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2006-12-25 20:16:47

PLoS ONE：经基因修饰的细胞可靶向治疗肿瘤

生物谷

生物谷报道：最近，来自St. Jude 儿童研究中心医院，城市卫生医学治疗中心，以及英国哥伦比亚大学的研究人员通过基因修饰的细胞搜寻肿瘤细胞，然后活化并诱导化疗药物直接作用于肿瘤细胞的机制，成功的治疗了患成神经细胞瘤的小鼠。（成神经细胞瘤是一种生长在颅外的神经系统实体瘤）。研究人员发现基因修饰的细胞可以准确的迁徙到肿瘤表面，无论肿瘤的大小和位置。该报道发表在12.20日的PLoS ONE网络版上。这个研究第一次提出了神经原始干细胞（NSPCs）可以治疗转移的实体瘤。在正常的发育过程中NSPCs将发育成大脑中各种类型的细胞。
该研究的研究基础是建立在以往报道过的一个实验理论上，研究者认为特定的NSPCs有搜寻脑组织受损或者癌性区域的能力。这个研究中，研究人员首先将基因修饰的NSPCs――含有药物活化兔(羧酸)酯酶，注射到患有成神经细胞瘤的小鼠体内。NSPCs 迁移到肿瘤组织，通过该基因产生(羧酸)酯酶。三天后再注射CPT-11（依立替康，一种已应用于肿瘤治疗的药物），CPT-11扩散至小鼠全身，但是药物只有在肿瘤组织中，才能被该处NSPCs 携带的(羧酸)酯酶激活。实验结果示：单独注射CPT-11的小鼠六个月生存率为50％（在一个10只鼠的实验小组中存活5只5/10），而同时注射CPT-11和修饰后的NSPCs的小鼠六个月的存活率为100％（10/10）。
St. Jude的分子药理学实验室研究员――Mary Danks,博士称：基因修饰后的细胞的靶向治疗能力在诸如高风险的成神经细胞瘤病例中尤为重要，因为，即使很小的肿瘤组织在经过最初的成功治疗后，也会产生一些肿瘤细胞分散到体内各处，并且这些肿瘤细胞将会对治疗无反应。所谓高危的成神经细胞瘤是指有特定基因突和在初诊时就发现了肿瘤扩散。对于高危成神经细胞瘤的患儿该研究具有特殊的意义，因为80％的该类患儿会复发并且有对化疗抵抗的癌转移。同时，小鼠成神经细胞瘤的治疗成功使科学家对于改善其他转移性实体瘤比如结肠癌，前列腺癌的治疗效果燃起了信心。

Figure . Schematic diagram of the protocol for NDEPT.

Human neuroblastoma tumor cells are injected intravenously to produce disseminated tumors.

At an appropriate time after injection of neuroblastoma cells, neural stem cells or neural progenitor cells transduced with adenovirus to express a prodrug-activating enzyme (in this study, a secreted form of rabbit carboxylesterase [rCE]) are injected intravenously.

Following migration of stem cells or progenitor cells to tumor foci and a delay of 3–4 days to allow relatively high level expression of the prodrug-activating enzyme into the extracellular milieu at the tumor sites, mice are treated with the prodrug (in this study, CPT-11).

The prodrug is activated selectively at tumor foci, to increase the therapeutic index of the prodrug.

原文出处：

doi:10.1371/journal.pone.0000023.g002
Development of a Tumor-Selective Approach to Treat Metastatic Cancer
Karen S. Aboody etal

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作者简介：

Mary Danks, PhD
Department of Molecular Pharmacology
St. Jude Children's Research Hospital

Education

BS - St. Louis College of Pharmacy, St. Louis, Missouri (1972)
PhD - University of Nebraska Medical Center (1980)

Research Interests

Development and characterization of enzyme/prodrug combinations for treatment of pediatric solid tumors.
Delivery of therapeutic transgenes to solid tumors, using neural progenitor cells as tumor-tropic vectors.
ICAM-2-mediated conversion of neuroblastoma cells from a metastatic to a nonmetastatic phenotype.

Selected Publications

Tumor-targeted enzyme-prodrug therapy mediates long-term disease-free survival of mice bearing disseminated neuroblastoma. Cancer Res 2006 (in press).

