小檗胺衍生物BBD24体内外抗骨肉瘤作用及其机制的研究
|
摘要
骨肉瘤是儿童及青少年最常见的骨的原发性恶性肿瘤,其发生率为每百万人口中4至5例,各种族间无差异。目前临床治疗骨肉瘤的化疗药物仍以阿霉素(ADM)、顺铂(DDP)、和大剂量的甲氨蝶岭(MTX)为主,其他还有近年来应用的异环磷酰胺(IFO)等。虽然化疗明显改善骨肉瘤患者的预后,并且近年来骨肉瘤的治疗取得了一定进展。但近二十多年来骨肉瘤患者的5年生存率仍徘徊在60%上下。在过去的20年中,新的化疗药层出不穷,如肺癌在新药物的使用下疗效明显改善。但是少有发现抗骨肉瘤的新药。仅Navid F发现联合应用吉西他滨和紫杉萜治疗骨与软组织肉瘤转移患者,有良好的抗肿瘤作用及耐受性。因此,开发新的高效低毒的抗骨肉瘤药物或新的化疗增效药,是目前骨肉瘤治疗中的重要课题。
小檗胺(Berbamine)是从小檗属植物的根茎中提取的一种药物。近年来,研究发现小檗胺对肝癌细胞(SMMC7721).宫颈癌细胞(Hela).白血病细胞(K562和HL-60)等都有抑制增殖作用,但是小檗胺对骨肉瘤作用的研究还未见报道。为近一步提高抗肿瘤作用,通过结构修饰化学合成了新型小檗胺衍生物BBD24。因此,本论文以小檗胺衍生物BBD24为切入点,旨在研究小檗胺衍生物BBD24体内外抗骨肉瘤的作用及其机制。MTT实验结果表明,BBD24能显著抑制骨肉瘤细胞系MNNG/HOS和MG63的生长,并且呈剂量依赖性和时间依赖性。进一步研究了BBD24对骨肉瘤细胞增殖抑制的分子机制发现,可以诱导骨肉瘤细胞发生凋亡、坏死和自噬。为了明确小檗胺类化合物在细胞内的分布,我们应用生物素标记的小檗胺和免疫荧光技术对小檗胺在人MNNG/HOS骨肉瘤细胞内的分布进行动态示踪和观察后发现,随着作用时间的延长,小檗胺的分布逐渐向细胞核周边的胞浆集中,并且48小时在细胞核内也可见红色荧光,提示小檗胺有可能进入细胞核内,发挥抗肿瘤活性。进一步对增殖相关的多个信号通路的研究发现,BBD24下调人骨肉瘤MNNG/HOS细胞Wnt/p-catenin信号通路和NF-κB信号通路。对BBD24和临床常用的骨肉瘤化疗药物顺铂联合作用骨肉瘤细胞系MNNG/HOS发现,二者具有协同作用。
本实验收集了8例骨肉瘤患者原代标本,通过MTT测定后发现,小檗胺衍生物BBD24可以有效杀伤原代骨肉瘤细胞,且呈现明显的剂量依赖性,IC50基本在1.0-2.0μg／ml。我们同时收集了4例正常人外周血单个核细胞标本,BBD24对正常细胞的毒性实验提示IC50基本在8.0-10.0μg／ml,明显低于骨肉瘤患者原代细胞。
小檗胺衍生物BBD24对裸鼠骨肉瘤移植模型的作用实验,以3×106／0.2ml细胞浓度接种于背部肩胛附近皮下,造模成功率为100%,接种24h后开始给药,给药时间及剂量为小檗胺衍生物BBD24 10mg／kg,灌胃,一天两次,连续给药20天。结果显示,BBD24可以显著抑制MNNG/HOS移植瘤,且对BALB/c-nu/nu裸鼠没有任何可见的毒副反应。
本研究表明小檗胺衍生物BBD24具有显著地体内外抗骨肉瘤作用,提示其具有一定的临床应用价值和开发前景。
Osteosarcoma is one of the most common types of primary bone tumors for children and adolescents with the incidence of 4-5*10-6 and no difference among various ethnic groups. Current common chemotherapeutic agents for osteosarcoma are adoxorubicin (ADM), cisplatin (DDP), methotrexate (MTX) and the recently-introduced ifosfamide (IFO). Chemotherapy improves outcome of patients with osteosarcoma and to some extent regimens of osteosarcoma have been progressing recently. However, the 5-year survival rate is about 60% during last 2 decades. An endless stream of new drugs emerged in the past 20 years. Patients with lung cancer, for example,have been greatly relieved by new agents. However, few novel effective candidates for osteosarcoma can used for osteosarcoma treatment, except that the combination of Gemcitabine and Yew terpene displays anti-tumor activity for patients with metastasis of bone and soft tissue sarcomas with good tolerance. So the major concern in osteosarcoma treatment is to develop novel chemotherapy agents with more potent anti-tumor activity and low toxicity.
Recent studies showed that berbamine, a natural product extracted from Berber is plants, inhibited the cell growth of a variety of human tumors such as SMMC7721 (hepatoma), HeLa (cervical cancer) and K562 (chronic myeloid leukemia, CML) and HL-60(acute myeloid leukemia, AML), but little is known about the effects of berbamine and derivatives on osteosarcoma. In this study, we investigated the effect and mechanism of BBD24, a novel berbamine derivative, on osteosarcoma in vivo and in vitro. MTT assay showed that BBD24 remarkably inhibited the growth of cell lines MNNG/HOS and MG63 with time-and dose-dependent manners. Cell cycle analysis showed that treatment of tumor cells with BBD24 resulted in cell arrest at G2/M phase. Interestingly, BBD24 could trigger a variety of cell death pathways including apoptosis, necrosis and autophagy. Subcellular distribution investigation using immunofluorescence assay (IFA) with biotinylated berbamine revealed that berbamine was mainly distributed in cytoplasm at 24 hours, but berbamine was predominantly localizated in nucleus at 48 hours. Studies of tumor-related signaling pathways indicated that berbamine derivative BBD24 activated caspase-dependent pathway, and down-regulated NF-kB, AKT, and ERK pathways. Combined treatments of BBD24 with cisplatin (DDP), a commomly-used chemotherapeutic agent for osteosarcoma, on cell line MNNG/HOS confirmed their synergistic effect.
Primary osteosarcoma cells were collected from eight untreated patients and MTT assay showed BBD24 effectively killed these primary cells in a obvious dose-dependent manner with IC50 1.0-2.0μg/ml, meanwhile, PBMCs were also collected from 4 health adults, and MTT assay showed that the IC50 was up to 8.0-10.0μg/ml in general, suggesting that BBD24 selectively inhibit the growth of osteosarcoma cells.
In this study, ostersarcoma xenograft model of nude mice (BALB/c-nu/nu) was used to evaluate the anti-tumor activity of BBD24 in vivo.3×106/0.2ml MNNG/HOS cells were injected subcutaneously near the scapular of mice, and osteosarcoma appeared in all experimental animals at 5 days after injection. BBD24 was orally administered 24 hours after being implanted with MNNG/HOS at 10mg/kg bid for 20 days. Experimental results showed that xenografts of MNNG/HOS were significantly inhibited and no obviously toxic or side effects were observed during experiments.
Taken together, our study results demonstrate berbamine derivative BBD24 posses a potent antitumor activity against osteosarcoma in vivo and in vitro, suggesting that it might be a potential agent for osteosarcoma, and deserving further investigation.
小檗胺(Berbamine)是从小檗属植物的根茎中提取的一种药物。近年来,研究发现小檗胺对肝癌细胞(SMMC7721).宫颈癌细胞(Hela).白血病细胞(K562和HL-60)等都有抑制增殖作用,但是小檗胺对骨肉瘤作用的研究还未见报道。为近一步提高抗肿瘤作用,通过结构修饰化学合成了新型小檗胺衍生物BBD24。因此,本论文以小檗胺衍生物BBD24为切入点,旨在研究小檗胺衍生物BBD24体内外抗骨肉瘤的作用及其机制。MTT实验结果表明,BBD24能显著抑制骨肉瘤细胞系MNNG/HOS和MG63的生长,并且呈剂量依赖性和时间依赖性。进一步研究了BBD24对骨肉瘤细胞增殖抑制的分子机制发现,可以诱导骨肉瘤细胞发生凋亡、坏死和自噬。为了明确小檗胺类化合物在细胞内的分布,我们应用生物素标记的小檗胺和免疫荧光技术对小檗胺在人MNNG/HOS骨肉瘤细胞内的分布进行动态示踪和观察后发现,随着作用时间的延长,小檗胺的分布逐渐向细胞核周边的胞浆集中,并且48小时在细胞核内也可见红色荧光,提示小檗胺有可能进入细胞核内,发挥抗肿瘤活性。进一步对增殖相关的多个信号通路的研究发现,BBD24下调人骨肉瘤MNNG/HOS细胞Wnt/p-catenin信号通路和NF-κB信号通路。对BBD24和临床常用的骨肉瘤化疗药物顺铂联合作用骨肉瘤细胞系MNNG/HOS发现,二者具有协同作用。
本实验收集了8例骨肉瘤患者原代标本,通过MTT测定后发现,小檗胺衍生物BBD24可以有效杀伤原代骨肉瘤细胞,且呈现明显的剂量依赖性,IC50基本在1.0-2.0μg／ml。我们同时收集了4例正常人外周血单个核细胞标本,BBD24对正常细胞的毒性实验提示IC50基本在8.0-10.0μg／ml,明显低于骨肉瘤患者原代细胞。
小檗胺衍生物BBD24对裸鼠骨肉瘤移植模型的作用实验,以3×106／0.2ml细胞浓度接种于背部肩胛附近皮下,造模成功率为100%,接种24h后开始给药,给药时间及剂量为小檗胺衍生物BBD24 10mg／kg,灌胃,一天两次,连续给药20天。结果显示,BBD24可以显著抑制MNNG/HOS移植瘤,且对BALB/c-nu/nu裸鼠没有任何可见的毒副反应。
本研究表明小檗胺衍生物BBD24具有显著地体内外抗骨肉瘤作用,提示其具有一定的临床应用价值和开发前景。
Osteosarcoma is one of the most common types of primary bone tumors for children and adolescents with the incidence of 4-5*10-6 and no difference among various ethnic groups. Current common chemotherapeutic agents for osteosarcoma are adoxorubicin (ADM), cisplatin (DDP), methotrexate (MTX) and the recently-introduced ifosfamide (IFO). Chemotherapy improves outcome of patients with osteosarcoma and to some extent regimens of osteosarcoma have been progressing recently. However, the 5-year survival rate is about 60% during last 2 decades. An endless stream of new drugs emerged in the past 20 years. Patients with lung cancer, for example,have been greatly relieved by new agents. However, few novel effective candidates for osteosarcoma can used for osteosarcoma treatment, except that the combination of Gemcitabine and Yew terpene displays anti-tumor activity for patients with metastasis of bone and soft tissue sarcomas with good tolerance. So the major concern in osteosarcoma treatment is to develop novel chemotherapy agents with more potent anti-tumor activity and low toxicity.
