基于力达霉素的靶向药物与肿瘤治疗
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摘要
作为一种抗肿瘤抗生素,力达霉素(lidamycin, LDM)对人类癌细胞显示出很强的细胞毒性。LDM由一个载体蛋白(LDP)和一个具有肿瘤杀伤活性的烯二炔发色团(AE)以非共价键方式组合而成,这一特征使得LDM成为构建肿瘤靶向药物的良好材料。通过基因重组技术将具有肿瘤靶向能力的蛋白质和(或)多肽与LDP偶联,由此获得具有肿瘤靶向能力的融合蛋白,在此基础上,再将AE整合到融合蛋白的LDP中,最终得到既具有肿瘤靶向能力,又具有LDM杀伤活性的肿瘤靶向药物。随着研究的逐步深入,可望有一批基于LDM的靶向药物能用于肿瘤的临床治疗。
As an anti-tumor antibiotic, lidamycin(LDM) has strong cytotoxicity to human cancer cells. LDM is composed of a carrier protein(LDP) and an active enediyne chromophore(AE) which has tumor-killing activity.LDP combines AE in a non-covalent manner, which makes LDM a good material for constructing tumor-targeting drugs. The tumor targeting fusion proteins could be obtained by coupling the proteins and/or peptide that have tumor targeting ability with LDP through gene recombination technology. And then, AE was integrated into the LDP of the fusion protein, which would finally produce the tumor targeting drugs with both tumor targeting ability and killing activity. With the deepening of research, it is expected that a number of LDM-based targeting drugs can be used in the clinical treatment of cancers.
As an anti-tumor antibiotic, lidamycin(LDM) has strong cytotoxicity to human cancer cells. LDM is composed of a carrier protein(LDP) and an active enediyne chromophore(AE) which has tumor-killing activity.LDP combines AE in a non-covalent manner, which makes LDM a good material for constructing tumor-targeting drugs. The tumor targeting fusion proteins could be obtained by coupling the proteins and/or peptide that have tumor targeting ability with LDP through gene recombination technology. And then, AE was integrated into the LDP of the fusion protein, which would finally produce the tumor targeting drugs with both tumor targeting ability and killing activity. With the deepening of research, it is expected that a number of LDM-based targeting drugs can be used in the clinical treatment of cancers.
引文
[1]Hu J,Xue Y,Xie M,et al.A new macromolecular antitumor antibiotic,C-1027.I.Discovery,taxonomy of producing organism,fermentation and biological activity.J Antibiot,1988,41:1575-9
[2]WangY,ZhaoX,YuH,etal.Releasing of the chromophore from the drug delivery protein C-1027:a molecular dynamics simulations study.J Struct Biol,2010,172:284-93
[3]邵荣光,甄永苏.新烯二炔类大分子抗肿瘤抗生素C1027的分子构成与活性关系.药学学报,1995,30:336-42
[4]Li X,Lei X,Zhang C,et al.Complete genome sequence of Streptomyces globisporus C-1027,the producer of an enediyne antibiotic lidamycin.J Biotechnol,2016,222:9-10
[5]陈淑珍,甄永苏,邵荣光.力达霉素抗肿瘤作用及其分子机制研究新进展.中国抗生素杂志,2010,35:401-7,413
[6]温艳清,孟志云,陈淑珍,等.力达霉素的体外代谢.药学学报,2011,46:1132-6
[7]Gao R,Li L,Shang B,et al.A gelatinases-targeting scFvbased fusion protein shows enhanced antitumour activity with endostar against hepatoma.Basic Clin Pharmacol Toxicol,2015,117:105-6
[8]Zhong GS,Wu MN,Guo XF,et al.Antitumor activities of dFv-LDP-AE:an enediyne-energized fusion protein targeting tumor-associated antigen gelatinases.Oncol Rep,2012,28:1193-9
[9]Zhong G,Xu Z,Yang R,et al.An arginine-rich cell penetrating peptide contained anti-gelatinase scFv-LDMfusion protein shows potent antitumor efficacy in pancreatic cancer.J Cancer,2018,9:674-82
[10]封云,何红伟,李保卫,等.抗IV型胶原酶抗体Fab'片段力达霉素偶联物的抗肿瘤侵袭转移作用.药学学报,2011,46:1462-5
[11]Xin C,Ye S,Ming Y,et al.Efficient inhibition of B-cell lymphoma xenografts with a novel recombinant fusion protein:anti-CD20Fab-LDM.Gene Ther,2010,17:1234-43
[12]Fang H,Miao Q,Zhang S,et al.Antitumor effects of an engineered and energized fusion protein consisting of an anti-CD20 scFv fragment and lidamycin.Sci Chn:Life Sci,2011,54:255-62
[13]Normanno N,De Luca A,Bianco C,et al.Epidermal growth factor receptor(EGFR)signaling in cancer.Gene,2006,366:2-16
