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中华肿瘤防治杂志 2006年第11期13卷 855-856页

作者：蔡炜嵩张可仞张锦华王维林中国医科大学第二临床学院盛京医院小儿外科卫生部小儿先天畸形重点实验室沈阳辽宁110004 中国医科大学第二临床学院盛京医院血液室沈阳辽宁110004

目的：观察评价拓扑替康联合环磷酰胺治疗神经母细胞瘤的疗效和毒性。方法：14例神经母细胞瘤患儿，应用拓扑替康联舍环磷酰胺联合静脉用药。大剂量应用环磷酰胺[70mg／（kg·d）×2d]和拓扑替康[2mg／（m^2·d）×3d]... 详细信息

目的：观察评价拓扑替康联合环磷酰胺治疗神经母细胞瘤的疗效和毒性。方法：14例神经母细胞瘤患儿，应用拓扑替康联舍环磷酰胺联合静脉用药。大剂量应用环磷酰胺[70mg／（kg·d）×2d]和拓扑替康[2mg／（m^2·d）×3d]。其中12例治疗2～13个周期，进行疗效和不良反应评价。结果：12例患者中，进展3例，稳定及缓解9例，总有效率为75％。不良反应主要为骨髓抑制和消化道反应，但对症治疗后，无相关性死亡。结论：拓扑替康联合环磷酰胺治疗儿童神经母细胞瘤安全有效。

关键词：神经母细胞瘤/药物疗法拓泊替坎/投药和剂量环磷酰胺/投药和剂量儿童

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MYCN enhances P-gp/MDR1 gene expression in the human metastatic neuroblastoma IGR-N-91 model

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AMERICAN JOURNAL OF PATHOLOGY 2003年第1期163卷 321-331页

作者： Blanc, E Goldschneider, D Ferrandis, E Barrois, M Le Roux, G Leonce, S Douc-Rasy, S Bénard, J Raguénez, G Inst Gustave Roussy UMR 8126 Serv Genet Dept Biol F-94805 Villejuif France Univ Paris Sud 11 CNRS UMR 8126 Paris France Inst Gustave Roussy Inst Federat Rech F-94805 Villejuif France Inst Rech Int Servier Dept Biol Croissy sur Seine France

Despite intensive high-dose chemotherapy and autologous hematopoietic stem cell transplantation, disseminated neuroblastoma (NB) frequently proves to be chemosensitive but not chemocurable, and more often so in NB-presenting MYCN amplification. To assess the direct relationship between the MYCN oncogene and chemoresistance acquisition during NB metastatic dissemination, we have studied MYCN and MDR1 genes using the human IGR-N-91 ectopic xenograft metastatic model. This characterized experimental in vitro model includes human neuroblasts derived from a subcutaneous primary tumor xenograft, disseminated blood cells, myocardium, and bone marrow (BM) metastatic cells. All IGR-N-91-derived neuroblasts harbor a consistent MYCN genomic content but, unlike primary tumor xenograft, BM, and myocardium, human neuroblasts elicit a concomitant increase in MYCN and MDR1 transcripts levels, consistent with chemoresistance phenotype and active P-gp. In contrast, no variation of MRP1 transcript level was associated with the metastatic process in this model. Using an MDR1 promoter-CAT construct, we have shown that the MycN protein activates MDR1 transcription both in exogenous transient MYCN-transfected SK-N-SH cells and in endogenous BM metastatic neuroblasts with an increase in the MYCN transcript level. Band-shift experiments indicate that IGR-N-91 cells enriched with the MycN transcription factor do bind to two E-box motifs localized within the MDR1 promoter. Overall, our data indicate that MYCN overexpression increment contributes to the acquired drug resistance that occurs throughout the NB metastatic process.

关键词：抗肿瘤药/代谢抗肿瘤药/治疗应用抗药性多药/生理学基因表达调控肿瘤小鼠裸肿瘤转移肿瘤移植神经母细胞瘤/药物疗法神经母细胞瘤/代谢神经母细胞瘤/病理学核蛋白质类/遗传学核蛋白质类/代谢癌基因蛋白质类/遗传学癌基因蛋白质类/代谢启动区遗传移植异种肿瘤细胞培养的动物儿童人类男(雄)性小鼠

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Prolonged CD4 depletion after sequential autologous peripheral blood progenitor cell infusions in children and young adults