Aboody KS, Bush RA, Garcia E, Metz M, Najbauer J, Justus KA, Phelps DA, Remack JS, Yoon KJ, Gillespie S, Kim SU, Glackin C, Potter PM, Danks MK. Neural progenitor cells expressing a therapeutic transgene target metastatic neuroblastoma and mediate long-term survival in a mouse model. PLoS ONE 2006 (in press).

Dickson PV, Hamner JB, Kim SU, Ng CYC, Garcia E, Aboody KS, Danks MK, Davidoff AM. Intravascular administration of tumor-tropic neuroprogenitor cells permits targeted delivery of interferon-β and restricts tumor growth in a murine model of disseminated neuroblastoma. J Ped Surg 2006 (in press).

Hyatt JL, Tsurkan L, Wierdl M, Edwards CC, Danks MK, Potter PM. Intracellular inhibition of Carboxylesterase by benzyl: Modulation of CPT-11 cytotoxicity. Mol Cancer Ther 5(9):2281-2287, 2006.

Yoon KJP, Valentine MB, Valentine VA, Ragsdale ST, Danks MK. Translocations of chromosome 17q21-qter in neuroblastoma cell lines infrequently include the topoisomerase IIα gene. Cancer Genetics and Cytogenetics 167:92-94, 2006.

Fouladi M, Blaney SM, Young-Poussaint T, Freeman BB, McLendon R, Fuller C, Adesina AM, Hancock ML, Remack JS, Danks MK, Stewart C, Boyett J, Kun LE, Gajjar A. A Phase II study of oxaliplatin in children with recurrent or refractory medulloblastoma, supratentorial primitive neuroectodermal tumors and atypical teratoid rhabdoid tumors: A Pediatric Brain Tumor Consortium Study. Cancer [Published online] Oct 3, 2006.

Yoon KJ, Qi J, Remack JS, Virga KG, Hatfield J, Potter PM, Lee RE, Danks MK. Development of an etoposide prodrug for dual prodrug-enzyme approach to antitumor therapy. Mol Cancer Ther 5:1577-1587, 2006.

Wagner LM, Burger RA, Guichard SM, Santana VM, Furman WL, Danks MK. Pilot study to evaluate MYCN expression as a neuroblastoma cell marker to detect minimal residual disease by RT-PCR. J Ped Hematol Oncol 28 (10) 635-641, 2006.

Morton CL, Iacono L, Hyatt JL, Taylor KR, Cheshire PJ, Houghton PJ, Danks MK, Stewart CF, Potter PM. Activation and antitumor activity of CPT-11 in plasma esterase-deficient mice. Cancer Chemother Pharmacol 56:629-636, 2005.

Hyatt JL, Stacy V, Wadkins RM, Yoon KJP, Wierdl M, Edwards CC, Zeller M, Hunter AD, Danks MK, Crundwell G, Potter PM. Inhibition of carboxylesterases by benzil (diphenylethane-1,2-dione) and heterocyclic analogs is dependent upon the aromaticity of the ring and the flexibility of the dione moiety. J Med Chem 48:5543-5550, 2005.

Tyminski E, LeRoy S, Terada K, Finkelstein KM, Hyatt JL, Danks MK, Potter PM, Saeki Y, Chiocca EA. Brain tumor oncolysis with replication-conditional HSV1 expressing the prodrug-activating genes CYP2B1 and secreted hiCE, in combination with cyclophosphamide and irinotecan. Cancer Res 65:6850-6857, 2005.

Wadkins RM, Hyatt JL, Wei, X, Yoon KJP, Wierdl M, Edwards CC, Morton CL, Obenauer JC, Damodaran, Beroza P, Danks MK, Potter PM. Identification and characterization of novel benzil analogues as inhibitors of mammalian carboxylesterases. J Med Chem 48:2906-2915, 2005

Yoon, KJP, Krull EJ, Hyatt JL, Morton CL, Lee RE, Potter PM, Danks MK. Characterization of inhibitors of specific carboxylesterases: development of compounds for translational application. Molecular Cancer Therapeutics 3:903-909, 2004.

