased. There were no other abnormal changes about blood and biochemical indexes, organ coefficient and organ pathology.
Therefore, the changes induced by 20(S)-ginsenoside Rg3 intramuscular administrated 4.2 mg/(kg?d), 10.0 mg/(kg?d) and 20.0 mg/(kg?d) for 26 weeks were caused by the drug concentration higher than absorbability and induced inflammation, not caused by 20(S)-ginsenoside Rg3 toxic reaction. There were no target organ and sensitive blood index of 20(S)-ginsenoside Rg3 on Wistar rats. And also no tardive toxic reaction could be observed.
Fourth, PhaseⅠclinical trial on 20(S)-ginsenoside Rg3 were performed for the first time.
Pharmacokinetic parameters of intramuscular injection 20(S)-Ginsenoside Rg3 in single-dose 10 mg, 30mg and 60mg were calculated by WinNonlin(Pharsight 4.0.1) process standards for non-compartmental model, the data were as follows: Tmax for 2 h, 4 h and 4 h (median) respectively, Cmax were 135.4±35.3, 162.1±47.2 and 399.8±217.0 ng/Ml, AUC0 -t were 3297.4±1318.1, 7694.9±1908.9 and 23798.6±9007.8 h?ng/mL, AUC0-inf were 3474.1±1312.3, 8156.5±1782.7 and 25666.8±9401.1 h? ng/mL, t1/2 were 32.0±26.7, 51.7±15.4 and 53.9±25.7 h, Cl/F were 3176.3±939.4, 3812.1±713.1 and 2719.4±1267.7 mL/h, Vd/F were 152369.0±155966.4, 290811.4±121121.1 and 230322.2±196756.8 mL; Excretion72h% were 0.53±0.14%, 0.44±0.09% and 0.37±0.17% respectively.
The pharmacokinetic parameters were analyzed by SPSS (v11.0) statistical analysis software. Coefficients correlation between doses and pharmacokinetic parameters (AUC0-t, AUC0-inf, Cmax) were 0.851, 0.859 and 0.665, P<0.05, indicated that AUC0-t, AUC0-inf and Cmax of 20(S)-ginsenoside Rg3 were dose-dependent pharmacokinetic parameters. No signifcant difference were showed between t1/2 and Cl/F by one-factor analysis of variance on three groups (P>0.05). t1/2 were signifcant difference between male and female (P<0.05). No signifcant difference in Cl/F, AUC0-t, AUC0-inf and Cmax between male and female (P>0.05).
No serious adverse events happened during the trial, and no subject withdrawn before the trial finished. Only one adverse event (head trauma, midrange) on Day-1 was not concerned with the test drug.
引文
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