臺灣博碩士論文加值系統

鼻咽癌好發於中國南方和東南亞地區，台灣亦是好發區域之ㄧ，它主要的致病因子可分為基因敏感性、化學致癌物與EB病毒的感染等因子。鼻咽癌是屬於高輻射敏感性與化療敏感性的癌症，在癌症初期，放射治療乃是主要的治療方式。但是當癌症發展成具高侵襲性的晚期，同步放射化療就是主要的治療方式。雖然早期的鼻咽癌容易被控制或治癒，但是對於晚期的病人卻有高的復發率與遠端轉移的潛在性。基質金屬蛋白水解酶(matrix metalloproteinase)-2及-9乃是屬於MMP家族之ㄧ，主要在分解第四型的膠原蛋白乃是屬於細胞外基質的主要成分，這被認為是造成腫瘤侵襲與轉移的重要因子。近來研究顯示在細胞株中可以觀察到EB病毒上的潛伏膜蛋白-1會促使MMP -9的活性表現，該研究也提出這可能就是潛伏的膜蛋白-1藉由誘發MMP-9的活化，因而造成鼻咽腫瘤侵襲與轉移的機制。另外又有研究指出，在肺癌、乳癌與直腸癌病人經由放射線的治療會使MMP-2及-9的活性表現上升。而MMP-2及-9的大量表現已在許多的癌症組織中可以觀察到，甚至也可在病人的周邊血液中測得該蛋白酶的高濃度表現。本篇研究主要探討藉由鼻咽癌病人在同步放射化學治療期間血漿中MMP-2及-9的變化與臨床表現的相關性。本實驗病人血液的收集皆來自中山醫學大學附設醫院放射腫瘤科，具臨床病理切片確認為鼻咽癌患者，腫瘤分期乃是根據2002年AJCC公佈的分期標準，病人皆接受相同的同步放射化學療法。20位鼻咽癌患者的血液樣本收集共分四階段，每次抽5mL的樣本儲存於EDTA採血管中，然後再進行明膠蛋白酵素電泳法分析該蛋白酶活性表現與酵素免疫分析法分析濃度的變化。
結果顯示血漿MMP -2和-9的濃度表現和鼻咽癌病人的年齡、性別、腫瘤大小和淋巴結轉移並無明顯相關性。血液中的嗜中性白血球計數與血漿中MMP -9則有直接的相關性，具有統計學的意義。另外，在較具侵襲性的鼻咽癌患者中其血漿中MMP -9的濃度（mean= 68.6 ng/mL）明顯高於其他鼻咽癌患者（mean= 45.7 ng/mL），但是這現象在血漿MMP -2並無明顯相關。另一個值得探討的是血漿中MMP -9在治療前後的濃度變化，在具侵襲性的鼻咽癌患者在合併前導性化療與同步放射化療之後，血漿中MMP -9的濃度依然維持高濃度。但因為我們的樣本數量太少，導致我們的結果並無統計學上的意義。
總結以上，同步放射化學治療可以降低血漿中MMP -9的濃度，但是在較具侵襲性的鼻咽癌患者方面並無觀察到相同反應。因此，我們推論血漿中高濃度的MMP -9也許會促進癌細胞的擴散，進而造成腫瘤持續的侵犯、復發與遠端轉移。

Nasopharyngeal carcinoma (NPC) is an endemic tumor in southern China and Southeast Asia, as well as in Taiwan. The main etiologic factors include genetic susceptibility, chemical carcinogens and association with Epstein-Barr virus (EBV) infection. NPC is highly radiosensitive and chemosensitive. Presently, radiotherapy remains a common treatment for early disease, while concurrent chemoradiotherapy is being increasingly accepted as the standard treatment for advanced disease. Although NPC at early stages can be cured by radical radiotherapy, there is a high recurrence rate in patients with advanced NPC. NPC is a highly metastatic and invasive malignant tumor in which the EBV genes encoding LMP-1 is expressed. Latent membrane protein 1 (LMP1), an EBV membrane protein is considered to be the EBV oncoprotein. Matrix metalloproteinase (MMP) -2, -9 are the MMP families, degrade Type IV collagen, a major component of extracellular matrix and is believed to be crucial for cancer invasion and metastasis. Recently, the study has shown that LMP1 induces MMP-9 in vitro cell line, which suggests the possibility of a mechanism in which LMP1 of EBV contributes to the invasion and metastasis of NPC by the induction of MMP-9. Upregulation of MMP-2 and -9 expression is observed in many cancers and high level of these proteins are found in peripheral blood of many cancer patients and increased plasma level of MMP-9 has been found in lung and breast and rectal cancer post radiotherapy. In this study, we aimed at evaluating the plasma pro-MMP-2 and pro-MMP-9 pro-enzymes levels during the course of CCRT and their clinical significances in patients with nasopharyngeal carcinoma.