Recent studies showed that berbamine, a natural product extracted from Berber is plants, inhibited the cell growth of a variety of human tumors such as SMMC7721 (hepatoma), HeLa (cervical cancer) and K562 (chronic myeloid leukemia, CML) and HL-60(acute myeloid leukemia, AML), but little is known about the effects of berbamine and derivatives on osteosarcoma. In this study, we investigated the effect and mechanism of BBD24, a novel berbamine derivative, on osteosarcoma in vivo and in vitro. MTT assay showed that BBD24 remarkably inhibited the growth of cell lines MNNG/HOS and MG63 with time-and dose-dependent manners. Cell cycle analysis showed that treatment of tumor cells with BBD24 resulted in cell arrest at G2/M phase. Interestingly, BBD24 could trigger a variety of cell death pathways including apoptosis, necrosis and autophagy. Subcellular distribution investigation using immunofluorescence assay (IFA) with biotinylated berbamine revealed that berbamine was mainly distributed in cytoplasm at 24 hours, but berbamine was predominantly localizated in nucleus at 48 hours. Studies of tumor-related signaling pathways indicated that berbamine derivative BBD24 activated caspase-dependent pathway, and down-regulated NF-kB, AKT, and ERK pathways. Combined treatments of BBD24 with cisplatin (DDP), a commomly-used chemotherapeutic agent for osteosarcoma, on cell line MNNG/HOS confirmed their synergistic effect.
Primary osteosarcoma cells were collected from eight untreated patients and MTT assay showed BBD24 effectively killed these primary cells in a obvious dose-dependent manner with IC50 1.0-2.0μg/ml, meanwhile, PBMCs were also collected from 4 health adults, and MTT assay showed that the IC50 was up to 8.0-10.0μg/ml in general, suggesting that BBD24 selectively inhibit the growth of osteosarcoma cells.
In this study, ostersarcoma xenograft model of nude mice (BALB/c-nu/nu) was used to evaluate the anti-tumor activity of BBD24 in vivo.3×106/0.2ml MNNG/HOS cells were injected subcutaneously near the scapular of mice, and osteosarcoma appeared in all experimental animals at 5 days after injection. BBD24 was orally administered 24 hours after being implanted with MNNG/HOS at 10mg/kg bid for 20 days. Experimental results showed that xenografts of MNNG/HOS were significantly inhibited and no obviously toxic or side effects were observed during experiments.
Taken together, our study results demonstrate berbamine derivative BBD24 posses a potent antitumor activity against osteosarcoma in vivo and in vitro, suggesting that it might be a potential agent for osteosarcoma, and deserving further investigation.
引文
[1]Rosen G, Marcove RC, Caparros B, Nirenberg A, Kosloff C, Huvos AG. Primary osteogenic sarcoma:the rationale for preoperative chemotherapy and delayed surgery. Cancer.1979.43(6):2163-77.
[2]Goorin AM, Schwartzentruber DJ, Devidas M, et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma:Pediatric Oncology Group Study POG-8651. J Clin Oncol.2003. 21(8):1574-80.
[3]Bielack SS, Kempf-Bielack B, Delling G, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk:an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol.2002. 20(3):776-90.
[4]Winkler K, Beron G, Delling G, et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol.1988.6(2):329-37.
[5]Hudson M, Jaffe MR, Jaffe N, et al. Pediatric osteosarcoma:therapeutic strategies, results, and prognostic factors derived from a 10-year experience. J Clin Oncol. 1990.8(12):1988-97.
[6]Rosen G. An opinion supporting the role of high-dose methotrexate in the treatment of osteosarcoma. Cancer Treat Res.1993.62:49-54.
[7]Knight KR, Kraemer DF, Neuwelt EA. Ototoxicity in children receiving platinum chemotherapy:underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol.2005.23(34):8588-96.
[8]Souhami RL, Craft AW, Van der Eijken JW, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma:a study of the European Osteosarcoma Intergroup. Lancet.1997.350(9082):911-7.
[9]Bacci G, Forni C, Ferrari S, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremity:intensification of preoperative treatment does not increase the rate of good histologic response to the primary tumor or improve the final outcome. J Pediatr Hematol Oncol.2003.25(11):845-53.
[10]Zelcer S, Kellick M, Wexler LH, et al. Methotrexate levels and outcome in osteosarcoma. Pediatr Blood Cancer.2005.44(7):638-42.
[11]Rosen G, Caparros B, Huvos AG, et al. Preoperative chemotherapy for osteogenic sarcoma:selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer.1982.49(6):1221-30.
[12]Bacci G, Loro L, Longhi A, et al. No correlation between methotrexate serum level and histologic response in the pre-operative treatment of extremity osteosarcoma. Anticancer Drugs.2006.17(4):411-5.
[13]Wunder JS, Bull SB, Aneliunas V, et al. MDR1 gene expression and outcome in osteosarcoma:a prospective, multicenter study. J Clin Oncol.2000.18(14): 2685-94.
[14]Bacci G, Picci P, Ferrari S, et al. Prognostic significance of serum alkaline pMNNG/HOSphatase measurements in patients with osteosarcoma treated with adjuvant or neoadjuvant chemotherapy. Cancer.1993.71(4):1224-30.
[15]Saeter G, Alvegard TA, Elomaa I, Stenwig AE, Holmstrom T, Solheim OP. Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate:a Scandinavian Sarcoma Group study. J Clin Oncol.1991.9(10): 1766-75.
[16]Provisor AJ, Ettinger LJ, Nachman JB, et al. Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: a report from the Children's Cancer Group. J Clin Oncol.1997.15(1):76-84.
[17]Navid F, Willert JR, McCarville MB, et al. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer.2008.113(2):419-25.
[18]Ren, Y., Lu, L., Guo, T.B., Qiu, J., Yang, Y., Liu, A. and Zhang, J.Z. Novel immunomodulatory properties of berbamine through selective down-regulation of STAT4 and action of IFN-gamma in experimental autoimmune encephalomyelitis. J Immunol,2008,181:1491-8.
[19]Zhao, X.Y., He, Z.W., Wu, D. and Xu, R.Z. Berbamine selectively induces apoptosis of human acute promyelocytic leukemia cells via survivin-mediated pathway. Chin Med J(Engl),2007,120:802-6.
[20]Wu, D., Lin, M.F. and Zhao, X.Y. [Effects of berbamine on K562 cells and its mechanisms in vitro and in vivo]. Zhongguo Shi Yan Xue Ye Xue Za Zhi,2005,13: 373-8.
[21]黄志煜,董庆华.小檗胺诱导人白血病Jurkat细胞凋亡的实验研究.中国肿瘤2007,16：722-724.
[22]Xu, R., Dong, Q., Yu, Y., Zhao, X., Gan, X., Wu, D., Lu, Q., Xu, X. and Yu, X.F. Berbamine:a novel inhibitor of bcr/abl fusion gene with potent anti-leukemia activity. Leuk Res,2006,30:17-23.
[23]Sun, J.R., Zhang, X.H., He, Z.W., Gu, Y., Yu, Y.Z., Fang, Y.M., Lu, Q.H., Dong, Q.H. and Xu, R.Z. [The mechanism of apoptosis of chronic myeloid leukemia cells induced by the novel p210 bcr/abl inhibitor berbamine]. Zhonghua Yi Xue Za Zhi,2006,86:2246-51.
[24]Dong, Q.H., Zheng, S., Xu, R.Z., Lu, Q. and He, L. [Study on effect of berbamine on multidrug resistance leukemia K562/Adr cells]. Zhongguo Zhong Xi Yi Jie He Za Zhi,2004,24:820-2.
[25]孙鹏,吕家驹,赵勇.小檗胺诱导前列腺癌PC-3细胞凋亡及其机制.中华实验外科杂志，2007,24：957-959.
[26]Wang, G.Y., Zhang, J.W., Lu, Q.H., Xu, R.Z. and Dong, Q.H. Berbamine induces apoptosis in human hepatoma cell line SMMC7721 by loss in mitochondrial transmembrane potential and caspase activation.J Zhejiang Univ Sci B,2007,8: 248-55.
[27]Ng, L.T., Chiang, L.C., Lin, Y.T. and Lin, C.C. Antiproliferative and apoptotic effects of tetrandrine on different human hepatoma cell lines. Am J Chin Med, 2006,34:125-35.
[28]Liu, B., Wang, T., Qian, X., Liu, G., Yu, L. and Ding, Y. Anticancer effect of tetrandrine on primary cancer cells isolated from ascites and pleural fluids. Cancer Lett,2008,268:166-75.