[14]Sheng W,Shang Y,Miao Q,et al.Antitumor efficacy of the scFv-based fusion protein and its enediyne-energized analogue directed against epidermal growth factor receptor.Anti cancer Drugs,2012,23:406-16
[15]Zhu D,Wang X,Shang Y,et al.A bispecific fusion protein and a bifunctional enediyne-energized fusion protein consisting of TRAIL,EGFR peptide ligand,and apoprotein of lidamycin against EGFR and DR4/5 show potent antitumor activity.Anticancer Drugs,2015,26:64-73
[16]Xu J,Du Y,Liu X,et al.Recombinant EGFR/MMP-2bi-targeted fusion protein markedly binding to non-small cell lung carcinoma and exerting potent therapeutic efficacy.Pharmacol Res,2017,126:66-76
[17]Guo XF,Zhu XF,Cao HY,et al.A bispecific enediyneenergized fusion protein targeting both epidermal growth factor receptor and insulin-like growth factor 1 receptor showing enhanced antitumor efficacy against non-small cell lung cancer.Oncotarget,2017,8:27286-99
[18]Nishioka K.Anti-tumour effect of the physiological tetrapeptide,tuftsin.Br J Cancer,1979,39:342-5
[19]Liu WJ,Liu XJ,Li L,et al.Tuftsin-based,EGFR-targeting fusion protein and its enediyne-energized analog show high antitumor efficacy associated with CD47 downregulation.Cancer Immunol Immun,2014,63:1261-72
[20]Guo XF,Zhu XF,Shang Y,et al.A bispecific enediyneenergized fusion protein containing ligand-based and antibody-based oligopeptides against epidermal growth factor receptor and human epidermal growth factor receptor 2 shows potent antitumor activity.Clin Cancer Res,2010,16:2085-94
[21]Sheng W,Shang Yh Li L,et al.An EGFR/CD13 bispecific fusion protein and its enediyne-energized analog show potent antitumor activity.Anticancer Drugs,2014,25:82-91
[22]Ru Q,Shang B,Miao Q,et al.A cell penetrating peptideintegrated and enediyne-energized fusion protein shows potent antitumor activity.Eur J Pharmaceut Sci,2012,47:781-9
[23]Zhang Q,Liu XJ,Hu L,et al.Factor VII light chaintargeted lidamycin targets tissue factor-overexpressing tumor cells for cancer therapy.Int J Mol Med,2012,29:409-15
[24]Zhang Q,Liu X,Li C,et al.Tissue factor-targeted lidamycin inhibits growth and metastasis of colon carcinoma.Oncol Lett,2013,6:801-6
[25]Wang R,Li L,Zhang S,et al.A novel enediyne-integrated antibody-drug conjugate shows promising antitumor efficacy against CD30+lymphomas.Mol Oncol,2018,12:339-55
[26]Jiang WG,Lu XA,Shang BY,et al.Genetically engineered endostatin-lidamycin fusion proteins effectively inhibit tumor growth and metastasis.BMCCancer,2013,13:479
[27]Xu J,Liu X,Li L,et al.An engineered TIMP2-based and enediyne-integrated fusion protein for targeting MMP-14shows potent antitumor efficacy.Oncotarget,2015,6:26322
[28]Li W,Li X,Huang T,et al.Engineered production of cancer targeting peptide(CTP)-containing C-1027 in Streptomyces globisporus and biological evaluation.Bioorg Med Chem,2016,24:3887-92
[29]Zhang Y,Liu R,Fan D,et al.The novel structure make LDM effectively remove CD123+AML stem cells in combination with interleukin 3.Cancer Biol Ther,2015,16:1514-25
[30]叶程,曹睿,宋文凭,等.双靶向配体化力达霉素DTLL的制备优化和稳定性研究.中国医药生物技术,2018,13:193-200
[2]WangY,ZhaoX,YuH,etal.Releasing of the chromophore from the drug delivery protein C-1027:a molecular dynamics simulations study.J Struct Biol,2010,172:284-93
[3]邵荣光,甄永苏.新烯二炔类大分子抗肿瘤抗生素C1027的分子构成与活性关系.药学学报,1995,30:336-42
[4]Li X,Lei X,Zhang C,et al.Complete genome sequence of Streptomyces globisporus C-1027,the producer of an enediyne antibiotic lidamycin.J Biotechnol,2016,222:9-10
[5]陈淑珍,甄永苏,邵荣光.力达霉素抗肿瘤作用及其分子机制研究新进展.中国抗生素杂志,2010,35:401-7,413
[6]温艳清,孟志云,陈淑珍,等.力达霉素的体外代谢.药学学报,2011,46:1132-6
[7]Gao R,Li L,Shang B,et al.A gelatinases-targeting scFvbased fusion protein shows enhanced antitumour activity with endostar against hepatoma.Basic Clin Pharmacol Toxicol,2015,117:105-6
[8]Zhong GS,Wu MN,Guo XF,et al.Antitumor activities of dFv-LDP-AE:an enediyne-energized fusion protein targeting tumor-associated antigen gelatinases.Oncol Rep,2012,28:1193-9