Patients with histological confirmed NPC attending the Department of Radiation Oncology at the Chung Chan Medical University Hospital. Cancer stage is according to 2002 AJCC staging system. All patients were treated with a concurrent chemoradiotherapy protocol. All patients were drawn 5mL of peripheral blood into an EDTA blood collection tubes with four times totally. The plasma pro-MMP2 and pro-MMP9 activity were measured in 20 NPC patients by gelatin zymography and the level were measured by enzyme linked immunosorbant assay (ELISA).
The study result showed the plasma MMP-2,-9 concentration were not correlated with sex, age, T stage, lymph node metastatsis. But the neutrophils count was positive correlation to the plasma MMP-9 concentration that were statistically significant. In addition, the plasma MMP-9 levels ( mean= 68.6 ng/ml ) in the advanced stage are higher than in early stage ( mean= 45.7 ng/ml ) patients, while no difference in plasma MMP-2 levels was found. Furthermore, the authors have also find the kinetic of plasma MMP-9 concentration during CCRT in Group 2. was different from Group 1. NPC patients. The plasma MMP-9 concentration was still at high level in Goup 2. patients post CCRT. Our results were not statistically significant, because the sample sizes were small.
Our conclusion, CCRT can be reduced effectively the plasma MMP-9 levels in early stage NPC. The more aggressive NPC patients still have high level of plasma MMP-9 post combine neo-adjuvant with CCRT. A high level of plasma MMP-9 may facilitate spreading of cancer cell and therefore a more aggressive tumor dissemination, recurrence and distant metastatsis.

中文摘要 Ⅰ
英文摘要 Ⅲ
縮 寫 Ⅵ
目 錄 Ⅶ
表目錄 Ⅸ
圖目錄 Ⅹ
壹. 文獻綜論 1
一. 鼻咽癌 1
1. 鼻咽癌的病原學 2
1.1. 鼻咽癌與EB病毒的關係 2
1.2. EB病毒的特性與在鼻咽癌發生過程中的角色 3
1.3. 潛伏性膜狀蛋白 4
2. 鼻咽癌的治療 6
2.1. 放射治療 6
2.1.1. 強度調控放射治療 7
2.1.2. 導航螺旋式光子刀 8
2.2. 同步放射化學療法 9
二. 基質金屬蛋白水解酶 10
三. 鼻咽癌與基質金屬蛋白水解酶的相關性 13
貳. 研究動機 15
參. 材料與方法 16
一. 研究對象選擇 16
1. 病理組織 16
2. 腫瘤分期系統 16
3. 放射治療 16
4. 化學療法 17
5. 治療反應與預後評估 17
二. 實驗方法 17
1. 血液樣本採集與處理 17
2. 基質金屬蛋白水解酶之活性分析 18
2.1. 明膠蛋白酵素電泳法 18
2.2. 酵素免疫分析法 19
三. 統計分析 24
肆. 結果 25
一. 臨床病人基本資料 25
二. 臨床生理數值 WBC count在治療前後的表現 27
三. MMP -9 治療前後的變化 27
四. MMP -2 治療前後的變化 28
五. MMP -9/ MMP -2 ratio的變化 29
六. MMP -9與臨床病理、治療反應的相關性 29
七. MMP -2與臨床病理、治療反應的相關性 29
八. MMP -9/ MMP -2 ratio與臨床病理、治療反應的相關性 30
九. MMP -9、MMP -2 和 MMP -9/ MMP -2 ratio與 白血球和嗜中性白血球的相關性 30
伍. 討論 31
一. 血漿 MMP -9、MMP -2與臨床病理的相關性 31
二. 血漿 MMP -9變化與臨床生化指標相關意義 31
三. 放射線治療可能引發血漿 MMP -9表現的分子機制 32
四. 高侵襲性鼻咽癌具有高度腫瘤持續發展或是遠端轉移潛在性 33
陸. 結論 35
柒. 未來展望 36
捌. 參考文獻 37
玖. 圖表與圖表說明 47
附錄 60

1.Vokes EE, Liebowitz DN, Weichselbaum RR. Nasopharyngeal carcinoma. Lancet. 1997; 350: 1087-91.