[29]Chen, Y., Chen, J.C. and Tseng, S.H. Tetrandrine suppresses tumor growth and angiogenesis of gliomas in rats. Int J Cancer.2008.
[30]Liu, J., Qi, S., Zhu, H., Zhang, J., Li, Z. and Wang, T. The effect of calmodulin antagonist berbaminederivative-EBB on hepatoma in vitro and in vivo. Chin Med J (Engl),2002,115:759-62.
[31]Fang, B.J., Yu, M.L., Yang, S.G., Liao, L.M., Liu, J.W. and Zhao, R.C. Effect of O-4-ethoxyl-butyl-berbamine in combination with pegylated liposomal doxorubicin on advanced hepatoma in mice. World J Gastroenterol,2004,10: 950-3.
[32]Edinger, A.L. and Thompson, C.B. Death by design:apoptosis, necrosis and autophagy. Curr Opin Cell Biol,2004,16:663-9.
[33]Majno, G. and I. Joris, Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol,1995.146(1):p.3-15.
[34]Elmore, S. Apoptosis:a review of programmed cell death. Toxicol Pathol,2007, 35:495-516.
[35]Ghobrial, I.M., Witzig, T.E. and Adjei, A.A. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin,2005,55:178-94.
[36]Youle, R.J. and Strasser, A. The BCL-2 protein family:opposing activities that mediate cell death. Nat Rev Mol Cell Biol,2008,9:47-59.
[37]D. Gozuacik, A. Kimchi. Autophagy as a cell death and tumor suppressor mechanism[J]. Oncogene,2004(23):2891-2906.
[38]S. Jin, E. White. Role of autophagy in cancer:management of metabolic stress[J]. Autophagy,2007(3):28-31.
[39]D. Gozuacik, A. Kimchi. Autophagy and cell death[J]. Curr Top Dev Biol, 2007(78):217-245.
[40]R.K. Amaravadi, C.B. Thompson. The roles of therapy-induced autophagy and necrosis in cancer treatment[J]. Clin Cancer Res,2007(13):7271-7279.
[41]R. Mathew, V. Karantza-Wadsworth, E. White. Role of autophagy in cancer[J]. Nat Rev Cancer,2007(7):961-967.
[42]D.J. Klionsky. The molecular machinery of autophagy:unanswered questions[J]. J Cell Sci,2005(118):7-18.
[43]Sperandio S, de Belle I, Bredesen DE. An alternative, nonapoptotic form of programmed cell death. ProcNatl Acad Sci U S A 2000;97(26):14376-81.
[44]Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G. Cell death by mitotic catastrophe:a molecular definition. Oncogene 2004;23(16):2825-37.
[45]Gilmore AP. Anoikis. Cell Death Differ 2005;12 Suppl 2:1473-7.
[46]Kupeli, E., Kosar, M., Yesilada, E., Husnu, K. and Baser, C. A comparative study on the anti-inflammatory, antinociceptive and antipyretic effects of isoquinoline alkaloids from the roots of Turkish Berberis species. Life Sci,2002,72:645-57.
[47]Cao, L., Luo, C., Bian, Q. and Xiao, P. Anti-inflammatory activity of berbamine. Jounal of Cinese pharmaceutical sciences,1999,8:93-94
[48]Anuchapreeda S, Leechanachai P, Smith MM, et al. Modulation of P-glycoprotein expression and function by curcumin in multidrug-resistant human KB cells. Biochem Pharmacol 2002;64:573-582.
[49]Limtrakul P, Anuchapreeda S, Buddhasukh D. Modulation of human multidrug-resistance MDR-1 gene by natural curcuminoids. BMC Cancer 2004;4:13.
[50]Wei D, Mei Y, Liu J. Quantification of doxorubicin and validation of reversal effect of tea polyphenols on multidrug resistance in human carcinoma cells. Biotechnol Lett 2003;25(4):291-4.
[51]Zhu A, Wang X, Guo Z. Study of tea polyphenol as a reversal agent for carcinoma cell lines'multidrug resistance (study of TP as a MDR reversal agent). Nucl Med Biol 2001;28(6):735-40.
[52]Castro AF, Altenberg GA. Inhibition of drug transport by genistein in multidrug-resistant cells expressing P-glycoprotein. Biochem Pharmacol 1997;53:89-93.
[53]Pan Q, Wang T, Lu Q, Hu X. Schisandrin B-a novel inhibitor of P-glycoprotein. Biochem Biophys Res Comm 2005;335:406-411.
[54]Perkins S, Richard D, Hill K, et al. Chemopreventive Efficacy and Pharmacokinetics of Curcumin in the Min/+ Mouse, a Model of Familial Adenomatous Polyposis. Cancer Epidemiology, Biomarkers & Prevention 2002;11: 535-540.
[55]Sharma RA, Gescher AJ, Steward WP. Curcumin:The story so far. European Journal of Cancer 2005;41:1955-1968.
[56]Jiang, B.H. and Liu, L.Z. PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim Biophys Acta,2008,1784:150-8.
[57]Chen, B.A., Qian, X.J., Cheng, J. and Gao, F. [Effect of tetrandrine combined with Droloxifen on the expression of bcr/abl of K562 at both mRNA and protein levels]. Zhongguo Shi Yan Xue Ye Xue Za Zhi,2005,,13:95-9.
[58]Ng, L.T., Chiang, L.C., Lin, Y.T. and Lin, C.C. Antiproliferative and apoptotic effects of tetrandrine on different human hepatoma cell lines. Am J Chin Med, 2006,34:125-35.
[59]Liu, B., Wang, T., Qian, X., Liu, G., Yu, L. and Ding, Y. Anticancer effect of tetrandrine on primary cancer cells isolated from ascites and pleural fluids. Cancer Lett,2008,268:166-75.
[60]Chen, Y, Chen, J.C. and Tseng, S.H. Tetrandrine suppresses tumor growth and angiogenesis of gliomas in rats. Int J Cancer.2008.
[61]Zhu, X., Sui, M. and Fan, W. In vitro and in vivo characterizations of tetrandrine on the reversal of P-glycoprotein-mediated drug resistance to paclitaxel. Anticancer Res,2005,25:1953-62.
[1]Grimer RJ, Belthur M, Carter SR, and et al. Extendible replacements of the proximal tibia for bone tumours. J Bone Joint Surg Br.2000,82(2):255-60
[2]Letson GD, Amato GD, Windham CH, et al. Extendable prostheses for the treatment of malignant bone tumors in growing children. Curr Opin Orthop, 2003,14:413-18.
[3]Muscolo DL, Ayerza MA, Aponte-Tinao LA, et al. Partial epiphyseal preservation and intercalary allograft reconstruction in high-grade metaphyseal osteosarcoma of the knee. J Bone Joint Surg Am 2005;87 S 1:226-36
[4]San-Julian M, Aquerreta JD, Benito A, and et al. Indications for epiphyseal preservation in metaphyseal malignant bone tumors of children:relationship between image methods and histological findings. J Pediatr Orthop. 1999;19(4):543-8.
[5]Manfrini M, Gasbarrini A, Malaguti C, and et al. Intraepiphyseal resection of the proximal tibia and its impact on lower limb growth.Clin Orthop Relat Res.1999 Jan;(358):111-9
[6]Kumta SM, Chow TC, Griffith J, and et al. Classifying the location of osteosarcoma with reference to the epiphyseal plate helps determine the optimal skeletal resection in limb salvage procedures. Arch Orthop Trauma Surg. 1999;119(5-6):327-31
[7]Bacci G, Ferrari S, Longhi A, et al. Non metastatic osteosarcoma of the extremity with pathologic fracture at presentation. Acta Orthop Scand 2003;74(4):449-54.
[8]Abudu A, Sferopoulos NK, Tillman RM, et al. The surgical treatment and outcome of pathological fractures in localized osteosarcoma. J Bone Joint Surg Br 1996;78:694-8.
[9]Scully SP, Ghert MA, Zurakowski D, et al. Pathologic fracture in osteosarcoma: prognostic importance and treatment implications. J Bone Joint Surg Am 2002;84:49-57.
[10]Papagelopoulos PJ, Mavrogenis AF, Savvidou OD, Benetos IS, Galanis EC, Soucacos PN Pathological fractures in primary bone sarcomas.Injury.2008, 39(4):395-403.
[11]Frassica FJ, Chao E, Sim F. Special problems in limb-salvage surgery. Semin Surg Oncol 1997;13:55-63.
[12]Thompson Jr RC, Pritchard DJ, Nelson TE. Pathologic fractures in osteosarcoma. J Bone Joint Surg Br 1992;74B(SIII):277.
[13]Ebeid W, Amin S, Abdelmegid A Limb salvage management of pathologic fractures of primary malignant bone tumors. Cancer Control.2005,12(1):57-61.
[14]Nathan SS, Gorlick R, Bukata S, Chou A, and et al.Treatment algorithm for locally recurrent osteosarcoma based on local disease free interval and the presence of lung metastasis. Cancer.2006,107(7):1607-16.
[15]Grimer RJ, Taminiau AM, Cannon SR. Surgical outcomes in osteosarcoma. J Bone Joint Surg Br.2002;84:395-400.
[16]Bacci G., Longhi A, Cesari M, and et al. Influence of local recurrence on survival in patients with extremity osteosarcoma treated with neoadjuvant chemotherapy: the experience of a single institution with 44 patients. Cancer.2006,106(12): 2701-6.
[17]Takeuchi A, Lewis VO, Yasko AW, and et al. Long-term Clinical Outcome of the Patient with Locally Recurrent Osteosarcoma.
[18]Bacci G, Ferrari S, Longhi A, et al. Pattern of relapse in patients with osteosarcoma of the extremities treated with neoadjuvant chemotherapy. Eur J Cancer.2001;37:32-38.
