新型阿霉素前体药PDOX药效及安全性实验研究
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摘要
第一部分新型阿霉素前体药PDOX对胃癌腹膜转移癌模型的分子靶向治疗研究
背景与目的：胃癌是发展中国家最常见的恶性肿瘤之一。胃癌很容易发展为腹膜转移癌,有30%的胃癌患者,在确诊时已经发展为腹膜转移癌,60%的胃癌患者死于腹膜转移癌。胃癌治疗通常为综合治疗,包括手术治疗、放化疗,化疗具有重要作用。临床化疗以传统化疗药物为主,但传统化疗药物特异性低,副作用大,应用受限。如DOX (Doxorubicin,可霉素),以心肌毒性显著,为维持DOX的治疗效果而又降低毒副作用,我们设计了一种DOX前体药PDOX(Ac-Phe-Lys-PABC-DOX).前期研究结果表明PDOX能够在体外血浆中稳定存在,在Cat B (Cathepsin B,组织蛋白酶B)溶液中快速释放游离DOX.本研究结合我国胃癌治疗实际,选择利用胃癌腹膜转移癌模型,首次评估分子靶向抗癌新药PDOX的疗效和毒副作用,为PDOX进一步研究奠定基础。
方法：首先进行体外细胞水平实验,选用SGC-7901胃癌细胞进行培养,分别给予不同剂量的DOX和PDOX进行处理,通过每天收集细胞计数,绘制细胞生长曲线；采用流式细胞分析仪研究DOX和PDOX对细胞周期的影响。然后进行体内动物水平实验,先利用4只Balb/c裸小鼠腹腔给药,探索并确定PDOX安全给药剂量；再利用Balb/c裸小鼠建立SGC-7901胃癌腹膜转移癌模型,并随机分为三组,对照组(n=9),DOX组(n=10)和PDOX组(n=10),分别于给予生理盐水(10ml/kg)、DOX (2.0mg/kg)和PDOX (7.2mg/kg)处理,腹腔内注射,共8次。每天观察动物整体状态,每4天称量动物体重。定期采取尾静脉血80μ1,行血常规检测。第40天或动物处于濒死状态时,给予安乐死处理,采集血液静置凝固,获取血清行血生化检测,主要指标包括ALT、AST、BUN、Cr、CK、CK-MB、LDH;重要脏器行组织病理学检查。收集腹腔灌洗液,离心获取脱落细胞,行流式细胞凋亡分析。
结果：体外研究结果表明,PDOX对SGC-7901细胞抑制率弱于DOX,流式细胞分析表明DOX能够显著抑制细胞周期,并诱导出明显的凋亡峰；而PDOX处理组未见明显凋亡峰,DNA含量分布与对照组相近。体内研究表明,PDOX最大安全剂量超过57.8mg/kg o对照组、DOX组和PDOX组实验性腹膜癌指数(ePCI)分别为6,1.5,1(P=0.004)；体重分别为24.32士1.40g,18.40±2.97g和23.61±0.80g(P=0.000)。血常规、血生化和组织病理学研究显示PDOX显著降低骨髓、肝脏、肾脏,尤其是心脏毒性,在对照组、DOX组和PDOX组,分别发现3、7和4例心肌损伤病例。
结论：PDOX在体外细胞毒性低,对细胞生长及周期影响小于DOX,提示PDOX在低活性Cat B条件下,毒副作用明显降低。PDOX安全治疗剂量下,能够显著抑制胃癌腹膜转移癌的形成,降低整体毒副作用,并降低心脏、肝脏、肾脏等毒性。PDOX有望开发成一种治疗胃癌腹膜转移癌及其它高表达Cat B肿瘤的靶向药物,能够增强疗效同时减轻毒副作用。
第二部分新型阿霉素前体药PDOX急性毒性实验研究
背景与目的：化疗是肿瘤综合治疗的重要组成部分,目前临床应用以传统化疗药物为主。传统化疗药物缺乏靶向性,常导致严重的毒副作用,临床应用受到限制,如DOX (Doxorubicin,阿霉素)。为提高DOX靶向性,降低副反应,提高治疗效果,在DOX分子上添加Cat B (Cathepsin B,组织蛋白酶)特异酶解修饰肽段,形成分子靶向抗癌前体药PDOX (Ac-Phe-Lys-PABC-DOX).在前期研究中,利用裸鼠胃癌腹膜转移癌模型、裸鼠胃癌原位移植瘤模型、裸鼠肝癌原位移植瘤模型以及家兔胃癌腹膜转移癌模型对PDOX药效和初步毒副作用进行研究。研究结果表明PDOX经修饰后能够维持DOX高效抗癌特点,毒副作用降低。为进一步系统了解PDOX毒理学特点,本研究拟通过研究PDOX腹腔和静脉给药两种途径的急性毒性反应,为其进一步抗癌谱研究和临床前研究提供可靠的剂量方案和给药途径,探讨PDOX可能存在的严重毒副反应和解决方案。