2.Hsu TY, Pai CY, Shieh SM, Cho SM, Liu MY, Chen JY, Yang CS. Use of antigen expressed in bacteria for detection of EBV-specific thymidine kinase antibodies in sera from patients with nasopharyngeal carcinoma. J Med Virol. 1992; 38: 214-9.
3.Wolf H, zur Hausen H, Becker V. EB viral genomes in epithelial nasopharyngeal carcinoma cells. Nat New Biol. 1973; 244: 245-7.
4.Roizman B, Carmichael LE, Deinhardt F, de-The G, Nahmias AJ, Plowright W, Rapp F, Sheldrick P, Takahashi M, Wolf K. Herpesviridae. Definition, provisional nomenclature, and taxonomy. The Herpesvirus Study Group, the International Committee on Taxonomy of Viruses. Intervirology. 1981; 16: 201-17.
5.Pritchett RF, Hayward SD, Kieff ED. DNA of Epstein-Barr virus. I. Comparative studies of the DNA of Epstein-Barr virus from HR-1 and B95-8 cells: size, structure, and relatedness. J Virol. 1975; 15: 556-9.
6.Petti L, Sample C, Kieff E. Subnuclear localization and phosphorylation of Epstein-Barr virus latent infection nuclear proteins. Virology. 1990; 176: 563-74.
7.Szigeti R, Rabin H, Timar L, Klein G. Leukocyte migration inhibition detects cross-reacting antigens between cells transformed by Epstein-Barr virus (EBV) and EBV-like simian viruses. Intervirology. 1986; 26: 121-8.
8.Sample J, Kieff E. Transcription of the Epstein-Barr virus genome during latency in growth-transformed lymphocytes. J Virol. 1990; 64: 1667-74.
9.Birkenbach M, Tong X, Bradbury LE, Tedder TF, Kieff E. Characterization of an Epstein-Barr virus receptor on human epithelial cells. J Exp Med. 1992; 176: 1405-14.
10.Sam CK, Brooks LA, Niedobitek G, Young LS, Prasad U,Rickinson AB. Analysis of Epstein-Barr virus infection in nasopharyngeal biopsies from a group at high risk of nasopharyngeal carcinoma. Int J Cancer. 1993; 53: 957-62.
11.Thorley-Lawson DA, Mann KP. Early events in Epstein-Barr virus infection provide a model for B cell activation. J Exp Med. 1985; 162: 45-59.
12.Henderson S, Rowe M, Gregory C, Croom-Carter D, Wang F, Longnecker R, Kieff E, Rickinson A. Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell. 1991; 65: 1107-15.
13.Dawson CW, Rickinson AB, Young LS. Epstein-Barr virus latent membrane protein inhibits human epithelial cell differentiation. Nature. 1990; 344: 777-80.
14.Yoshizaki T, Horikawa T, Qing-Chun R, Wakisaka N, Takeshita H, Sheen TS, Lee SY, Sato H, Furukawa M. Induction of interleukin-8 by Epstein-Barr virus latent membrane protein-1 and its correlation to angiogenesis in nasopharyngeal carcinoma. Clin Cancer Res. 2001; 7: 1946-51.
15.Wang D, Liebowitz D, Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell. 1985; 43: 831-40.
16.Huen DS, Henderson SA, Croom-Carter D, Rowe M. The Epstein-Barr virus latent membrane protein-1 (LMP1) mediates activation of NF-kappa B and cell surface phenotype via two effector regions in its carboxy-terminal cytoplasmic domain. Oncogene. 1995; 10: 549-60.
