这里收集了一些摘自中英文网站有关骨软骨肉瘤和恶性肿瘤治疗的研究发展文章，点击下列连接浏览详细内容：

  1. 癌症靶向治疗新视点
  2. COX-2酶和骨软骨肉瘤的关系：
    1. Cyclooxygenase-2 Expression in Chondrosarcoma
            COX-2酶在骨软骨肉瘤中的表现
Karen M. Sutton, Marianne Wright, Gertrud Fondren, Christine A. Towle, Henry J. Mankin
Orthopedic Biological Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston,Mass., USA 骨科生物研究实验室，马萨诸塞综合医院，哈佛医学院，
Oncology 2004;66:275-280 (DOI: 10.1159/000078327) 肿瘤杂志，2004年
  Abstract 摘要
Objective: In recent years it has become evident that tissue cyclooxygenase-2 (COX-2) may play a role in carcinogenesis and tumor malignancy. There is now a mounting body of information that strongly implies that COX-2 inhibitors may be of some value in the management of patients with carcinomas, and most recently several similar reports have appeared relating to sarcomas. Methods: The authors studied 32 samples of cartilage tumors from our tumor tissue bank for the presence of COX-2 by a Western blot technique. There were 29 patients from whom the samples were obtained, including 8 with enchondromas and 21 with chondrosarcomas. Results: Thirteen of the 24 chondrosarcoma samples and none of the 8 enchondromas were positive for COX-2. An attempt was made to correlate these results with clinical data including age, gender, staging according to the Musculoskeletal Tumor Society, anatomical site, ploidic pattern, presence of metastases and death rate but no statistically valid correlation could be found. Conclusion: It is evident that COX-2 may play some role in chondrosarcoma but not in the benign enchondroma and that further studies with COX-2 inhibitors are warranted.
目的：最近几年的研究证明COX-2酶可能在癌变和恶性肿瘤中的作用。现在大量的信息表明COX-2抑制剂可能在治疗癌症中的作用，最近的几个报告和肉瘤相关。
方法：作者研究了32个软骨肿瘤的样本用Western blot技术来判断COX-2在样本是否存在，样本是从我们的肿瘤组织样本库中提取的。32个样本是从29个病人中提取的，8个人是良性肿瘤（enchondromas），21个是骨软骨肉瘤。
结果：在24个骨软骨肉瘤的样本中13个有COX-2，而8个良性瘤中无1例有COX-2。作者也试图把结果和病人的临床数据例如年龄，性别，肿瘤级别，肿瘤位置，ploidic pattern，是否存在转移，和死亡率联系起来，但是无法得到有证明性的统计数据。
结论：可以证明COX-2在骨软骨肉瘤中起一些作用，而不在良性软骨瘤中存在。关于COX-2抑制剂的更进一步的研究是需要的。
 
b.                   Cyclooxygenase-2 overexpression associated with a poor prognosis in chondrosarcomas

COX-2酶的过度表达和骨软骨肉瘤预后不良的关系

Hum Pathol. 2006 Apr;37(4):471-6. Epub 2006 Feb 3. 人类病理学杂志，2006年4月

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed

Endo M, Matsumura T, Yamaguchi T, Yamaguchi U, Morimoto Y, Nakatani F, Kawai A, Chuman H, Beppu Y, Shimoda T, Hasegawa T.
Division of Orthopaedic Oncology, National Cancer Centre Hospital, Tokyo 104-0045, Japan.

日本东京国立肿瘤中心医院，骨肿瘤部

Recent studies have shown increased levels of cyclooxygenase (COX)-2 in various human malignancies, including some bone and soft tissue tumors, but little is known about the presence of COX-2 in chondrosarcomas. We performed immunohistochemical staining for COX-2 in 74 chondrosarcomas and compared the staining results with the characteristics and outcome of the patients. Thirty-seven men and 37 women between the ages of 14 and 81 years (median, 50
years) participated in the study. The tumors were located in the axial skeleton in 47 cases and in the long bones in 27 cases. The largest diameters of the tumors ranged from 2.7 to 32 cm (median, 8.0 cm). The immunohistochemistry findings revealed the overexpression of COX-2 in 16 (22%) of the 74 patients. Thirteen (41%) of 32 grade 2 and 2 (67%) of 3 grade 3 chondrosarcomas showed overexpression for COX-2, whereas only 1 (3%) of 39 grade 1 chondrosarcomas showed overexpression. Overexpression of COX-2 was significantly associated with histologic grade (P < .001) and a decreased disease-specific survival (P < .001). These findings suggest that COX-2 overexpression in chondrosarcoma is a negative prognostic factor that may be strongly associated with histologic grade.