方法：参考预实验结果和文献报道,设计PDOX急性毒性实验剂量。首先利用昆明种小鼠进行腹腔给药急性毒性实验,分为空白组、90.0mg/kg组、112.0mg/kg组、120.6mg/kg组、130.0mg/kg组、140.0mg/kg组,每组10只昆明小鼠(雌雄各半),观察给药后动物反应,称量动物体重,血常规检测及动物脏器指数研究,对PDOX腹腔给药进行研究；再利用昆明种小鼠进行静脉给药急性毒性实验,设DOX为阳性对照组,分为空白组、DOX不同剂量组(15.0mg/kg、18.0mg/kg、21.6mg/kg、25.9mg/kg、31.1mg/kg)和PDOX不同剂量组(47.1mg/kg、51.4mg/kg、56.0mg/kg、61.1mg/kg、66.7mg/kg),观察给药后动物反应、体重变化,行血生化检测、动物脏器指数研究,以及组织病理学检查。采用Bliss法计算LD50(Half lethal dose,半数致死剂量)。
结果：PDOX急性毒性反应主要发生在急性期,对恢复期影响较小,DOX对动物有持续性毒性反应,长达1周；PDOX对动物整体状态和体重影响较DOX显著减少。组织病理学研究显示PDOX对心、肝等毒性明显降低。PDOX腹腔给药LD50=129.61mg/kg,为DOX腹腔给药LD5o的5.45倍,为72.01mg/kg DOX当量；DOX静脉给药LD50=22.30mg/kg, PDOX静脉给药LD50=55.17mg/kg, PDOX静脉给药LD5o为DOX的1.37倍,为30.65mg/kg DOX当量。PDOX经修饰后腹腔给药LD5o有明显提高,静脉给药提高不够明显。
结论：PDOX经修饰后,LD50得到提高。相比DOX,对动物重要脏器毒性反应有所降低,存在一定的剂量依赖关系,其主要毒副反应以急性期肺部病变为主。最佳给药方案有待进一步长期实验研究。
Part Ⅰ:The study of a novel prodrug of Doxorubicin (PDOX) in the treatment of a gastric cancer peritoneal carcinomatosis mice model
Background and Objective Gastric cancer is one of the most common malignant cancer in developing countries, and it's likely to develop peritoneal carcinomatosis. Up to30%of gastric cancer patients have been developed peritoneal carcinomatosis at the time of diagnosis. Nearly60%of gastric cancer patients died from peritoneal carcinomatosis. Doxorubicin (DOX) is effective in gastric cancer treatment, however it has severe dose-dependent toxicities. A novel prodrug of DOX (Ac-Phe-Lys-PABC-DOX, PDOX) is designed by the authors to delivery free DOX relying on Cathepsin B (Cat B) and reduce side effects. In the current study, the authors examined the antitumor effect and toxicities of PDOX against gastric cancer peritoneal carcinomatosis.