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BLOOD 2000年第2期96卷 754-762页

作者： Mackall, CL Stein, D Fleisher, TA Brown, MR Hakim, FT Bare, CV Leitman, SF Read, EJ Carter, CS Wexler, LH Gress, RE NCI Pediat Oncol Branch Bethesda MD 20892 USA NCI Med Branch Bethesda MD 20892 USA NCI Expt Immunol Branch Bethesda MD 20892 USA NIH Dept Transfus Med Ctr Clin Bethesda MD 20892 USA

Administration of mobilized peripheral blood progenitor cells (PBPCs) after high-dose chemotherapy rapidly restores multilineage hematopoiesis, but the ability of such products to restore lymphocyte populations remains unclear. In this report, we evaluated immune reconstitution in a series of patients treated with sequential cycles of high-dose chemotherapy, followed by autologous PBPC infusions (median CD34(+) cell dose 7.2 x 10(6) cells/kg [range 2-29.3]), Although patients experienced rapid reconstitution of B cells and CD8(+) T cells, we observed CD4 depletion and diminished immune responsiveness in all patients for several months after completion of therapy. Mature CD4(+) T cells contained within the grafts did not appear to contribute substantially to immune reconstitution because CD4 counts did not differ between recipients of unmanipulated T-cell replete Infusions versus CD34 selected, T-cell-depleted infusions. Rather, at 12 months after therapy, total CD4 count was inversely proportional to age (rho = -0.78, P = .04), but showed no relationship to CD34 cell dose (rho = -0.42, P = .26), suggesting that age-related changes within the host are largely responsible for the limited immune reconstitution observed. These results demonstrate that in the autologous setting, the infusion of large numbers of PBPCs is not sufficient to restore T-cell Immune competence and emphasize that specific approaches to enhance immune reconstitution are necessary if immune-based therapy is to be used to eradicate minimal residual disease after autologous PBPC transplantation.

关键词： B淋巴细胞 CD4淋巴细胞计数 CD8阳性T淋巴细胞血细胞生成造血干细胞移植造血干细胞/细胞学造血干细胞/免疫学免疫杀伤细胞天然淋巴细胞计数神经母细胞瘤/药物疗法肉瘤/药物疗法移植自体儿童儿童学龄前人类

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Detection of leukemia-associated MLL-GAS7 translocation early during chemotherapy with DNA topoisomerase II inhibitors

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第6期97卷 2814-2819页

作者： Megonigal, MD Cheung, NKV Rappaport, EF Nowell, PC Wilson, RB Jones, DH Addya, K Leonard, DGB Kushner, BH Williams, TM Lange, BJ Felix, CA Univ Penn Abramson Res Ctr Div Oncol Childrens Hosp PhiladelphiaSch Med Philadelphia PA 19104 USA Univ Penn Sch Med Joseph Stokes Jr Res Inst Philadelphia PA 19104 USA Univ Penn Sch Med Dept Pediat Philadelphia PA 19104 USA Univ Penn Sch Med Dept Pathol & Lab Med Philadelphia PA 19104 USA Mem Sloan Kettering Canc Ctr Dept Pediat New York NY 10021 USA Univ Iowa Iowa City IA 52222 USA

Leukemias with MLL gene translocations are a complication of primary cancer treatment with DNA topoisomerase II inhibitors, How early translocations appear during primary cancer treatment has not been investigated. We tracked the leukemic clone with an MLL gene translocation during neuroblastoma therapy in a child who developed acute myeloid leukemia, The karyotype of the leukemic clone showed del(11)(q23). We used panhandle PCR-based methods to isolate the breakpoint junction involving MLL and an unknown partner gene. Marrow DNA from neuroblastoma diagnosis and DNA and RNA from serial preleukemic marrows were examined for the translocation, The karyotypic del(11)(q23) was a cryptic t(11;17), GAS7, a growth arrest-specific gene at chromosome band 17p13, was the partner gene of MLL. Two different MLL-GAS7 fusion transcripts were expressed, The translocation was already detectable by 1.5 months after the start of neuroblastoma treatment. The translocation was not detectable in the marrow at neuroblastoma diagnosis or in peripheral blood lymphocyte DNAs of six normal subjects. GAS7 is a new partner gene of MLL in treatment-related acute myeloid leukemia, MLL gene translocations can be present early during anticancer treatment at low cumulative doses of DNA topoisomerase II inhibitors. Although MLL has many partner genes and most have not been characterized, panhandle PCR strategies afford new means for detecting MLL gene translocations early during therapy when the partner gene is unknown.