最近的研究显示COX-2酶在不同的人恶性肿瘤的过度表达，包括一些骨与软组织肿瘤，但是对COX-2在骨软骨肉瘤中的表达知道的并不多。我们用免疫组织化学染色法对74个骨软骨肉瘤细胞进行分析，并把结果和病人的情况进行比较。37个男病人和37个女病人年龄从14岁到81岁（中位年龄50岁）。47例肿瘤在中轴骨骼，27例在长骨。最大的肿瘤直径从2.7到32CM（中位8.0CM）。免疫组织化学染色法揭示COX-2在16(74例的22%)例中过度表达。32例2度肿瘤中13例(41%)过度表达，2例3度肿瘤中2例(100%)都过度表达，而在39例1度肿瘤中只有1例(3%)过度表达。COX-2的过度表达和肿瘤的恶性程度及存活率下降显著相关。这些发现显示COX-2在骨软骨肉瘤中过度表达是预后不良的指数并和恶性程度相关。

  1. Constitutive Hedgehog Signaling in Chondrosarcoma Up-Regulates Tumor Cell Proliferation
  2. 凋亡途径与肿瘤治疗 (http://www.wjgnet.com/1009-3079/13/2469.pdf)
  3. 血管内皮抑制素与肿瘤治疗
    1. Judah Folkman and His Research
    2. 恩度(Endostar)的通用名为重组 人血管内皮抑制素注射液(Recombinant Human Endostatin Injection)
  4. Estrogen Signaling Is Active in Cartilaginous Tumors: Implications for Antiestrogen Therapy as Treatment Option of Metastasized or Irresectable Chondrosarcoma (在软骨肿瘤中雌激素信号是活跃的：推断抗雌激素疗法作为转移了和不可切除的骨软骨肉瘤的治疗选择)
  5.  Ecteinascidin-743 (ET-743, YondelisTM, Pharma Mar/Johnson & Johnson) – A Review
  6. Genetic approaches to sarcoma diagnosis
  7. The effects of ciprofloxacin and paclitaxel on metastatic and recurrent chondrosarcoma (环丙沙星和紫杉醇治疗转移和复发的骨软骨肉瘤病人的效果)

Edward J. Fox, MD, Jess T. Torbert, MD, Anne-Marie Martin, PhD, Arthur P. Staddon, MD, Joseph L. Finstein, MD, and Richard D. Lackman, MD

Department of Orthopaedic Surgery, The University of Pennsylvania, Philadelphia, PA

Abstract:
Chondrosarcoma treatment is surgical resection without acceptable adjuvant therapy. Fluoroquinolones have shown toxicity in immature cartilage, induction of apoptosis and decrease proliferation of human chondrosarcoma. Since our previous in vitro studies suggest that has a synergistic effect on Chondrosarcoma, we study ciprofloxacin/paclitaxel's use in recurrent/metastatic chondrosarcoma patients and the genes responsible for ciprofloxacin's in vitro effects. Four patients received ciprofloxacin 750mg/bid/po and paclitaxel 90mg/m2 over 1hr weekly for 6/8 weeks of each cycle. Patient#1 remains stable(32.8weeks) after treatment was initiated. Patient#2 showed a 60% decrease in growth rate, but progressed(10.3weeks). Patient#3 progressed(9weeks), remained stable for 16months, then progressed after treatment was discontinued. Patient#4 had three lesions: the recurrent lesion progressed despite treatment, showing an 8% increase in growth rate; metastasis#1 remained stable(18weeks); metastasis#2 progressed. For in vitro study, normal articular cartilage and chondrosarcoma cells were exposed to ciprofloxacin and analyzed using expression profiling(AffymetrixGeneChip) yielding DDX5/MYST2/ISGF3/APC/TARBP/EIF4G2/ERH as the genes differentially expressed.