[19]Picci P. Osteosarcoma:relationship of response to preoperative chemotherapy and type of surgery to local recurrence. J Clin Oncol 1994; 12:2699-705.
[1]Rytting M, Pearson P, Raymond AK, et al. Osteosarcoma in preadolescent patients. Clin Orthop Relat Res.2000. (373):39-50.
[2]Fraumeni JF Jr. Stature and malignant tumors of bone in childhood and adolescence. Cancer.1967.20(6):967-73.
[3]Campanacci M, Bacci G, Bertoni F, Picci P, Minutillo A, Franceschi C. The treatment of osteosarcoma of the extremities:twenty year's experience at the Istituto Ortopedico Rizzoli. Cancer.1981.48(7):1569-81.
[4]Enneking WF. Advances and treatment of primary bone tumors. J Fla Med Assoc.1979.66(1):28-30.
[5]Rosenburg SA, Chabner BA, Young RC, et al. Treatment of osteogenic sarcoma. I. Effect of adjuvant high-dose methotrexate after amputation. Cancer Treat Rep. 1979.63(5):739-51.
[6]Meyers PA, Heller G, Healey J, et al. Chemotherapy for nonmetastatic osteogenic sarcoma:the Memorial Sloan-Kettering experience. J Clin Oncol. 1992.10(1):5-15.
[7]Avella M, Bacci G, McDonald DJ, Di SM, Picci P, Campanacci M. Adjuvant chemotherapy with six drugs (adriamycin, methotrexate, cisplatinum, bleomycin, cyclophosphamide and dactinomycin) for non-metastatic high grade osteosarcoma of the extremities. Results of 32 patients and comparison to 127 patients concomitantly treated with the same drugs in a neoadjuvant form. Chemioterapia.1988.7(2):133-7.
[8]Bacci G, Ferrari S, Longhi A, et al. High dose ifosfamide in combination with high dose methotrexate, adriamycin and cisplatin in the neoadjuvant treatment of extremity osteosarcoma:preliminary results of an Italian Sarcoma Group/Scandinavian Sarcoma Group pilot study. J Chemother.2002.14(2): 198-206.
[9]Ninane J, Baurain R, de Kraker J, Ferster A, Trouet A, Cornu G. Alkylating activity in serum, urine, and CSF following high-dose ifosfamide in children. Cancer Chemother Pharmacol.1989.24 Suppl 1:S2-6; discussion S7.
[10]Bacci G, Forni C, Ferrari S, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremity:intensification of preoperative treatment does not increase the rate of good histologic response to the primary tumor or improve the final outcome. J Pediatr Hematol Oncol.2003.25(11):845-53.
[11]Rosen G, Caparros B, Huvos AG, et al. Preoperative chemotherapy for osteogenic sarcoma:selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer.1982. 49(6):1221-30.
[12]Rosen G, Caparros B, Huvos AG, et al. Preoperative chemotherapy for osteogenic sarcoma:selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer.1982. 49(6):1221-30.
[13]Rosen G, Marcove RC, Caparros B, Nirenberg A, Kosloff C, Huvos AG. Primary osteogenic sarcoma:the rationale for preoperative chemotherapy and delayed surgery. Cancer.1979.43(6):2163-77.
[14]Goorin AM, Schwartzentruber DJ, Devidas M, et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma:Pediatric Oncology Group Study POG-8651. J Clin Oncol.2003. 21(8):1574-80.
[15]Bielack SS, Kempf-Bielack B, Delling G, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk:an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002.20(3):776-90.
[16]Winkler K, Beron G, Delling G, et al. Neoadjuvant chemotherapy of osteosarcoma:results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol.1988.6(2): 329-37.
[17]Hudson M, Jaffe MR, Jaffe N, et al. Pediatric osteosarcoma:therapeutic strategies, results, and prognostic factors derived from a 10-year experience. J Clin Oncol.1990.8(12):1988-97.
[18]Glasser DB, Lane JM, Huvos AG, Marcove RC, Rosen G. Survival, prognosis, and therapeutic response in osteogenic sarcoma. The Memorial Hospital experience. Cancer.1992.69(3):698-708.
[19]Bacci G, Bertoni F, Longhi A, et al. Neoadjuvant chemotherapy for high-grade central osteosarcoma of the extremity. Histologic response to preoperative chemotherapy correlates with histologic subtype of the tumor. Cancer.2003. 97(12):3068-75.
[20]Goorin AM, Schwartzentruber DJ, Devidas M, et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma:Pediatric Oncology Group Study POG-8651. J Clin Oncol.2003. 21(8):1574-80.
[21]Jaffe N, Prudich J, Knapp J, et al. Treatment of primary osteosarcoma with intra-arterial and intravenous high-dose methotrexate. J Clin Oncol.1983.1(7): 428-31.
[22]Bielack SS, Bieling P, Erttmann R, Winkler K. Intraarterial chemotherapy for osteosarcoma:does the result really justify the effort. Cancer Treat Res.1993.62: 85-92.
[23]Fuchs N, Bielack SS, Epler D, et al. Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group's protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol.1998.9(8):893-9.
[24]Bacci G, Ferrari S, Bertoni F, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol:an updated report. J Clin Oncol.2000.18(24):4016-27.
[25]Bielack S, Kempf-Bielack B, Schwenzer D, et al. [Neoadjuvant therapy for localized osteosarcoma of extremities. Results from the Cooperative osteosarcoma study group COSS of 925 patients]. Klin Padiatr.1999.211(4): 260-70.
[26]Souhami RL, Craft AW, Van der Eijken JW, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma:a study of the European Osteosarcoma Intergroup. Lancet.1997.350(9082):911-7.
[27]Smeland S, Muller C, Alvegard TA, et al. Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII:prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders. Eur J Cancer.2003.39(4):488-94.
[28]Bacci G, Ferrari S, Longhi A, et al. High dose ifosfamide in combination with high dose methotrexate, adriamycin and cisplatin in the neoadjuvant treatment of extremity osteosarcoma:preliminary results of an Italian Sarcoma Group/Scandinavian Sarcoma Group pilot study. J Chemother.2002.14(2): 198-206.
[29]Ferrari S, Smeland S, Mercuri M, et al. Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity:a joint study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol.2005.23(34):8845-52.
[30]Bruland OS, Pihl A. On the current management of osteosarcoma. A critical evaluation and a proposal for a modified treatment strategy. Eur J Cancer.1997. 33(11):1725-31.
[31]Oeffinger KC, Hudson MM. Long-term complications following childhood and adolescent cancer:foundations for providing risk-based health care for survivors. CA Cancer J Clin.2004.54(4):208-36.
[32]Kremer LC, van DEC, Offringa M, Voute PA. Frequency and risk factors of anthracycline-induced clinical heart failure in children:a systematic review. Ann Oncol.2002.13(4):503-12.
[33]Geidel S, Garn M, Gravinghoff L, et al. [Cardiomyopathy after osteosarcoma treatment:a contribution to the cardiotoxicity of adriamycin]. Klin Padiatr.1991. 203(4):257-61.
[34]Meadows AT, Baum E, Fossati-Bellani F, et al. Second malignant neoplasms in children:an update from the Late Effects Study Group. J Clin Oncol.1985.3(4): 532-8.
[35]Hawkins MM, Draper GJ, Kingston JE. Incidence of second primary tumours among childhood cancer survivors. Br J Cancer.1987.56(3):339-47.
[36]Pratt CB, Meyer WH, Luo X, et al. Second malignant neoplasms occuring in survivors of osteosarcoma. Cancer.1997.80(5):960-5.
[37]Aung L, Gorlick RG, Shi W, et al. Second malignant neoplasms in long-term survivors of osteosarcoma:Memorial Sloan-Kettering Cancer Center Experience. Cancer.2002.95(8):1728-34.
[38]Longhi A, Macchiagodena M, Vitali G, Bacci G. Fertility in male patients treated with neoadjuvant chemotherapy for osteosarcoma. J Pediatr Hematol Oncol. 2003.25(4):292-6.
[39]Longhi A, Porcu E, Petracchi S, Versari M, Conticini L, Bacci G. Reproductive functions in female patients treated with adjuvant and neoadjuvant chemotherapy for localized osteosarcoma of the extremity. Cancer.2000.89(9): 1961-5.
[40]Zelcer S, Kellick M, Wexler LH, et al. Methotrexate levels and outcome in osteosarcoma. Pediatr Blood Cancer.2005.44(7):638-42.
[41]Bacci G, Loro L, Longhi A, et al. No correlation between methotrexate serum level and histologic response in the pre-operative treatment of extremity osteosarcoma. Anticancer Drugs.2006.17(4):411-5.
[42]Wunder JS, Bull SB, Aneliunas V, et al. MDR1 gene expression and outcome in osteosarcoma:a prospective, multicenter study. J Clin Oncol.2000.18(14): 2685-94.
[43]Bacci G, Picci P, Ferrari S, et al. Prognostic significance of serum alkaline phosphatase measurements in patients with osteosarcoma treated with adjuvant or neoadjuvant chemotherapy. Cancer.1993.71(4):1224-30.
[44]Saeter G, Alvegard TA, Elomaa I, Stenwig AE, Holmstrom T, Solheim OP. Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate:a Scandinavian Sarcoma Group study. J Clin Oncol. 1991.9(10):1766-75.
[45]Provisor AJ, Ettinger LJ, Nachman JB, et al. Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy:a report from the Children's Cancer Group. J Clin Oncol.1997. 15(1):76-84.
[46]Edmonson JH, Long HJ, Kvols LK, Mann BS, Grill JP. Can molgramostim enhance the antitumor effects of cytotoxic drugs in patients with advanced sarcomas. Ann Oncol.1997.8(7):637-41.