17.Gires O, Kohlhuber F, Kilger E, Baumann M, Kieser A, Kaiser C, Zeidler R, Scheffer B, Ueffing M, Hammerschmidt W. Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins. EMBO J. 1999; 18: 3064-73.
18.Hu L, Troyanovsky B, Zhang X, Trivedi P, Ernberg I, Klein G. Differences in the immunogenicity of latent membrane protein 1 (LMP1) encoded by Epstein-Barr virus genomes derived from LMP1-positive and -negative nasopharyngeal carcinoma. Cancer Res. 2000; 60: 5589-93.
19.Sultanem K, Shu HK, Xia P, Akazawa C, Quivey JM, Verhey LJ, Fu KK. Three-dimensional intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: the University of California-San Francisco experience. Int J Radiat Oncol Biol Phys. 2000; 48: 711-22.
20.Lee N, Xia P, Quivey JM, Sultanem K, Poon I, Akazawa C, Akazawa P, Weinberg V, Fu KK. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience. Int J Radiat Oncol Biol Phys. 2002; 53: 12-22.
21.Wolden SL, Chen WC, Pfister DG, Kraus DH, Berry SL, Zelefsky MJ. Intensity-modulated radiation therapy (IMRT) for nasopharynx cancer: update of the Memorial Sloan-Kettering experience. Int J Radiat Oncol Biol Phys. 2006; 64: 57-62.
22.Al-Sarraf M, LeBlanc M, Giri PG, Fu KK, Cooper J, Vuong T, Forastiere AA, Adams G, Sakr WA, Schuller DE, Ensley JF. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol. 1998; 16: 1310-7.
23.Al-Sarraf M, Reddy MS. Nasopharyngeal carcinoma. Curr Treat Options Oncol. 2002; 3: 21-32.
24.Wee J, Tan EH, Tai BC, Wong HB, Leong SS, Tan T, Chua ET, Yang E, Lee KM, Fong KW, Tan HS, Lee KS, Loong S, Sethi V, Chua EJ, Machin D. Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol. 2005; 23: 6730-8.
25.Lin JC, Liang WM, Jan JS, Jiang RS, Lin AC. Another way to estimate outcome of advanced nasopharyngeal carcinoma--is concurrent chemoradiotherapy adequate? Int J Radiat Oncol Biol Phys. 2004; 60: 156-64.
26.Chan AT, Teo PM, Ngan RK, Leung TW, Lau WH, Zee B, Leung SF, Cheung FY, Yeo W, Yiu HH, Yu KH, Chiu KW, Chan DT, Mok T, Yuen KT, Mo F, Lai M, Kwan WH, Choi P, Johnson PJ. Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: progression-free survival analysis of a phase III randomized trial. J Clin Oncol. 2002; 20: 2038-44.
27.Zhang L, Zhao C, Peng PJ, Lu LX, Huang PY, Han F, Wu SX. Phase III study comparing standard radiotherapy with or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal carcinoma: preliminary results. J Clin Oncol. 2005; 23: 8461-8.
28.Shapiro SD. Matrix metalloproteinase degradation of extracellular matrix: biological consequences. Curr Opin Cell Biol. 1998; 10: 602-8.
29.Basset P, Okada A, Chenard MP, Kannan R, Stoll I, Anglard P, Bellocq JP, Rio MC. Matrix metalloproteinases as stromal effectors of human carcinoma progression: therapeutic implications. Matrix Biol. 1997; 15: 535-41.
30.Johnsen M, Lund LR, Romer J, Almholt K, Dano K. Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation. Curr Opin Cell Biol. 1998; 10: 667-71.
31.Woessner JF, Jr. The family of matrix metalloproteinases. Ann N Y Acad Sci. 1994; 732: 11-21.
32.Birkedal-Hansen H. Matrix metalloproteinases. Adv Dent Res. 1995; 9: 16.
33.Yong VW, Krekoski CA, Forsyth PA, Bell R, Edwards DR. Matrix metalloproteinases and diseases of the CNS. Trends Neurosci. 1998; 21: 75-80.
34.Nagase H. Activation mechanisms of matrix metalloproteinases. Biol Chem. 1997; 378: 151-60.