关键词：抗肿瘤联合化疗方案/副作用碱基序列印迹法 DNA 染色体人 11对顺铂/副作用环磷酰胺/副作用 DNA结合蛋白质类/遗传学多柔比星/副作用依托泊甙/副作用外显子致命性结局组蛋白赖氨酸N-甲基转移酶白血病髓样/化学诱导白血病髓样/遗传学分子序列数据髓淋巴细胞性白血病蛋白质神经组织蛋白质类/遗传学神经母细胞瘤/药物疗法神经母细胞瘤/遗传学聚合酶链反应原癌基因时间因素拓扑异构酶II抑制剂转录因子易位遗传长春新碱/副作用青少年人类男(雄)性

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Is there a role for retinoids to treat minimal residual disease in neuroblastoma?

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BRITISH JOURNAL OF CANCER 2000年第9期83卷 1121-1123页

作者： Matthay, KK Reynolds, CP Univ Calif San Francisco Sch Med Dept Pediat San Francisco CA 94143 USA Univ So Calif Sch Med Dept Pediat Los Angeles CA 90027 USA Childrens Hosp Los Angeles Los Angeles CA 90027 USA

A variety of pre-clinical and clinical data point toward high drug levels of retinoids being required to achieve optimal efficacy against neuroblastoma. The results of the Kohler trial reported in this issue demonstrate that low-dose 13-cis-RA does not have clinical efficacy against neuroblastoma in a setting of minimal residual disease. A comparison of the Kohler trial with the US CCG trial provides clinical evidence that high-dose levels of retinoids are optimal for treating minimal residual disease in neuroblastoma. The comparison of high-dose and low-dose 13-cis-RA studies in neuroblastoma suggests the intriguing possibility that high dose, pulse schedules of other retinoids could be effective as therapeutic and chemopreventive agents in diseases where low-dose, chronic retinoid administration was not effective. Pre-clinical and perhaps clinical studies of the latter concept should be considered. (C) 2000 Cancer Research Campaign.

关键词：肿瘤残余/药物疗法神经母细胞瘤/药物疗法维生素A酸类/治疗应用人类

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Investigation of in vitro toxicity of jet fuels JP-8 and Jet A

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DRUG AND CHEMICAL TOXICOLOGY 2000年第1期23卷 279-291页

作者： Grant, GM Shaffer, KM Kao, WY Stenger, DA Pancrazio, JJ George Mason Univ Fairfax VA 22030 USA Geocenters Inc Ft Washington MD 20744 USA USN Res Lab Ctr Biomol Sci & Engn Washington DC 20375 USA

The in vitro cytotoxicity and electrophysiological toxicity of Jet Propulsion-8 (JP-8 jet fuel) on four cell types: H41IE liver cell line, NIH Swiss 3T3 cell line, neuroblastoma x glioma NG108-15 cells, and embryonic hippocampal neurons were investigated. H4IIE cells exposed to Jet A (a commercial fuel) and JP-8 demonstrated identical toxicity with an IC50 of 12.6 +/- 0.4 mu g/ml for the two fuels. Comparison of H4IIE and NIH/3T3 toxicity to JP-8 revealed that NIH/3T3 cells were more sensitive to JP-8 than H4IIE cells, with an IC50 8.5 +/- 0.1 mu g/ml. JP-8 exposure for the hippocampal neurons proved to be highly toxic (IC50 of < 2 mu g/ml), while in contrast, the NG108-15 cells were much less sensitive. Electrophysiological examination of NG108-15 cells showed that administration of JP-8 at 1 mu g/ml did not alter significantly any of the electrophysiological properties. However, exposure to JP-8 at 10 mu g/ml during a current stimulus of +46 pA decreased the amplitude of the action potential to 83 +/- 7% (n = 4), the rate of rise, dV/dt(MAX) to 50 +/- 8% (n = 4), and the spiking rate to 35 +/- 11% (n = 4) of the corresponding control levels. These results demonstrate JP-8 induced cytotoxic varies among cell types. The possible mechanisms underlying these observations are presented.

关键词： 3T3细胞/细胞学 3T3细胞/药物作用 3T3细胞/生理学细胞系/细胞学细胞系/药物作用细胞系/生理学细胞存活/药物作用电生理学神经胶质瘤/药物疗法海马/细胞学海马/胚胎学烃类/毒性煤油/毒性肝/细胞学肝/药物作用神经母细胞瘤/药物疗法神经元/细胞学神经元/药物作用神经元/生理学膜片钳术危险性评估动物小鼠大鼠

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Fenretinide: the death of a tumor cell

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JOURNAL OF THE NATIONAL CANCER INSTITUTE 1999年第13期91卷 1099-1100页