[47]Anderson PM, Markovic SN, Sloan JA, et al. Aerosol granulocyte macrophage-colony stimulating factor:a low toxicity, lung-specific biological therapy in patients with lung metastases. Clin Cancer Res.1999.5(9):2316-23.
[48]Rao RD, Anderson PM, Arndt CA, Wettstein PJ, Markovic SN. Aerosolized granulocyte macrophage colony-stimulating factor (GM-CSF) therapy in metastatic cancer. Am J Clin Oncol.2003.26(5):493-8.
[49]Meyers PA, Schwartz CL, Krailo M, et al. Osteosarcoma:a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol.2005.23(9): 2004-11.
[50]Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma:the addition of muramyl tripeptide to chemotherapy improves overall survival-a report from the Children's Oncology Group. J Clin Oncol.2008.26(4):633-8.
[51]Nilsonne U, Brostrom LA, Aparisi T. Local tumour resection in interferon treated osteosarcoma patients. Ann Chir Gynaecol.1995.84(1):63-70.
[52]Edmonson JH, Long HJ, Frytak S, Smithson WA, Itri LM. Phase Ⅱ study of recombinant alfa-2a interferon in patients with advanced bone sarcomas. Cancer Treat Rep.1987.71(7-8):747-8.
[53]Smeland S, Muller C, Alvegard TA, et al. Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII:prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders. Eur J Cancer.2003.39(4):488-94.
[54]Ma J, Pollak MN, Giovannucci E, et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst.1999.91(7):620-5.
[55]Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like growth factor-I and prostate cancer risk:a prospective study. Science.1998.279(5350): 563-6.
[56]Pollak MN, Polychronakos C, Richard M. Insulinlike growth factor I:a potent mitogen for human osteogenic sarcoma. J Natl Cancer Inst.1990.82(4):301-5.
[57]Ouban A, Muraca P, Yeatman T, Coppola D. Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas. Hum Pathol.2003. 34(8):803-8.
[58]Shimizu C, Hasegawa T, Tani Y, et al. Expression of insulin-like growth factor 1 receptor in primary breast cancer:immunohistochemical analysis. Hum Pathol. 2004.35(12):1537-42.
[59]Mansky PJ, Liewehr DJ, Steinberg SM, et al. Treatment of metastatic osteosarcoma with the somatostatin analog OncoLar:significant reduction of insulin-like growth factor-1 serum levels. J Pediatr Hematol Oncol.2002.24(6): 440-6.
[60]Benini S, Baldini N, Manara MC, et al. Redundancy of autocrine loops in human osteosarcoma cells. Int J Cancer.1999.80(4):581-8.
[61]Sachdev D, Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther.2007.6(1):1-12.
[62]Kolb EA, Gorlick R, Houghton PJ, et al. Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the pediatric preclinical testing program. Pediatr Blood Cancer.2008.50(6):1190-7.
[63]Zhou H, Randall RL, Brothman AR, Maxwell T, Coffin CM, Goldsby RE. Her-2/neu expression in osteosarcoma increases risk of lung metastasis and can be associated with gene amplification. J Pediatr Hematol Oncol.2003.25(1): 27-32.
[64]Anninga JK, de Vijver MJ v, Cleton-Jansen AM, et al. Overexpression of the HER-2 oncogene does not play a role in high-grade osteosarcomas. Eur J Cancer. 2004.40(7):963-70.
[65]Maitra A, Wanzer D, Weinberg AG, Ashfaq R. Amplification of the HER-2/neu oncogene is uncommon in pediatric osteosarcomas. Cancer.2001.92(3):677-83.
[66]Hughes DP, Thomas DG, Giordano TJ, Baker LH, McDonagh KT. Cell surface expression of epidermal growth factor receptor and Her-2 with nuclear expression of Her-4 in primary osteosarcoma. Cancer Res.2004.64(6):2047-53.
[67]Gorlick R, Huvos AG, Heller G, et al. Expression of HER2/erbB-2 correlates with survival in osteosarcoma. J Clin Oncol.1999.17(9):2781-8.
[68]McGary EC, Weber K, Mills L, et al. Inhibition of platelet-derived growth factor-mediated proliferation of osteosarcoma cells by the novel tyrosine kinase inhibitor STI571. Clin Cancer Res.2002.8(11):3584-91.
[69]Sulzbacher I, Traxler M, Mosberger I, Lang S, Chott A. Platelet-derived growth factor-AA and-alpha receptor expression suggests an autocrine and/or paracrine loop in osteosarcoma. Mod Pathol.2000.13(6):632-7.
[70]Kubo T, Piperdi S, Rosenblum J, et al. Platelet-derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma. Cancer.2008.112(10):2119-29.
[71]Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer.2007.7(4):295-308.
[72]Bjornsti MA, Houghton PJ. The TOR pathway:a target for cancer therapy. Nat Rev Cancer.2004.4(5):335-48.
[73]Wan X, Helman LJ. The biology behind mTOR inhibition in sarcoma. Oncologist.2007.12(8):1007-18.
[74]Wan X, Mendoza A, Khanna C, Helman LJ. Rapamycin inhibits ezrin-mediated metastatic behavior in a murine model of osteosarcoma. Cancer Res.2005.65(6): 2406-11.
[75]Brose MS, Volpe P, Feldman M, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res.2002.62(23):6997-7000.
[76]Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature.2002.417(6892):949-54.
[77]Karnoub AE, Weinberg RA. Ras oncogenes:split personalities. Nat Rev Mol Cell Biol.2008.9(7):517-31.
[78]Sankhala KK, Pandya DM, Sarantopoulos J, Soefje SA, Giles FJ, Chawla SP. Prevention of chemotherapy induced nausea and vomiting:a focus on aprepitant. Expert Opin Drug Metab Toxicol.2009.5(12):1607-14.
[79]Goel S, Desai K, Karri S, et al. Pharmacokinetic and safety study of weekly irinotecan and oral capecitabine in patients with advanced solid cancers. Invest New Drugs.2007.25(3):237-45.
[80]Leu KM, Ostruszka LJ, Shewach D, et al. Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin Oncol.2004.22(9):1706-12.
[81]Navid F, Willert JR, McCarville MB, et al. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer.2008.113(2):419-25.
[82]Guo W, Healey JH, Meyers PA, et al. Mechanisms of methotrexate resistance in osteosarcoma. Clin Cancer Res.1999.5(3):621-7.
[83]Malempati S, Nicholson HS, Reid JM, et al. Phase Ⅰ trial and pharmacokinetic study of pemetrexed in children with refractory solid tumors:the Children's Oncology Group. J Clin Oncol.2007.25(12):1505-11.
[84]ChouAJ, Bell MD, Mackinson C, et al. Phase Ib/IIa study of sustained release lipid inhalation targeting cisplatin by inhalation in the treatment of patients with relapsed/progressive osteosarcoma metastatic to the lung. ASCO Annual Meeting Proceedings Part I. J. Clin. Oncol.25,18S,9525 (2007).
[2]Goorin AM, Schwartzentruber DJ, Devidas M, et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma:Pediatric Oncology Group Study POG-8651. J Clin Oncol.2003. 21(8):1574-80.
[3]Bielack SS, Kempf-Bielack B, Delling G, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk:an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol.2002. 20(3):776-90.
[4]Winkler K, Beron G, Delling G, et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol.1988.6(2):329-37.
[5]Hudson M, Jaffe MR, Jaffe N, et al. Pediatric osteosarcoma:therapeutic strategies, results, and prognostic factors derived from a 10-year experience. J Clin Oncol. 1990.8(12):1988-97.
[6]Rosen G. An opinion supporting the role of high-dose methotrexate in the treatment of osteosarcoma. Cancer Treat Res.1993.62:49-54.
[7]Knight KR, Kraemer DF, Neuwelt EA. Ototoxicity in children receiving platinum chemotherapy:underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol.2005.23(34):8588-96.
[8]Souhami RL, Craft AW, Van der Eijken JW, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma:a study of the European Osteosarcoma Intergroup. Lancet.1997.350(9082):911-7.
[9]Bacci G, Forni C, Ferrari S, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremity:intensification of preoperative treatment does not increase the rate of good histologic response to the primary tumor or improve the final outcome. J Pediatr Hematol Oncol.2003.25(11):845-53.
[10]Zelcer S, Kellick M, Wexler LH, et al. Methotrexate levels and outcome in osteosarcoma. Pediatr Blood Cancer.2005.44(7):638-42.
[11]Rosen G, Caparros B, Huvos AG, et al. Preoperative chemotherapy for osteogenic sarcoma:selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer.1982.49(6):1221-30.
[12]Bacci G, Loro L, Longhi A, et al. No correlation between methotrexate serum level and histologic response in the pre-operative treatment of extremity osteosarcoma. Anticancer Drugs.2006.17(4):411-5.
[13]Wunder JS, Bull SB, Aneliunas V, et al. MDR1 gene expression and outcome in osteosarcoma:a prospective, multicenter study. J Clin Oncol.2000.18(14): 2685-94.
[14]Bacci G, Picci P, Ferrari S, et al. Prognostic significance of serum alkaline pMNNG/HOSphatase measurements in patients with osteosarcoma treated with adjuvant or neoadjuvant chemotherapy. Cancer.1993.71(4):1224-30.
[15]Saeter G, Alvegard TA, Elomaa I, Stenwig AE, Holmstrom T, Solheim OP. Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate:a Scandinavian Sarcoma Group study. J Clin Oncol.1991.9(10): 1766-75.
[16]Provisor AJ, Ettinger LJ, Nachman JB, et al. Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: a report from the Children's Cancer Group. J Clin Oncol.1997.15(1):76-84.
[17]Navid F, Willert JR, McCarville MB, et al. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer.2008.113(2):419-25.