[9]Zhong G,Xu Z,Yang R,et al.An arginine-rich cell penetrating peptide contained anti-gelatinase scFv-LDMfusion protein shows potent antitumor efficacy in pancreatic cancer.J Cancer,2018,9:674-82
[10]封云,何红伟,李保卫,等.抗IV型胶原酶抗体Fab'片段力达霉素偶联物的抗肿瘤侵袭转移作用.药学学报,2011,46:1462-5
[11]Xin C,Ye S,Ming Y,et al.Efficient inhibition of B-cell lymphoma xenografts with a novel recombinant fusion protein:anti-CD20Fab-LDM.Gene Ther,2010,17:1234-43
[12]Fang H,Miao Q,Zhang S,et al.Antitumor effects of an engineered and energized fusion protein consisting of an anti-CD20 scFv fragment and lidamycin.Sci Chn:Life Sci,2011,54:255-62
[13]Normanno N,De Luca A,Bianco C,et al.Epidermal growth factor receptor(EGFR)signaling in cancer.Gene,2006,366:2-16
[14]Sheng W,Shang Y,Miao Q,et al.Antitumor efficacy of the scFv-based fusion protein and its enediyne-energized analogue directed against epidermal growth factor receptor.Anti cancer Drugs,2012,23:406-16
[15]Zhu D,Wang X,Shang Y,et al.A bispecific fusion protein and a bifunctional enediyne-energized fusion protein consisting of TRAIL,EGFR peptide ligand,and apoprotein of lidamycin against EGFR and DR4/5 show potent antitumor activity.Anticancer Drugs,2015,26:64-73
[16]Xu J,Du Y,Liu X,et al.Recombinant EGFR/MMP-2bi-targeted fusion protein markedly binding to non-small cell lung carcinoma and exerting potent therapeutic efficacy.Pharmacol Res,2017,126:66-76
[17]Guo XF,Zhu XF,Cao HY,et al.A bispecific enediyneenergized fusion protein targeting both epidermal growth factor receptor and insulin-like growth factor 1 receptor showing enhanced antitumor efficacy against non-small cell lung cancer.Oncotarget,2017,8:27286-99
[18]Nishioka K.Anti-tumour effect of the physiological tetrapeptide,tuftsin.Br J Cancer,1979,39:342-5
[19]Liu WJ,Liu XJ,Li L,et al.Tuftsin-based,EGFR-targeting fusion protein and its enediyne-energized analog show high antitumor efficacy associated with CD47 downregulation.Cancer Immunol Immun,2014,63:1261-72
[20]Guo XF,Zhu XF,Shang Y,et al.A bispecific enediyneenergized fusion protein containing ligand-based and antibody-based oligopeptides against epidermal growth factor receptor and human epidermal growth factor receptor 2 shows potent antitumor activity.Clin Cancer Res,2010,16:2085-94
[21]Sheng W,Shang Yh Li L,et al.An EGFR/CD13 bispecific fusion protein and its enediyne-energized analog show potent antitumor activity.Anticancer Drugs,2014,25:82-91
[22]Ru Q,Shang B,Miao Q,et al.A cell penetrating peptideintegrated and enediyne-energized fusion protein shows potent antitumor activity.Eur J Pharmaceut Sci,2012,47:781-9
[23]Zhang Q,Liu XJ,Hu L,et al.Factor VII light chaintargeted lidamycin targets tissue factor-overexpressing tumor cells for cancer therapy.Int J Mol Med,2012,29:409-15
[24]Zhang Q,Liu X,Li C,et al.Tissue factor-targeted lidamycin inhibits growth and metastasis of colon carcinoma.Oncol Lett,2013,6:801-6
[25]Wang R,Li L,Zhang S,et al.A novel enediyne-integrated antibody-drug conjugate shows promising antitumor efficacy against CD30+lymphomas.Mol Oncol,2018,12:339-55
[26]Jiang WG,Lu XA,Shang BY,et al.Genetically engineered endostatin-lidamycin fusion proteins effectively inhibit tumor growth and metastasis.BMCCancer,2013,13:479
[27]Xu J,Liu X,Li L,et al.An engineered TIMP2-based and enediyne-integrated fusion protein for targeting MMP-14shows potent antitumor efficacy.Oncotarget,2015,6:26322
[28]Li W,Li X,Huang T,et al.Engineered production of cancer targeting peptide(CTP)-containing C-1027 in Streptomyces globisporus and biological evaluation.Bioorg Med Chem,2016,24:3887-92
[29]Zhang Y,Liu R,Fan D,et al.The novel structure make LDM effectively remove CD123+AML stem cells in combination with interleukin 3.Cancer Biol Ther,2015,16:1514-25
[30]叶程,曹睿,宋文凭,等.双靶向配体化力达霉素DTLL的制备优化和稳定性研究.中国医药生物技术,2018,13:193-200