35.Gomez DE, Alonso DF, Yoshiji H, Thorgeirsson UP. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol. 1997; 74: 111-22.
36.Minden A, Karin M. Regulation and function of the JNK subgroup of MAP kinases. Biochim Biophys Acta. 1997; 1333: F85-104.
37.Karin M, Liu Z, Zandi E. AP-1 function and regulation. Curr Opin Cell Biol. 1997; 9: 240-6.
38.Robinson JJ. Characterization of a metalloproteinase: a late stage specific gelatinase activity in the sea urchin embryo. J Cell Biochem. 1997; 66: 337-45.
39.Lewis MP, Norman JT. Differential response of activated versus non-activated renal fibroblasts to tubular epithelial cells: a model of initiation and progression of fibrosis? Exp Nephrol. 1998; 6: 132-43.
40.Hao L, Zhang C, Qiu Y, Wang L, Luo Y, Jin M, Zhang Y, Guo TB, Matsushima K. Recombination of CXCR4, VEGF, and MMP-9 predicting lymph node metastasis in human breast cancer. Cancer Lett. 2007; 253: 34-42.
41.Leinonen T, Pirinen R, Bohm J, Johansson R, Kosma VM. Increased expression of matrix metalloproteinase-2 (MMP-2) predicts tumour recurrence and unfavourable outcome in non-small cell lung cancer. Histol Histopathol. 2008; 23: 693-700.
42.Luo HZ, Zhou ZG, Yang L, Yu YY, Tian C, Zhou B, Zheng XL, Xia QJ, Li Y,Wang R. Clinicopathologic and prognostic significance of MMP-7 (matrilysin) expression in human rectal cancer. Jpn J Clin Oncol. 2005; 35: 739-44.
43.Yoshizaki T, Sato H, Furukawa M, Pagano JS. The expression of matrix metalloproteinase 9 is enhanced by Epstein-Barr virus latent membrane protein 1. Proc Natl Acad Sci U S A. 1998; 95: 3621-6.
44.Lu J, Chua HH, Chen SY, Chen JY, Tsai CH. Regulation of matrix metalloproteinase-1 by Epstein-Barr virus proteins. Cancer Res. 2003; 63: 256-62.
45.Zhang Y, Wang C, Mizukami H, Itoh H, Kusama M, Ozawa K, Jinbu Y. Increased expression and activation of matrix metalloproteinase-2 (MMP-2) in O-1N: hamster oral squamous cell carcinoma with high potential lymph node metastasis. J Exp Clin Cancer Res. 2006; 25: 417-23.
46.Cui D, Zhang X, Fu Y. [Expressions of COX-2 and MMP-2 in nasopharyngeal carcinoma and the their relationship with lymph node metastasis]. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2008; 22: 692-4.
47.Chen WZ, Zhou DL, Luo KS. Long-term observation after radiotherapy for nasopharyngeal carcinoma (NPC). Int J Radiat Oncol Biol Phys. 1989; 16: 311-4.
48.Lee AW, Poon YF, Foo W, Law SC, Cheung FK, Chan DK, Tung SY, Thaw M, Ho JH. Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976-1985: overall survival and patterns of failure. Int J Radiat Oncol Biol Phys. 1992; 23: 261-70.
49.Au JS, Law CK, Foo W, Lau WH. In-depth evaluation of the AJCC/UICC 1997 staging system of nasopharyngeal carcinoma: prognostic homogeneity and proposed refinements. Int J Radiat Oncol Biol Phys. 2003; 56: 413-26.
50.Hsu MM,Tu SM. Nasopharyngeal carcinoma in Taiwan. Clinical manifestations and results of therapy. Cancer. 1983; 52: 362-8.
51.Schabinger PR, Reddy S, Hendrickson FR, Phillips RL, Saxena V. Carcinoma of the nasopharynx: survival and patterns of recurrence. Int J Radiat Oncol Biol Phys. 1985; 11: 2081-4.
52.Horikawa T, Yoshizaki T, Sheen TS, Lee SY, Furukawa M. Association of latent membrane protein 1 and matrix metalloproteinase 9 with metastasis in nasopharyngeal carcinoma. Cancer. 2000; 89: 715-23.