[18]Ren, Y., Lu, L., Guo, T.B., Qiu, J., Yang, Y., Liu, A. and Zhang, J.Z. Novel immunomodulatory properties of berbamine through selective down-regulation of STAT4 and action of IFN-gamma in experimental autoimmune encephalomyelitis. J Immunol,2008,181:1491-8.
[19]Zhao, X.Y., He, Z.W., Wu, D. and Xu, R.Z. Berbamine selectively induces apoptosis of human acute promyelocytic leukemia cells via survivin-mediated pathway. Chin Med J(Engl),2007,120:802-6.
[20]Wu, D., Lin, M.F. and Zhao, X.Y. [Effects of berbamine on K562 cells and its mechanisms in vitro and in vivo]. Zhongguo Shi Yan Xue Ye Xue Za Zhi,2005,13: 373-8.
[21]黄志煜,董庆华.小檗胺诱导人白血病Jurkat细胞凋亡的实验研究.中国肿瘤2007,16：722-724.
[22]Xu, R., Dong, Q., Yu, Y., Zhao, X., Gan, X., Wu, D., Lu, Q., Xu, X. and Yu, X.F. Berbamine:a novel inhibitor of bcr/abl fusion gene with potent anti-leukemia activity. Leuk Res,2006,30:17-23.
[23]Sun, J.R., Zhang, X.H., He, Z.W., Gu, Y., Yu, Y.Z., Fang, Y.M., Lu, Q.H., Dong, Q.H. and Xu, R.Z. [The mechanism of apoptosis of chronic myeloid leukemia cells induced by the novel p210 bcr/abl inhibitor berbamine]. Zhonghua Yi Xue Za Zhi,2006,86:2246-51.
[24]Dong, Q.H., Zheng, S., Xu, R.Z., Lu, Q. and He, L. [Study on effect of berbamine on multidrug resistance leukemia K562/Adr cells]. Zhongguo Zhong Xi Yi Jie He Za Zhi,2004,24:820-2.
[25]孙鹏,吕家驹,赵勇.小檗胺诱导前列腺癌PC-3细胞凋亡及其机制.中华实验外科杂志，2007,24：957-959.
[26]Wang, G.Y., Zhang, J.W., Lu, Q.H., Xu, R.Z. and Dong, Q.H. Berbamine induces apoptosis in human hepatoma cell line SMMC7721 by loss in mitochondrial transmembrane potential and caspase activation.J Zhejiang Univ Sci B,2007,8: 248-55.
[27]Ng, L.T., Chiang, L.C., Lin, Y.T. and Lin, C.C. Antiproliferative and apoptotic effects of tetrandrine on different human hepatoma cell lines. Am J Chin Med, 2006,34:125-35.
[28]Liu, B., Wang, T., Qian, X., Liu, G., Yu, L. and Ding, Y. Anticancer effect of tetrandrine on primary cancer cells isolated from ascites and pleural fluids. Cancer Lett,2008,268:166-75.
[29]Chen, Y., Chen, J.C. and Tseng, S.H. Tetrandrine suppresses tumor growth and angiogenesis of gliomas in rats. Int J Cancer.2008.
[30]Liu, J., Qi, S., Zhu, H., Zhang, J., Li, Z. and Wang, T. The effect of calmodulin antagonist berbaminederivative-EBB on hepatoma in vitro and in vivo. Chin Med J (Engl),2002,115:759-62.
[31]Fang, B.J., Yu, M.L., Yang, S.G., Liao, L.M., Liu, J.W. and Zhao, R.C. Effect of O-4-ethoxyl-butyl-berbamine in combination with pegylated liposomal doxorubicin on advanced hepatoma in mice. World J Gastroenterol,2004,10: 950-3.
[32]Edinger, A.L. and Thompson, C.B. Death by design:apoptosis, necrosis and autophagy. Curr Opin Cell Biol,2004,16:663-9.
[33]Majno, G. and I. Joris, Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol,1995.146(1):p.3-15.
[34]Elmore, S. Apoptosis:a review of programmed cell death. Toxicol Pathol,2007, 35:495-516.
[35]Ghobrial, I.M., Witzig, T.E. and Adjei, A.A. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin,2005,55:178-94.
[36]Youle, R.J. and Strasser, A. The BCL-2 protein family:opposing activities that mediate cell death. Nat Rev Mol Cell Biol,2008,9:47-59.
[37]D. Gozuacik, A. Kimchi. Autophagy as a cell death and tumor suppressor mechanism[J]. Oncogene,2004(23):2891-2906.
[38]S. Jin, E. White. Role of autophagy in cancer:management of metabolic stress[J]. Autophagy,2007(3):28-31.
[39]D. Gozuacik, A. Kimchi. Autophagy and cell death[J]. Curr Top Dev Biol, 2007(78):217-245.
[40]R.K. Amaravadi, C.B. Thompson. The roles of therapy-induced autophagy and necrosis in cancer treatment[J]. Clin Cancer Res,2007(13):7271-7279.
[41]R. Mathew, V. Karantza-Wadsworth, E. White. Role of autophagy in cancer[J]. Nat Rev Cancer,2007(7):961-967.
[42]D.J. Klionsky. The molecular machinery of autophagy:unanswered questions[J]. J Cell Sci,2005(118):7-18.
[43]Sperandio S, de Belle I, Bredesen DE. An alternative, nonapoptotic form of programmed cell death. ProcNatl Acad Sci U S A 2000;97(26):14376-81.
[44]Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G. Cell death by mitotic catastrophe:a molecular definition. Oncogene 2004;23(16):2825-37.
[45]Gilmore AP. Anoikis. Cell Death Differ 2005;12 Suppl 2:1473-7.
[46]Kupeli, E., Kosar, M., Yesilada, E., Husnu, K. and Baser, C. A comparative study on the anti-inflammatory, antinociceptive and antipyretic effects of isoquinoline alkaloids from the roots of Turkish Berberis species. Life Sci,2002,72:645-57.
[47]Cao, L., Luo, C., Bian, Q. and Xiao, P. Anti-inflammatory activity of berbamine. Jounal of Cinese pharmaceutical sciences,1999,8:93-94
[48]Anuchapreeda S, Leechanachai P, Smith MM, et al. Modulation of P-glycoprotein expression and function by curcumin in multidrug-resistant human KB cells. Biochem Pharmacol 2002;64:573-582.
[49]Limtrakul P, Anuchapreeda S, Buddhasukh D. Modulation of human multidrug-resistance MDR-1 gene by natural curcuminoids. BMC Cancer 2004;4:13.
[50]Wei D, Mei Y, Liu J. Quantification of doxorubicin and validation of reversal effect of tea polyphenols on multidrug resistance in human carcinoma cells. Biotechnol Lett 2003;25(4):291-4.
[51]Zhu A, Wang X, Guo Z. Study of tea polyphenol as a reversal agent for carcinoma cell lines'multidrug resistance (study of TP as a MDR reversal agent). Nucl Med Biol 2001;28(6):735-40.
[52]Castro AF, Altenberg GA. Inhibition of drug transport by genistein in multidrug-resistant cells expressing P-glycoprotein. Biochem Pharmacol 1997;53:89-93.
[53]Pan Q, Wang T, Lu Q, Hu X. Schisandrin B-a novel inhibitor of P-glycoprotein. Biochem Biophys Res Comm 2005;335:406-411.
[54]Perkins S, Richard D, Hill K, et al. Chemopreventive Efficacy and Pharmacokinetics of Curcumin in the Min/+ Mouse, a Model of Familial Adenomatous Polyposis. Cancer Epidemiology, Biomarkers & Prevention 2002;11: 535-540.
[55]Sharma RA, Gescher AJ, Steward WP. Curcumin:The story so far. European Journal of Cancer 2005;41:1955-1968.
[56]Jiang, B.H. and Liu, L.Z. PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim Biophys Acta,2008,1784:150-8.
[57]Chen, B.A., Qian, X.J., Cheng, J. and Gao, F. [Effect of tetrandrine combined with Droloxifen on the expression of bcr/abl of K562 at both mRNA and protein levels]. Zhongguo Shi Yan Xue Ye Xue Za Zhi,2005,,13:95-9.
[58]Ng, L.T., Chiang, L.C., Lin, Y.T. and Lin, C.C. Antiproliferative and apoptotic effects of tetrandrine on different human hepatoma cell lines. Am J Chin Med, 2006,34:125-35.
[59]Liu, B., Wang, T., Qian, X., Liu, G., Yu, L. and Ding, Y. Anticancer effect of tetrandrine on primary cancer cells isolated from ascites and pleural fluids. Cancer Lett,2008,268:166-75.
[60]Chen, Y, Chen, J.C. and Tseng, S.H. Tetrandrine suppresses tumor growth and angiogenesis of gliomas in rats. Int J Cancer.2008.
[61]Zhu, X., Sui, M. and Fan, W. In vitro and in vivo characterizations of tetrandrine on the reversal of P-glycoprotein-mediated drug resistance to paclitaxel. Anticancer Res,2005,25:1953-62.
[1]Grimer RJ, Belthur M, Carter SR, and et al. Extendible replacements of the proximal tibia for bone tumours. J Bone Joint Surg Br.2000,82(2):255-60
[2]Letson GD, Amato GD, Windham CH, et al. Extendable prostheses for the treatment of malignant bone tumors in growing children. Curr Opin Orthop, 2003,14:413-18.
[3]Muscolo DL, Ayerza MA, Aponte-Tinao LA, et al. Partial epiphyseal preservation and intercalary allograft reconstruction in high-grade metaphyseal osteosarcoma of the knee. J Bone Joint Surg Am 2005;87 S 1:226-36
[4]San-Julian M, Aquerreta JD, Benito A, and et al. Indications for epiphyseal preservation in metaphyseal malignant bone tumors of children:relationship between image methods and histological findings. J Pediatr Orthop. 1999;19(4):543-8.