Methods SGC-7901gastric cancer cell line was used for the study. The in vitro study investigated the effects of DOX and PDOX on cell growth dynamics and cell colony-forming ability and cell cycle. The in vivo study investigated the efficacy and toxicity of PDOX on nude mice model of peritoneal carcinomatosis, with DOX as positive control. The status and weight of mice were recorded, and blood routine was monitored. At the end point or when the mouse was on the brink of death, mice were sacrificed, then serum was obtained for biochemical analysis, including ALT, AST, BUN, Cr, Ck, CK-MB and LDH. The lavage fluid of peritoneal cavity was also collected for apoptosis analysis.
Results In the in vitro study, PDOX had a lower dose dependent inhibitory effect on SGC-7901cells than DOX. DOX inhibited the cell cycle and induced obviously a peak of apoptosis, while PDOX showed no apoptotic peak. In the in vivo study on control, DOX and PDOX groups, the median experimental peritoneal carcinomatosis indexes were6,1.5, and1, respectively (P=0.004); the body weights were24.32±1.40g,18.40±2.97g, and23.61±0.80g, respectively (P=0.000). Biochemical studies showed that PDOX had significantly lower toxicities on the bone marrow, liver, kidney and particularly the heart. Histopathological studies on control, DOX and PDOX groups found significant myocardium toxicities in3,7,4animals, respectively.
Conclusions PDOX could be an effective molecular targeting drug to treat gastric cancer peritoneal carcinomatosis at present dosage without serious cardiac toxicities. PDOX is also a potential drug for other tumors that produces Cat B, with enhanced efficacy and reduced toxicity.
Part II:Acute toxicity study of a novel prodrug of Doxorubicin (PDOX) in mice, administrated intraperitoneally and intravenously
Background and Objective Chemotherapy is an important part of comprehensive cancer treatment. Now clinical applications are mainly traditional chemotherapy drugs, such as Doxorubicin (DOX). Being lack of targeting ability, they always cause serious side effects. In order to reduce the cardiac toxicity of DOX, we design a prodrug of DOX, named PDOX (Ac-Phe-Lys-PABC-DOX). PDOX is stable in normal tissue, and will be specifically cleaved in tumor local-region by Cathepsin B (Cat B). Previous studies shown PDOX was effective in gastric cancer peritoneal carcinomatosis mice model, gastric cancer orthotopic xenograft mice model, hepatocellular cancer orthotopic xenograft mice model and gastric cancer peritoneal carcinomatosis rabbit model, with lower side effects than DOX. The purpose of this study was to investigate the acute toxicity of PDOX, and find out the most optimal dosing regimen and the maximally tolerated dose.
Methods According to previous study and results reported in the literatures, PDOX acute toxicity study doses were designed. First, Kunming mice were divided into control group (vehicle), five PDOX groups (90.0mg/kg,112.0mg/kg,120.6mg/kg,130.0mg/kg and140.0mg/kg group),10mice per group (half male and half female), and used to evaluate the LD50of PDOX administrated intraperitoneally. The reaction to PDOX of mice and weight were recorded. When sacrificed, blood routine was tested, and then autopsy was done to research animal viscera index. To evaluate the LD5o of PDOX administrated intravenously, DOX was used as positive control group. Kunming mice were divided into control group, DOX group in different doses (15.0mg/kg,18.0mg/kg,21.6mg/kg,25.9mg/kg,31.1mg/kg) and PDOX group in different doses (47.1mg/kg,51.4mg/kg,56.0mg/kg,61.1mg/kg,66.7mg/kg),10mice per group (half male and half female). The reaction of animal and changes in body weight were observed, blood serum was collected for biochemical analysis. Animal viscera index and histopathology were also studied.
Results The acute toxicity of PDOX mainly occurred in the acute phase, and it had little impact to recovery phase, while DOX had a continuous effect to mice last up to a week. PDOX reduced side effects on the status and weight significantly than DOX. The biochemical and histopathological study shown the same results, PDOX reduced cardiac and hepatic toxicities. The LD50of PDOX when given intraperitoneally and intravenously were129.61mg/kg and55.17mg/kg, respectively, and were5.45and1.37times higher than that of DOX, respectively.
Conclusions Compared to DOX, the LD50of modified PDOX is increased, on contrast, side effects on important organs are decreased. PDOX has a certain dose-dependent toxicity, the main toxicities were acute lung disease. The optimal dosing regimen should be designed in the further long-term toxicity study.
