生物谷報道：最近,，來自St. Jude 兒童研究中心醫(yī)院，城市衛(wèi)生醫(yī)學(xué)治療中心,，以及英國哥倫比亞大學(xué)的研究人員通過基因修飾的細胞搜尋腫瘤細胞,，然后活化并誘導(dǎo)化療藥物直接作用于腫瘤細胞的機制，成功的治療了患成神經(jīng)細胞瘤的小鼠,。（成神經(jīng)細胞瘤是一種生長在顱外的神經(jīng)系統(tǒng)實體瘤）,。研究人員發(fā)現(xiàn)基因修飾的細胞可以準(zhǔn)確的遷徙到腫瘤表面，無論腫瘤的大小和位置,。該報道發(fā)表在12.20日的PLoS ONE網(wǎng)絡(luò)版上,。這個研究第一次提出了神經(jīng)原始干細胞（NSPCs）可以治療轉(zhuǎn)移的實體瘤。在正常的發(fā)育過程中NSPCs將發(fā)育成大腦中各種類型的細胞,。
該研究的研究基礎(chǔ)是建立在以往報道過的一個實驗理論上,，研究者認為特定的NSPCs有搜尋腦組織受損或者癌性區(qū)域的能力。這個研究中,，研究人員首先將基因修飾的NSPCs――含有藥物活化兔(羧酸)酯酶,，注射到患有成神經(jīng)細胞瘤的小鼠體內(nèi)。NSPCs 遷移到腫瘤組織,，通過該基因產(chǎn)生(羧酸)酯酶,。三天后再注射CPT-11（依立替康，一種已應(yīng)用于腫瘤治療的藥物）,，CPT-11擴散至小鼠全身,，但是藥物只有在腫瘤組織中，才能被該處NSPCs 攜帶的(羧酸)酯酶激活,。實驗結(jié)果示：單獨注射CPT-11的小鼠六個月生存率為50％（在一個10只鼠的實驗小組中存活5只5/10）,，而同時注射CPT-11和修飾后的NSPCs的小鼠六個月的存活率為100％（10/10）。
St. Jude的分子藥理學(xué)實驗室研究員――Mary Danks,博士稱：基因修飾后的細胞的靶向治療能力在諸如高風(fēng)險的成神經(jīng)細胞瘤病例中尤為重要,，因為,，即使很小的腫瘤組織在經(jīng)過最初的成功治療后，也會產(chǎn)生一些腫瘤細胞分散到體內(nèi)各處,，并且這些腫瘤細胞將會對治療無反應(yīng),。所謂高危的成神經(jīng)細胞瘤是指有特定基因突和在初診時就發(fā)現(xiàn)了腫瘤擴散。對于高危成神經(jīng)細胞瘤的患兒該研究具有特殊的意義,，因為80％的該類患兒會復(fù)發(fā)并且有對化療抵抗的癌轉(zhuǎn)移,。同時，小鼠成神經(jīng)細胞瘤的治療成功使科學(xué)家對于改善其他轉(zhuǎn)移性實體瘤比如結(jié)腸癌,，前列腺癌的治療效果燃起了信心,。
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.
原文出處：
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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作者簡介：
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.