[5]Manfrini M, Gasbarrini A, Malaguti C, and et al. Intraepiphyseal resection of the proximal tibia and its impact on lower limb growth.Clin Orthop Relat Res.1999 Jan;(358):111-9
[6]Kumta SM, Chow TC, Griffith J, and et al. Classifying the location of osteosarcoma with reference to the epiphyseal plate helps determine the optimal skeletal resection in limb salvage procedures. Arch Orthop Trauma Surg. 1999;119(5-6):327-31
[7]Bacci G, Ferrari S, Longhi A, et al. Non metastatic osteosarcoma of the extremity with pathologic fracture at presentation. Acta Orthop Scand 2003;74(4):449-54.
[8]Abudu A, Sferopoulos NK, Tillman RM, et al. The surgical treatment and outcome of pathological fractures in localized osteosarcoma. J Bone Joint Surg Br 1996;78:694-8.
[9]Scully SP, Ghert MA, Zurakowski D, et al. Pathologic fracture in osteosarcoma: prognostic importance and treatment implications. J Bone Joint Surg Am 2002;84:49-57.
[10]Papagelopoulos PJ, Mavrogenis AF, Savvidou OD, Benetos IS, Galanis EC, Soucacos PN Pathological fractures in primary bone sarcomas.Injury.2008, 39(4):395-403.
[11]Frassica FJ, Chao E, Sim F. Special problems in limb-salvage surgery. Semin Surg Oncol 1997;13:55-63.
[12]Thompson Jr RC, Pritchard DJ, Nelson TE. Pathologic fractures in osteosarcoma. J Bone Joint Surg Br 1992;74B(SIII):277.
[13]Ebeid W, Amin S, Abdelmegid A Limb salvage management of pathologic fractures of primary malignant bone tumors. Cancer Control.2005,12(1):57-61.
[14]Nathan SS, Gorlick R, Bukata S, Chou A, and et al.Treatment algorithm for locally recurrent osteosarcoma based on local disease free interval and the presence of lung metastasis. Cancer.2006,107(7):1607-16.
[15]Grimer RJ, Taminiau AM, Cannon SR. Surgical outcomes in osteosarcoma. J Bone Joint Surg Br.2002;84:395-400.
[16]Bacci G., Longhi A, Cesari M, and et al. Influence of local recurrence on survival in patients with extremity osteosarcoma treated with neoadjuvant chemotherapy: the experience of a single institution with 44 patients. Cancer.2006,106(12): 2701-6.
[17]Takeuchi A, Lewis VO, Yasko AW, and et al. Long-term Clinical Outcome of the Patient with Locally Recurrent Osteosarcoma.
[18]Bacci G, Ferrari S, Longhi A, et al. Pattern of relapse in patients with osteosarcoma of the extremities treated with neoadjuvant chemotherapy. Eur J Cancer.2001;37:32-38.
[19]Picci P. Osteosarcoma:relationship of response to preoperative chemotherapy and type of surgery to local recurrence. J Clin Oncol 1994; 12:2699-705.
[1]Rytting M, Pearson P, Raymond AK, et al. Osteosarcoma in preadolescent patients. Clin Orthop Relat Res.2000. (373):39-50.
[2]Fraumeni JF Jr. Stature and malignant tumors of bone in childhood and adolescence. Cancer.1967.20(6):967-73.
[3]Campanacci M, Bacci G, Bertoni F, Picci P, Minutillo A, Franceschi C. The treatment of osteosarcoma of the extremities:twenty year's experience at the Istituto Ortopedico Rizzoli. Cancer.1981.48(7):1569-81.
[4]Enneking WF. Advances and treatment of primary bone tumors. J Fla Med Assoc.1979.66(1):28-30.
[5]Rosenburg SA, Chabner BA, Young RC, et al. Treatment of osteogenic sarcoma. I. Effect of adjuvant high-dose methotrexate after amputation. Cancer Treat Rep. 1979.63(5):739-51.
[6]Meyers PA, Heller G, Healey J, et al. Chemotherapy for nonmetastatic osteogenic sarcoma:the Memorial Sloan-Kettering experience. J Clin Oncol. 1992.10(1):5-15.
[7]Avella M, Bacci G, McDonald DJ, Di SM, Picci P, Campanacci M. Adjuvant chemotherapy with six drugs (adriamycin, methotrexate, cisplatinum, bleomycin, cyclophosphamide and dactinomycin) for non-metastatic high grade osteosarcoma of the extremities. Results of 32 patients and comparison to 127 patients concomitantly treated with the same drugs in a neoadjuvant form. Chemioterapia.1988.7(2):133-7.
[8]Bacci G, Ferrari S, Longhi A, et al. High dose ifosfamide in combination with high dose methotrexate, adriamycin and cisplatin in the neoadjuvant treatment of extremity osteosarcoma:preliminary results of an Italian Sarcoma Group/Scandinavian Sarcoma Group pilot study. J Chemother.2002.14(2): 198-206.
[9]Ninane J, Baurain R, de Kraker J, Ferster A, Trouet A, Cornu G. Alkylating activity in serum, urine, and CSF following high-dose ifosfamide in children. Cancer Chemother Pharmacol.1989.24 Suppl 1:S2-6; discussion S7.
[10]Bacci G, Forni C, Ferrari S, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremity:intensification of preoperative treatment does not increase the rate of good histologic response to the primary tumor or improve the final outcome. J Pediatr Hematol Oncol.2003.25(11):845-53.
[11]Rosen G, Caparros B, Huvos AG, et al. Preoperative chemotherapy for osteogenic sarcoma:selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer.1982. 49(6):1221-30.
[12]Rosen G, Caparros B, Huvos AG, et al. Preoperative chemotherapy for osteogenic sarcoma:selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer.1982. 49(6):1221-30.
[13]Rosen G, Marcove RC, Caparros B, Nirenberg A, Kosloff C, Huvos AG. Primary osteogenic sarcoma:the rationale for preoperative chemotherapy and delayed surgery. Cancer.1979.43(6):2163-77.
[14]Goorin AM, Schwartzentruber DJ, Devidas M, et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma:Pediatric Oncology Group Study POG-8651. J Clin Oncol.2003. 21(8):1574-80.
[15]Bielack SS, Kempf-Bielack B, Delling G, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk:an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002.20(3):776-90.
[16]Winkler K, Beron G, Delling G, et al. Neoadjuvant chemotherapy of osteosarcoma:results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol.1988.6(2): 329-37.
[17]Hudson M, Jaffe MR, Jaffe N, et al. Pediatric osteosarcoma:therapeutic strategies, results, and prognostic factors derived from a 10-year experience. J Clin Oncol.1990.8(12):1988-97.
[18]Glasser DB, Lane JM, Huvos AG, Marcove RC, Rosen G. Survival, prognosis, and therapeutic response in osteogenic sarcoma. The Memorial Hospital experience. Cancer.1992.69(3):698-708.
[19]Bacci G, Bertoni F, Longhi A, et al. Neoadjuvant chemotherapy for high-grade central osteosarcoma of the extremity. Histologic response to preoperative chemotherapy correlates with histologic subtype of the tumor. Cancer.2003. 97(12):3068-75.
[20]Goorin AM, Schwartzentruber DJ, Devidas M, et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma:Pediatric Oncology Group Study POG-8651. J Clin Oncol.2003. 21(8):1574-80.
[21]Jaffe N, Prudich J, Knapp J, et al. Treatment of primary osteosarcoma with intra-arterial and intravenous high-dose methotrexate. J Clin Oncol.1983.1(7): 428-31.
[22]Bielack SS, Bieling P, Erttmann R, Winkler K. Intraarterial chemotherapy for osteosarcoma:does the result really justify the effort. Cancer Treat Res.1993.62: 85-92.
[23]Fuchs N, Bielack SS, Epler D, et al. Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group's protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol.1998.9(8):893-9.
[24]Bacci G, Ferrari S, Bertoni F, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol:an updated report. J Clin Oncol.2000.18(24):4016-27.
[25]Bielack S, Kempf-Bielack B, Schwenzer D, et al. [Neoadjuvant therapy for localized osteosarcoma of extremities. Results from the Cooperative osteosarcoma study group COSS of 925 patients]. Klin Padiatr.1999.211(4): 260-70.
[26]Souhami RL, Craft AW, Van der Eijken JW, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma:a study of the European Osteosarcoma Intergroup. Lancet.1997.350(9082):911-7.
[27]Smeland S, Muller C, Alvegard TA, et al. Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII:prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders. Eur J Cancer.2003.39(4):488-94.
[28]Bacci G, Ferrari S, Longhi A, et al. High dose ifosfamide in combination with high dose methotrexate, adriamycin and cisplatin in the neoadjuvant treatment of extremity osteosarcoma:preliminary results of an Italian Sarcoma Group/Scandinavian Sarcoma Group pilot study. J Chemother.2002.14(2): 198-206.
[29]Ferrari S, Smeland S, Mercuri M, et al. Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity:a joint study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol.2005.23(34):8845-52.
[30]Bruland OS, Pihl A. On the current management of osteosarcoma. A critical evaluation and a proposal for a modified treatment strategy. Eur J Cancer.1997. 33(11):1725-31.
[31]Oeffinger KC, Hudson MM. Long-term complications following childhood and adolescent cancer:foundations for providing risk-based health care for survivors. CA Cancer J Clin.2004.54(4):208-36.
[32]Kremer LC, van DEC, Offringa M, Voute PA. Frequency and risk factors of anthracycline-induced clinical heart failure in children:a systematic review. Ann Oncol.2002.13(4):503-12.