背景与目的：胃癌是发展中国家最常见的恶性肿瘤之一。胃癌很容易发展为腹膜转移癌,有30%的胃癌患者,在确诊时已经发展为腹膜转移癌,60%的胃癌患者死于腹膜转移癌。胃癌治疗通常为综合治疗,包括手术治疗、放化疗,化疗具有重要作用。临床化疗以传统化疗药物为主,但传统化疗药物特异性低,副作用大,应用受限。如DOX (Doxorubicin,可霉素),以心肌毒性显著,为维持DOX的治疗效果而又降低毒副作用,我们设计了一种DOX前体药PDOX(Ac-Phe-Lys-PABC-DOX).前期研究结果表明PDOX能够在体外血浆中稳定存在,在Cat B (Cathepsin B,组织蛋白酶B)溶液中快速释放游离DOX.本研究结合我国胃癌治疗实际,选择利用胃癌腹膜转移癌模型,首次评估分子靶向抗癌新药PDOX的疗效和毒副作用,为PDOX进一步研究奠定基础。
方法：首先进行体外细胞水平实验,选用SGC-7901胃癌细胞进行培养,分别给予不同剂量的DOX和PDOX进行处理,通过每天收集细胞计数,绘制细胞生长曲线；采用流式细胞分析仪研究DOX和PDOX对细胞周期的影响。然后进行体内动物水平实验,先利用4只Balb/c裸小鼠腹腔给药,探索并确定PDOX安全给药剂量；再利用Balb/c裸小鼠建立SGC-7901胃癌腹膜转移癌模型,并随机分为三组,对照组(n=9),DOX组(n=10)和PDOX组(n=10),分别于给予生理盐水(10ml/kg)、DOX (2.0mg/kg)和PDOX (7.2mg/kg)处理,腹腔内注射,共8次。每天观察动物整体状态,每4天称量动物体重。定期采取尾静脉血80μ1,行血常规检测。第40天或动物处于濒死状态时,给予安乐死处理,采集血液静置凝固,获取血清行血生化检测,主要指标包括ALT、AST、BUN、Cr、CK、CK-MB、LDH;重要脏器行组织病理学检查。收集腹腔灌洗液,离心获取脱落细胞,行流式细胞凋亡分析。
结果：体外研究结果表明,PDOX对SGC-7901细胞抑制率弱于DOX,流式细胞分析表明DOX能够显著抑制细胞周期,并诱导出明显的凋亡峰；而PDOX处理组未见明显凋亡峰,DNA含量分布与对照组相近。体内研究表明,PDOX最大安全剂量超过57.8mg/kg o对照组、DOX组和PDOX组实验性腹膜癌指数(ePCI)分别为6,1.5,1(P=0.004)；体重分别为24.32士1.40g,18.40±2.97g和23.61±0.80g(P=0.000)。血常规、血生化和组织病理学研究显示PDOX显著降低骨髓、肝脏、肾脏,尤其是心脏毒性,在对照组、DOX组和PDOX组,分别发现3、7和4例心肌损伤病例。
结论：PDOX在体外细胞毒性低,对细胞生长及周期影响小于DOX,提示PDOX在低活性Cat B条件下,毒副作用明显降低。PDOX安全治疗剂量下,能够显著抑制胃癌腹膜转移癌的形成,降低整体毒副作用,并降低心脏、肝脏、肾脏等毒性。PDOX有望开发成一种治疗胃癌腹膜转移癌及其它高表达Cat B肿瘤的靶向药物,能够增强疗效同时减轻毒副作用。
第二部分新型阿霉素前体药PDOX急性毒性实验研究
背景与目的：化疗是肿瘤综合治疗的重要组成部分,目前临床应用以传统化疗药物为主。传统化疗药物缺乏靶向性,常导致严重的毒副作用,临床应用受到限制,如DOX (Doxorubicin,阿霉素)。为提高DOX靶向性,降低副反应,提高治疗效果,在DOX分子上添加Cat B (Cathepsin B,组织蛋白酶)特异酶解修饰肽段,形成分子靶向抗癌前体药PDOX (Ac-Phe-Lys-PABC-DOX).在前期研究中,利用裸鼠胃癌腹膜转移癌模型、裸鼠胃癌原位移植瘤模型、裸鼠肝癌原位移植瘤模型以及家兔胃癌腹膜转移癌模型对PDOX药效和初步毒副作用进行研究。研究结果表明PDOX经修饰后能够维持DOX高效抗癌特点,毒副作用降低。为进一步系统了解PDOX毒理学特点,本研究拟通过研究PDOX腹腔和静脉给药两种途径的急性毒性反应,为其进一步抗癌谱研究和临床前研究提供可靠的剂量方案和给药途径,探讨PDOX可能存在的严重毒副反应和解决方案。
方法：参考预实验结果和文献报道,设计PDOX急性毒性实验剂量。首先利用昆明种小鼠进行腹腔给药急性毒性实验,分为空白组、90.0mg/kg组、112.0mg/kg组、120.6mg/kg组、130.0mg/kg组、140.0mg/kg组,每组10只昆明小鼠(雌雄各半),观察给药后动物反应,称量动物体重,血常规检测及动物脏器指数研究,对PDOX腹腔给药进行研究；再利用昆明种小鼠进行静脉给药急性毒性实验,设DOX为阳性对照组,分为空白组、DOX不同剂量组(15.0mg/kg、18.0mg/kg、21.6mg/kg、25.9mg/kg、31.1mg/kg)和PDOX不同剂量组(47.1mg/kg、51.4mg/kg、56.0mg/kg、61.1mg/kg、66.7mg/kg),观察给药后动物反应、体重变化,行血生化检测、动物脏器指数研究,以及组织病理学检查。采用Bliss法计算LD50(Half lethal dose,半数致死剂量)。