  1. Fluoroquinolone’s Effect on Growth of Human Chondrocytes and Chondrosarcomas inVitro and in Vivo Correlation

H. A. B. Multhaupt, PhD, J. C. Alvarez, MD, P. A. Rafferty, BS, M. J. Warhol, MD and R. D. Lackman, MD

The Journal of Bone and Joint Surgery (American) 83:S56-61 (2001)

Abstract

Clinical and in vitro studies have demonstrated that fluoroquinolones are toxic to chondrocytes; however, the exact mechanism of fluoroquinolone arthropathy is unknown. We investigated the toxicity of ciprofloxacin on normal cartilage and on cartilaginous tumors. Normal human cartilage, enchondroma, and chondrosarcoma explants were cultured either alone or with the addition of ciprofloxacin at 1, 10, or 20 mg/L of medium. Samples were collected up to twenty-one days after treatment and were processed for electron microscopy and conventional light microscopy. The specimens were characterized morphologically with use of conventional light microscopy, electron microscopy, and immunohistochemistry to identify extracellular matrix, cell proliferation, and apoptosis.

Cultures of normal chondrocytes expressed type-II collagen. Electron microscopy revealed a large amount of glycogen in the cells; the presence of fat droplets, rough endoplasmic reticulum, and prominent Golgi apparatus; and a proteoglycan layer surrounding the cells. With prolonged ciprofloxacin treatment and with increased doses, there was an increase in dilated rough endoplasmic reticulum, the appearance of phagosomes, and disintegrated bundles of vimentin filaments. The treated chondrocytes showed a decrease in cell proliferation, but there was no induction of apoptosis or effect on the expression of extracellular matrix proteins. Ciprofloxacintreated chondrosarcoma cultures and tissue samples showed changes in cartilage matrix composition. Ultrastructural analysis demonstrated clumped glycogen, dilation of endoplasmic reticulum, numerous abnormal lysosomes containing degeneration products, and a decreased proteoglycan deposit surrounding the tumor cells.

Treated chondrosarcoma cells and tissue specimens did not proliferate, and apoptosis was induced. In contrast, the in vitro growth of other noncartilaginous malignant tumors like osteosarcoma and liposarcoma was unaffected by ciprofloxacin.

Our results indicate that ciprofloxacin is toxic to chondrocytes. In vitro and in vivo treated chondrosarcomas are the most affected.

  1. Dysregulation of Indian hedgehog - parathyroid hormone related protein signalling in cartilaginous neoplasia

Hopyan, Sevan，University of Toronto

  1. Morphine, Gabapentin, or Their Combination for Neuropathic Pain Gabapentin 用来治疗癌症引起的神经痛

Ian Gilron, M.D., Joan M. Bailey, R.N., M.Ed., Dongsheng Tu, Ph.D., Ronald R. Holden, Ph.D., Donald F. Weaver, M.D., Ph.D., and Robyn L. Houlden, M.D.

The New England Journal of Medicine Volume 352:1324-1334   March 31, 2005   Number 13

  1. Low-dose/Metronomic Chemotherapy
    1. Highly Efficacious Nontoxic Preclinical Treatment for Advanced Metastatic Breast Cancer Using Combination Oral UFT-Cyclophosphamide Metronomic Chemotherapy

Raquel Munoz, Shan Man, Yuval Shaked, Christina R. Lee, John Wong, Giulio Francia, and Robert S. Kerbel

Sunnybrook and Women’s College Health Sciences Centre S-217, Toronto, Ontario, Canada; and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    1. Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects

M. Colleoni, L. Orlando, G. Sanna, A. Rocca, P. Maisonneuve, G. Peruzzotti, R. Ghisini, M. T. Sandri, L. Zorzino, F. Nolè, G. Viale and A. Goldhirsch

Annals of Oncology 2006 17(2):232-238; doi:10.1093/annonc/mdj066

Abstract:　Background: We previously demonstrated efficacy and impact on serum vascular endothelial growth factor (VEGF) for metronomic cyclophosphamide (C) and methotrexate (M) in patients with breast cancer. New metronomic schedules were investigated.