[33]Geidel S, Garn M, Gravinghoff L, et al. [Cardiomyopathy after osteosarcoma treatment:a contribution to the cardiotoxicity of adriamycin]. Klin Padiatr.1991. 203(4):257-61.
[34]Meadows AT, Baum E, Fossati-Bellani F, et al. Second malignant neoplasms in children:an update from the Late Effects Study Group. J Clin Oncol.1985.3(4): 532-8.
[35]Hawkins MM, Draper GJ, Kingston JE. Incidence of second primary tumours among childhood cancer survivors. Br J Cancer.1987.56(3):339-47.
[36]Pratt CB, Meyer WH, Luo X, et al. Second malignant neoplasms occuring in survivors of osteosarcoma. Cancer.1997.80(5):960-5.
[37]Aung L, Gorlick RG, Shi W, et al. Second malignant neoplasms in long-term survivors of osteosarcoma:Memorial Sloan-Kettering Cancer Center Experience. Cancer.2002.95(8):1728-34.
[38]Longhi A, Macchiagodena M, Vitali G, Bacci G. Fertility in male patients treated with neoadjuvant chemotherapy for osteosarcoma. J Pediatr Hematol Oncol. 2003.25(4):292-6.
[39]Longhi A, Porcu E, Petracchi S, Versari M, Conticini L, Bacci G. Reproductive functions in female patients treated with adjuvant and neoadjuvant chemotherapy for localized osteosarcoma of the extremity. Cancer.2000.89(9): 1961-5.
[40]Zelcer S, Kellick M, Wexler LH, et al. Methotrexate levels and outcome in osteosarcoma. Pediatr Blood Cancer.2005.44(7):638-42.
[41]Bacci G, Loro L, Longhi A, et al. No correlation between methotrexate serum level and histologic response in the pre-operative treatment of extremity osteosarcoma. Anticancer Drugs.2006.17(4):411-5.
[42]Wunder JS, Bull SB, Aneliunas V, et al. MDR1 gene expression and outcome in osteosarcoma:a prospective, multicenter study. J Clin Oncol.2000.18(14): 2685-94.
[43]Bacci G, Picci P, Ferrari S, et al. Prognostic significance of serum alkaline phosphatase measurements in patients with osteosarcoma treated with adjuvant or neoadjuvant chemotherapy. Cancer.1993.71(4):1224-30.
[44]Saeter G, Alvegard TA, Elomaa I, Stenwig AE, Holmstrom T, Solheim OP. Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate:a Scandinavian Sarcoma Group study. J Clin Oncol. 1991.9(10):1766-75.
[45]Provisor AJ, Ettinger LJ, Nachman JB, et al. Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy:a report from the Children's Cancer Group. J Clin Oncol.1997. 15(1):76-84.
[46]Edmonson JH, Long HJ, Kvols LK, Mann BS, Grill JP. Can molgramostim enhance the antitumor effects of cytotoxic drugs in patients with advanced sarcomas. Ann Oncol.1997.8(7):637-41.
[47]Anderson PM, Markovic SN, Sloan JA, et al. Aerosol granulocyte macrophage-colony stimulating factor:a low toxicity, lung-specific biological therapy in patients with lung metastases. Clin Cancer Res.1999.5(9):2316-23.
[48]Rao RD, Anderson PM, Arndt CA, Wettstein PJ, Markovic SN. Aerosolized granulocyte macrophage colony-stimulating factor (GM-CSF) therapy in metastatic cancer. Am J Clin Oncol.2003.26(5):493-8.
[49]Meyers PA, Schwartz CL, Krailo M, et al. Osteosarcoma:a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol.2005.23(9): 2004-11.
[50]Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma:the addition of muramyl tripeptide to chemotherapy improves overall survival-a report from the Children's Oncology Group. J Clin Oncol.2008.26(4):633-8.
[51]Nilsonne U, Brostrom LA, Aparisi T. Local tumour resection in interferon treated osteosarcoma patients. Ann Chir Gynaecol.1995.84(1):63-70.
[52]Edmonson JH, Long HJ, Frytak S, Smithson WA, Itri LM. Phase Ⅱ study of recombinant alfa-2a interferon in patients with advanced bone sarcomas. Cancer Treat Rep.1987.71(7-8):747-8.
[53]Smeland S, Muller C, Alvegard TA, et al. Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII:prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders. Eur J Cancer.2003.39(4):488-94.
[54]Ma J, Pollak MN, Giovannucci E, et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst.1999.91(7):620-5.
[55]Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like growth factor-I and prostate cancer risk:a prospective study. Science.1998.279(5350): 563-6.
[56]Pollak MN, Polychronakos C, Richard M. Insulinlike growth factor I:a potent mitogen for human osteogenic sarcoma. J Natl Cancer Inst.1990.82(4):301-5.
[57]Ouban A, Muraca P, Yeatman T, Coppola D. Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas. Hum Pathol.2003. 34(8):803-8.
[58]Shimizu C, Hasegawa T, Tani Y, et al. Expression of insulin-like growth factor 1 receptor in primary breast cancer:immunohistochemical analysis. Hum Pathol. 2004.35(12):1537-42.
[59]Mansky PJ, Liewehr DJ, Steinberg SM, et al. Treatment of metastatic osteosarcoma with the somatostatin analog OncoLar:significant reduction of insulin-like growth factor-1 serum levels. J Pediatr Hematol Oncol.2002.24(6): 440-6.
[60]Benini S, Baldini N, Manara MC, et al. Redundancy of autocrine loops in human osteosarcoma cells. Int J Cancer.1999.80(4):581-8.
[61]Sachdev D, Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther.2007.6(1):1-12.
[62]Kolb EA, Gorlick R, Houghton PJ, et al. Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the pediatric preclinical testing program. Pediatr Blood Cancer.2008.50(6):1190-7.
[63]Zhou H, Randall RL, Brothman AR, Maxwell T, Coffin CM, Goldsby RE. Her-2/neu expression in osteosarcoma increases risk of lung metastasis and can be associated with gene amplification. J Pediatr Hematol Oncol.2003.25(1): 27-32.
[64]Anninga JK, de Vijver MJ v, Cleton-Jansen AM, et al. Overexpression of the HER-2 oncogene does not play a role in high-grade osteosarcomas. Eur J Cancer. 2004.40(7):963-70.
[65]Maitra A, Wanzer D, Weinberg AG, Ashfaq R. Amplification of the HER-2/neu oncogene is uncommon in pediatric osteosarcomas. Cancer.2001.92(3):677-83.
[66]Hughes DP, Thomas DG, Giordano TJ, Baker LH, McDonagh KT. Cell surface expression of epidermal growth factor receptor and Her-2 with nuclear expression of Her-4 in primary osteosarcoma. Cancer Res.2004.64(6):2047-53.
[67]Gorlick R, Huvos AG, Heller G, et al. Expression of HER2/erbB-2 correlates with survival in osteosarcoma. J Clin Oncol.1999.17(9):2781-8.
[68]McGary EC, Weber K, Mills L, et al. Inhibition of platelet-derived growth factor-mediated proliferation of osteosarcoma cells by the novel tyrosine kinase inhibitor STI571. Clin Cancer Res.2002.8(11):3584-91.
[69]Sulzbacher I, Traxler M, Mosberger I, Lang S, Chott A. Platelet-derived growth factor-AA and-alpha receptor expression suggests an autocrine and/or paracrine loop in osteosarcoma. Mod Pathol.2000.13(6):632-7.
[70]Kubo T, Piperdi S, Rosenblum J, et al. Platelet-derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma. Cancer.2008.112(10):2119-29.
[71]Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer.2007.7(4):295-308.
[72]Bjornsti MA, Houghton PJ. The TOR pathway:a target for cancer therapy. Nat Rev Cancer.2004.4(5):335-48.
[73]Wan X, Helman LJ. The biology behind mTOR inhibition in sarcoma. Oncologist.2007.12(8):1007-18.
[74]Wan X, Mendoza A, Khanna C, Helman LJ. Rapamycin inhibits ezrin-mediated metastatic behavior in a murine model of osteosarcoma. Cancer Res.2005.65(6): 2406-11.
[75]Brose MS, Volpe P, Feldman M, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res.2002.62(23):6997-7000.
[76]Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature.2002.417(6892):949-54.
[77]Karnoub AE, Weinberg RA. Ras oncogenes:split personalities. Nat Rev Mol Cell Biol.2008.9(7):517-31.
[78]Sankhala KK, Pandya DM, Sarantopoulos J, Soefje SA, Giles FJ, Chawla SP. Prevention of chemotherapy induced nausea and vomiting:a focus on aprepitant. Expert Opin Drug Metab Toxicol.2009.5(12):1607-14.
[79]Goel S, Desai K, Karri S, et al. Pharmacokinetic and safety study of weekly irinotecan and oral capecitabine in patients with advanced solid cancers. Invest New Drugs.2007.25(3):237-45.
[80]Leu KM, Ostruszka LJ, Shewach D, et al. Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin Oncol.2004.22(9):1706-12.
[81]Navid F, Willert JR, McCarville MB, et al. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer.2008.113(2):419-25.
[82]Guo W, Healey JH, Meyers PA, et al. Mechanisms of methotrexate resistance in osteosarcoma. Clin Cancer Res.1999.5(3):621-7.
[83]Malempati S, Nicholson HS, Reid JM, et al. Phase Ⅰ trial and pharmacokinetic study of pemetrexed in children with refractory solid tumors:the Children's Oncology Group. J Clin Oncol.2007.25(12):1505-11.
[84]ChouAJ, Bell MD, Mackinson C, et al. Phase Ib/IIa study of sustained release lipid inhalation targeting cisplatin by inhalation in the treatment of patients with relapsed/progressive osteosarcoma metastatic to the lung. ASCO Annual Meeting Proceedings Part I. J. Clin. Oncol.25,18S,9525 (2007).