结果：PDOX急性毒性反应主要发生在急性期,对恢复期影响较小,DOX对动物有持续性毒性反应,长达1周；PDOX对动物整体状态和体重影响较DOX显著减少。组织病理学研究显示PDOX对心、肝等毒性明显降低。PDOX腹腔给药LD50=129.61mg/kg,为DOX腹腔给药LD5o的5.45倍,为72.01mg/kg DOX当量；DOX静脉给药LD50=22.30mg/kg, PDOX静脉给药LD50=55.17mg/kg, PDOX静脉给药LD5o为DOX的1.37倍,为30.65mg/kg DOX当量。PDOX经修饰后腹腔给药LD5o有明显提高,静脉给药提高不够明显。
结论：PDOX经修饰后,LD50得到提高。相比DOX,对动物重要脏器毒性反应有所降低,存在一定的剂量依赖关系,其主要毒副反应以急性期肺部病变为主。最佳给药方案有待进一步长期实验研究。
Part Ⅰ:The study of a novel prodrug of Doxorubicin (PDOX) in the treatment of a gastric cancer peritoneal carcinomatosis mice model
Background and Objective Gastric cancer is one of the most common malignant cancer in developing countries, and it's likely to develop peritoneal carcinomatosis. Up to30%of gastric cancer patients have been developed peritoneal carcinomatosis at the time of diagnosis. Nearly60%of gastric cancer patients died from peritoneal carcinomatosis. Doxorubicin (DOX) is effective in gastric cancer treatment, however it has severe dose-dependent toxicities. A novel prodrug of DOX (Ac-Phe-Lys-PABC-DOX, PDOX) is designed by the authors to delivery free DOX relying on Cathepsin B (Cat B) and reduce side effects. In the current study, the authors examined the antitumor effect and toxicities of PDOX against gastric cancer peritoneal carcinomatosis.
Methods SGC-7901gastric cancer cell line was used for the study. The in vitro study investigated the effects of DOX and PDOX on cell growth dynamics and cell colony-forming ability and cell cycle. The in vivo study investigated the efficacy and toxicity of PDOX on nude mice model of peritoneal carcinomatosis, with DOX as positive control. The status and weight of mice were recorded, and blood routine was monitored. At the end point or when the mouse was on the brink of death, mice were sacrificed, then serum was obtained for biochemical analysis, including ALT, AST, BUN, Cr, Ck, CK-MB and LDH. The lavage fluid of peritoneal cavity was also collected for apoptosis analysis.