Patients and methods: Patients with advanced breast cancer were randomized to receive oral C (50 mg daily) and M (2.5 mg twice daily on days 1 and 4) (arm A) or the same regimen plus thalidomide (200 mg daily) (arm B).

Results: The mean VEGF level decreased from 378.9 (± 274.4) pg/ml at baseline to 305.9 (± 203.6) pg/ml at 2 months (P < 0.001), with similar change with respect to baseline in both arms. In 171 evaluable patients we observed three complete remissions (CR) in both arms A and B, 15 partial remission (PR) in arm A and seven in arm B, for an overall response of 20.9% [95% confidence interval (CI) 12.9% to 31%] in arm A and 11.8% (95% CI 5.8% to 20.6%) in arm B. The clinical benefit (CR + PR + SD ≥24 weeks) was 41.5% for both arms. Toxicity was generally mild. Higher neurological toxicity (2% versus 60%; P < 0.0001) and constipation (8% versus 51%; P < 0.0001) was observed in arm B.

Conclusions: Metronomic low-dose CM induced a drop in VEGF, and was effective and minimally toxic. The addition of thalidomide did not improve results.

 

  1. Apo2L/TRAIL Clinical Trial（Apo2L/TRAIL试验疗法）
    1. A Phase I safety and pharmacokinetic (PK) study of recombinant Apo2L/TRAIL, an apoptosis-inducing protein in patients with advanced cancer (Apo2L/TRAIL, 一种诱导癌细胞凋亡蛋白对晚期癌症病人的一期临床试验，安全性和药物动力学研究)

Abramson Cancer Center of the University of Pennsylvania, June 3, 2006

    1. Information From Genentech Company
  1. Treatment of Metastatic Cancer with Tetrathiomolybdate, an Anticopper, Antiangiogenic Agent: Phase I Study
  2. Trail-induced apoptosis and interaction with cytotoxic agents in soft tissue sarcoma cell lines
    TRAIL和细胞毒性药物引起的软组织肿瘤细胞凋亡

Eur J Cancer. 2003 Jun;39(9):1318-29.