Wadkins RM, Hyatt JL, Yoon KJP, Morton CL, Lee RE, Damodaran K, Beroza P, Danks MK, Potter PM. Discovery of novel selective inhibitors of human intestinal carboxylesterase: Synthesis, QSAR analysis, and biological activity. Mol Pharm 65:1336-1343, 2004.

Yoon KJP, Krull EJK, Morton CL, Bornmann WG, Lee RE, Potter PM, Danks MK. Activation of a novel camptothecin prodrug by specific carboxylesterases as predicted by quantitative structure activity relationship and docking studies. Molecular Cancer Therapeutics 2:1171-1181, 2003.

Stubdal H, Perin N, Lemmon M, Holman P, Potter PM, Danks MK, Bauzon M, Fattaey A, Dubensky T, Johnson L. A Prodrug strategy using ONYX-015-based replicating adenoviruses to deliver rabbit carboxylesterase to tumor cells for conversion of CPT-11 to SN-38. Cancer Res 63:6900-6908, 2003.

Wierdl M, Wall A, Morton CL, Sampath J, Danks MK, Schuetz JD, Potter PM. Sensitization of human tumor cells to CPT-11 by carboxylesterases cannot override BCRP-mediated drug resistance. Molecular Pharm 64:279-288, 2003.

Yoon KJP, Morton, CL, Potter PM, Danks MK, Lee RE. Synthesis and evaluation of esters and carbamates to identify critical functional groups for esterase-specific metabolism. Bioorg Med Chem 11:5237-5244, 2003.

McKenzie PP, Danks MK, Kriwacki RW, Harris LC. Cyclin E-dependent cdk2 activity in neuroblastoma is insensitive to inhibition by p21Waf-1/Cip-1. Cancer Res 63:3840-3844, 2003.

Bencharit S, Morton CL, Hyatt JL, Kuhn P, Danks MK, Potter PM, Redinbo MR. Crystal structure of human carboxylesterase 1 complexes with the Alzheimer's drug tacrine: From binding promiscuity to selective inhibition. Chemistry and Biology 10:341-249, 2003.

Wierdl M, Morton CL, Harris LC, Danks MK, Schuetz JD, Potter PM. p53-Mediated regulation of expression of a rabbit liver carboxylesterase confers sensitivity to CPT-11. Molecular Pharm 304:699-705, 2003.

Bencharit S, Morton CL, Howard-Williams EL, Danks MK, Potter PM, Redinbo MR. Structural insights into CPT-11 activation by mammalian carboxylesterases. Nature Structural Biology 9:337-342, 2002.

Wagner LM, Guichard SM, Burger RA, Straign CM, Ashmun RA, Harris LC, Houghton PJ, Potter PM, Danks MK. Efficacy and toxicity of a VDEPT purging method: Preclinical assessment and application to bone marrow samples from neuroblastoma patients. Cancer Res 62:5001-5007, 2002.

Wadkins RM, Morton CL, Weeks JK, Oliver L, Danks MK, Potter PM. Structural constraints dictate the metabolism of CPT-11 by esterases. Molecular Pharm 60(2):355-362, 2001.

Wierdl M, Morton CL, Weeks JK, Danks MK, Harris LC, Potter PM. Sensitization of human tumor cells to CPT-11 via adenoviral-mediated delivery of a rabbit liver carboxylesterase. Cancer Res 61(13): 5078-5082, 2001.

Meck MM, Wierdl M, Wagner LM, Burger RA, Krull EJ, Harris LC, Potter PM, Danks MK. A VDEPT approach to purging neuroblastoma cells from hematopoietic cells using adenovirus encoding rabbit carboxylesterase and CPT-11. Cancer Res 61(13):5083-5089, 2001.

Iyengar R, Pawlik CA, Krull EJ, Phelps DA, Burger, RA, Harris LC, Potter PM, Danks MK. Use of a modified ornithine decarboxylase promoter to achieve efficient c-MYC- or N-MYC-regulated protein expression. Cancer Res 3045-3052, 2001.

Thompson J, Guichard SM, Cheshire PJ, Richmond LB, Webber BL, Poquette CA, Ragsdale ST, Danks MK, Houghton PJ. Development, characterization and therapy of a disseminated model of childhood neuroblastoma in SCID mice. Cancer Chemother Pharmacol 47:211-221, 2001.

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