Results In the in vitro study, PDOX had a lower dose dependent inhibitory effect on SGC-7901cells than DOX. DOX inhibited the cell cycle and induced obviously a peak of apoptosis, while PDOX showed no apoptotic peak. In the in vivo study on control, DOX and PDOX groups, the median experimental peritoneal carcinomatosis indexes were6,1.5, and1, respectively (P=0.004); the body weights were24.32±1.40g,18.40±2.97g, and23.61±0.80g, respectively (P=0.000). Biochemical studies showed that PDOX had significantly lower toxicities on the bone marrow, liver, kidney and particularly the heart. Histopathological studies on control, DOX and PDOX groups found significant myocardium toxicities in3,7,4animals, respectively.
Conclusions PDOX could be an effective molecular targeting drug to treat gastric cancer peritoneal carcinomatosis at present dosage without serious cardiac toxicities. PDOX is also a potential drug for other tumors that produces Cat B, with enhanced efficacy and reduced toxicity.
Part II:Acute toxicity study of a novel prodrug of Doxorubicin (PDOX) in mice, administrated intraperitoneally and intravenously
Background and Objective Chemotherapy is an important part of comprehensive cancer treatment. Now clinical applications are mainly traditional chemotherapy drugs, such as Doxorubicin (DOX). Being lack of targeting ability, they always cause serious side effects. In order to reduce the cardiac toxicity of DOX, we design a prodrug of DOX, named PDOX (Ac-Phe-Lys-PABC-DOX). PDOX is stable in normal tissue, and will be specifically cleaved in tumor local-region by Cathepsin B (Cat B). Previous studies shown PDOX was effective in gastric cancer peritoneal carcinomatosis mice model, gastric cancer orthotopic xenograft mice model, hepatocellular cancer orthotopic xenograft mice model and gastric cancer peritoneal carcinomatosis rabbit model, with lower side effects than DOX. The purpose of this study was to investigate the acute toxicity of PDOX, and find out the most optimal dosing regimen and the maximally tolerated dose.
Methods According to previous study and results reported in the literatures, PDOX acute toxicity study doses were designed. First, Kunming mice were divided into control group (vehicle), five PDOX groups (90.0mg/kg,112.0mg/kg,120.6mg/kg,130.0mg/kg and140.0mg/kg group),10mice per group (half male and half female), and used to evaluate the LD50of PDOX administrated intraperitoneally. The reaction to PDOX of mice and weight were recorded. When sacrificed, blood routine was tested, and then autopsy was done to research animal viscera index. To evaluate the LD5o of PDOX administrated intravenously, DOX was used as positive control group. Kunming mice were divided into control group, DOX group in different doses (15.0mg/kg,18.0mg/kg,21.6mg/kg,25.9mg/kg,31.1mg/kg) and PDOX group in different doses (47.1mg/kg,51.4mg/kg,56.0mg/kg,61.1mg/kg,66.7mg/kg),10mice per group (half male and half female). The reaction of animal and changes in body weight were observed, blood serum was collected for biochemical analysis. Animal viscera index and histopathology were also studied.
Results The acute toxicity of PDOX mainly occurred in the acute phase, and it had little impact to recovery phase, while DOX had a continuous effect to mice last up to a week. PDOX reduced side effects on the status and weight significantly than DOX. The biochemical and histopathological study shown the same results, PDOX reduced cardiac and hepatic toxicities. The LD50of PDOX when given intraperitoneally and intravenously were129.61mg/kg and55.17mg/kg, respectively, and were5.45and1.37times higher than that of DOX, respectively.
Conclusions Compared to DOX, the LD50of modified PDOX is increased, on contrast, side effects on important organs are decreased. PDOX has a certain dose-dependent toxicity, the main toxicities were acute lung disease. The optimal dosing regimen should be designed in the further long-term toxicity study.
引文
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