作者： Reed, JC Burnham Inst La Jolla CA 92037 USA

Reports how 4-hydroxylphenyl retinamide (4-HPR) like fenretinide induce apoptosis of neuroblastoma cell lines through generation of the lipid second messenger ceramide. Mechanisms of 4-HPR in reactive oxygen species (... 详细信息

关键词：抗肿瘤药/药理学细胞凋亡/药物作用半胱氨酸天冬氨酸蛋白酶/拮抗剂和抑制剂神经酰胺类/生物合成芬维A铵/药理学神经母细胞瘤/药物疗法活性氧/代谢肿瘤细胞培养的人类

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Neuroblastoma in two siblings supports the role of 1p36 deletion in tumor development

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CANCER GENETICS AND CYTOGENETICS 1999年第2期109卷 126-130页

作者： Lo Cunsolo, C Iolascon, A Cavazzana, A Cusano, R Strigini, P Mazzocco, K Giordani, L Massimo, L De Bernardi, B Conte, M Tonini, GP Adv Biotechnol Ctr Unit Solid Tumor Biol I-16132 Genoa Italy Natl Inst Canc Res Lab Genet Populat Genoa Italy Natl Inst Canc Res Sess Genet Epidemiol Genoa Italy G Gaslini Childrens Hosp Genet Mol Lab Genoa Italy G Gaslini Childrens Hosp Lab Oncol Genoa Italy G Gaslini Childrens Hosp Dept Hematol Oncol Genoa Italy Univ Bari Dept Biomed Evolut Age Bari Italy Osped S Camillo Forlanini Rome Italy

Familial neuroblastoma occurs rarely. We studied a family with three children;one of them has a disseminated (stage 4) and another has a localized (stage 2) neuroblastoma. We observed subtelomeric locus D1Z2 (1p36) deletion in both tumors by using double-color fluorescence in situ hybridization. The MYNC gene rr as found in single copy in both tumors. Loss of heterozygosity (LOH) and restriction fragment length polymorphism analyses were performed by using DNA from frozen tumor cells and from microdissected tumor areas excised from paraffin-embedded sections. We detected somatic LOH at locus D1S468 (1p36) in a tumor-cell population with a trisomy 1 of the stage-2 patient. Neuroblastoma cells of the stage-4 patient rr ere diploid and showed allelic loss at the following loci: D1S172, D1S80, D1S94, D1S243, D1S468, D1S214, D1S241, and D1S164. Haplotype study showed that the siblings inherited the same paternal 1p36-->pter chromosome region by homologous recombination and that, in the two tumors, arm Ip of different chromosomes of maternal origin was damaged. Our results suggest that the siblings inherited the predisposition to neuroblastoma associated with paternal 1p36 region and that tumors developed as a consequence of somatic loss of the maternal Ip36 allele. (C) Elsevier Science Inc., 1999. All rights reserved.

关键词：腹部肿瘤/药物疗法腹部肿瘤/遗传学腹部肿瘤/病理学染色体人 1对基因 myc 疾病遗传易感性原位杂交荧光杂合子丢失微卫星重复肿瘤分期神经母细胞瘤/药物疗法神经母细胞瘤/遗传学神经母细胞瘤/病理学系谱儿童学龄前女(雌)性人类男(雄)性妊娠

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ADRIAMYCIN - REVIEW

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JOURNAL OF THE NATIONAL CANCER INSTITUTE 1975年第6期55卷 1265-1274页

作者： CARTER, SK NCI DIV CANC TREATMENTBETHESDAMD 20014

Adriamycin is adding significantly to the effects achieved with cancer chemotherapy. It is the purpose of this editorial to put this drug into current perspective. The following chapters are discussed: preclinical stu... 详细信息

关键词：腺癌/药物疗法乳腺肿瘤/药物疗法癌支气管原/药物疗法多柔比星/投药和剂量多柔比星/副作用多柔比星/类似物和衍生物多柔比星/代谢多柔比星/药理学多柔比星/治疗应用药物评价药物评价临床前药物疗法联合心力衰竭/化学诱导霍奇金病/药物疗法免疫/药物作用白血病淋巴样/药物疗法淋巴瘤大B细胞弥漫性/药物疗法淋巴瘤非霍奇金/药物疗法小鼠近交系有丝分裂/药物作用肿瘤转移/药物疗法肿瘤/药物疗法肿瘤实验性/药物疗法神经母细胞瘤/药物疗法骨肉瘤/药物疗法肉瘤/药物疗法甲状腺肿瘤/药物疗法膀胱肿瘤/药物疗法动物人类小鼠

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