Tomek S, Koestler W, Horak P, Grunt T, Brodowicz T, Pribill I, Halaschek J, Haller G, Wiltschke C, Zielinski CC, Krainer M.
Clinical Division of Oncology, Department of Medicine I, Waehringer Guertel 18-20, A-1090, Vienna, Austria.
对五种人体软组织肿瘤细胞(HTB-82横纹肌肉瘤，HTB-91纤维肉瘤，HTB-92脂肪肉瘤，HTB-93滑膜肉瘤，和HTB-94骨软骨肉瘤)对TRAIL的敏感性的敏感性和在这些细胞里的TRAIL凋亡路径的功能进行了分析。TRAIL对HTB-92和HTB-93细胞引起了大量凋亡(>90%)，在HTB-82, HTB-91和HTB-94细胞中并没有观察到明显的效果。TRAIL-Receptor1(TRAIL-R1)在对TRAIL敏感的HTB-92和HTB-93细胞中有表达，但在对TRAIL不敏感的HTB-91和HTB-94细胞中不表达。在HTB-82细胞中虽然有TRAIL-R1表达，但expressed the long (c-FLIP(L)) and short (c-FLIP(S)) splice variants of the FLICE-like inhibitory protein (FLIP)。TRAIL-R2,-R3,-R4和osteoprotegerin(OPG)的表达和TRAIL的敏感性不相关。多柔比星和TRAIL的联合作用使TRAIL-R2过度表达，造成了多柔比星和TRAIL对TRAIL敏感的细胞的增效作用，并且克服了对TRAIL抑制的肿瘤细胞对TRAIL的不敏感，除了缺少caspase 8 表达的HTB-91以外。这些数据显示了TRAIL，作为单独的药或和细胞毒性药物结合，可能代表了对化疗无效的晚期骨与软组织肿瘤的一种新的治疗方式。
Five human soft tissue sarcoma (STS) cell lines (HTB-82 rhabdomyosarcoma, HTB-91 fibrosarcoma, HTB-92 liposarcoma, HTB-93 synovial sarcoma and HTB-94 chondrosarcoma) were analysed for their sensitivity to tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and the function of the TRAIL apoptotic pathway in these cells. TRAIL induced significant apoptosis (>90%)
in HTB-92 and HTB-93 cells, whereas no effect was observed in HTB-82, HTB-91 and HTB-94 cells. TRAIL-Receptor 1 (TRAIL-R1) was expressed in TRAIL-sensitive HTB-92 and HTB-93 cell lines, but not in TRAIL-resistant HTB-91 and HTB-94 cells. HTB-82 cells, which expressed the long (c-FLIP(L)) and short (c-FLIP(S)) splice variants of the FLICE-like inhibitory protein (FLIP), were resistant to TRAIL in spite of the presence of TRAIL-R1. TRAIL-R2,-R3,-R4 and osteoprotegerin (OPG) expression did not correlate with TRAIL sensitivity. Coincubation of TRAIL and doxorubicin led to the overexpression of TRAIL-R2 resulting in a synergistic effect of doxorubicin and TRAIL in TRAIL-sensitive cell lines and in the overcoming of TRAIL-resistance in all of the TRAIL-resistant cell lines, except HTB-91, which lacked caspase 8 expression. These data suggest that TRAIL, either as a single agent or in combination with cytotoxic agents, might represent a new treatment option for advanced STS, which constitutes a largely chemotherapy-resistant disease.

  1. Sensitivity of fresh isolates of soft tissue sarcoma, osteosarcoma and giant cell tumour cells to Apo2L/TRAIL and doxorubicin

Apo2L/TRAIL和多柔比星联合对软组织肉瘤，骨肉瘤和巨细胞瘤的敏感性

 

Bouralexis S, Clayer M, Atkins GJ, Labrinidis A, Hay S, Graves S, Findlay DM, Evdokiou A.
Department of Orthopaedics, Royal Adelaide Hospital, Adelaide University, Hanson Institute, Adelaide, South Australia, Australia.
Chemotherapy is an established treatment modality for bone sarcomas such as osteosarcoma (OS). However, the use of chemotherapy in high-grade soft tissue sarcomas remains controversial, with the most active chemotherapeutic agent, doxorubicin (DOX), reported to have a response rate of, at best only 34% and most studies reporting lower response rates. Apo2L/TRAIL is a member of the tumour necrosis factor (TNF) family of cytokines and induces death of tumour cells, but not normal cells. Its potent apoptotic activity is mediated through cell surface death domain-containing receptors, DR4/TRAIL-R1 and DR5/TRAIL-R2. We investigated the efficacy of Apo2L/TRAIL as a single agent, and in combination with clinically relevant chemotherapeutic drugs, in fresh isolates of primary malignant cells obtained from biopsy material. The data presented here demonstrate that, in a range of primary bone related tumours, as well as soft tissue sarcomas, chemotherapeutic agents were only moderately effective, in terms of induction of cell death. Apo2L/TRAIL alone had little or no effect on any bone-related tumour or sarcoma in culture. In contrast, the combination of Apo2L/TRAIL and
chemotherapeutic drugs produced a significant increase in tumour cell death, with DOX and Apo2L/TRAIL proving to be the most effective combination. These data suggest the potential for
Apo2L/TRAIL to increase the effectiveness of chemotherapeutic drugs in bone and soft tissue sarcomas, while perhaps concurrently allowing a reduction in the exposure to drugs such as DOX, and a consequent reduction in toxicity. The synergistic action between these two different classes of agents has yet to be tested in vivo but may prove clinically relevant in the treatment of this refractive class of malignancies.

 

 

 

 

更多的最新研究发展，请查询美国国家卫生研究院资料库（http://www.ncbi.nlm.nih.gov/pubmed/）

 

 

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