53.Kumar A, Collins HM, Scholefield JH, Watson SA. Increased type-IV collagenase (MMP-2 and MMP-9) activity following preoperative radiotherapy in rectal cancer. Br J Cancer. 2000; 82: 960-5.
54.Unsal Kilic D, Uner A, Akyurek N, Erpolat P, Dursun A, Pak Y. Matrix metalloproteinase-9 expression correlated with tumor response in patients with locally advanced rectal cancer undergoing preoperative chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2007; 67: 196-203.
55.McNally LR, Rosenthal EL, Zhang W, Buchsbaum DJ. Therapy of head and neck squamous cell carcinoma with replicative adenovirus expressing tissue inhibitor of metalloproteinase-2 and chemoradiation. Cancer Gene Ther. 2009; 16: 246-55.
56.Kunigal S, Lakka SS, Joseph P, Estes N, Rao JS. Matrix metalloproteinase-9 inhibition down-regulates radiation-induced nuclear factor-kappa B activity leading to apoptosis in breast tumors. Clin Cancer Res. 2008; 14: 3617-26.
57.Fleming ID PJ, Menck HR, Murphy GP, Winchester DP. The National Cancer Data Base report on recent hospital cancer program progress toward complete American Joint Committee on Cancer/TNM staging. Cancer. 1997; 80: 2305-10.
58.Endo K, Maehara Y, Baba H, Yamamoto M, Tomisaki S, Watanabe A, Kakeji Y, Sugimachi K. Elevated levels of serum and plasma metalloproteinases in patients with gastric cancer. Anticancer Res. 1997; 17: 2253-8.
59.Riedel F, Gotte K, Schwalb J, Hormann K. Serum levels of matrix metalloproteinase-2 and -9 in patients with head and neck squamous cell carcinoma. Anticancer Res. 2000; 20: 3045-9.
60.Hayasaka A, Suzuki N, Fujimoto N, Iwama S, Fukuyama E, Kanda Y, Saisho H. Elevated plasma levels of matrix metalloproteinase-9 (92-kd type IV collagenase/gelatinase B) in hepatocellular carcinoma. Hepatology. 1996; 24: 1058-62.
61.Kanoh Y, Akahoshi T, Ohara T, Ohtani N, Mashiko T, Ohtani S, Egawa S, Baba S. Expression of matrix metalloproteinase-2 and prostate-specific antigen in localized and metastatic prostate cancer. Anticancer Res. 2002; 22: 1813-7.
62.Laack E, Kohler A, Kugler C, Dierlamm T, Knuffmann C, Vohwinkel G, Niestroy A, Dahlmann N, Peters A, Berger J, Fiedler W, Hossfeld DK. Pretreatment serum levels of matrix metalloproteinase-9 and vascular endothelial growth factor in non-small-cell lung cancer. Ann Oncol. 2002; 13: 1550-7.
63.Sheen-Chen SM, Chen HS, Eng HL, Sheen CC, Chen WJ. Serum levels of matrix metalloproteinase 2 in patients with breast cancer. Cancer Lett. 2001; 173: 79-82.
64.Franchi A, Santucci M, Masini E, Sardi I, Paglierani M, Gallo O. Expression of matrix metalloproteinase 1, matrix metalloproteinase 2, and matrix metalloproteinase 9 in carcinoma of the head and neck. Cancer. 2002; 95: 1902-10.
65.Kawamata H, Uchida D, Hamano H, Kimura-Yanagawa T, Nakashiro KI, Hino S, Omotehara F, Yoshida H, Sato M. Active-MMP2 in cancer cell nests of oral cancer patients: correlation with lymph node metastasis. Int J Oncol. 1998; 13: 699-704.
66.Justicia C, Panes J, Sole S, Cervera A, Deulofeu R, Chamorro A, Planas AM. Neutrophil infiltration increases matrix metalloproteinase-9 in the ischemic brain after occlusion/reperfusion of the middle cerebral artery in rats. J Cereb Blood Flow Metab. 2003; 23: 1430-40.
67.Susskind H, Hymowitz MH, Lau YH, Atkins HL, Hurewitz AN, Valentine ES, Meek AG, Zucker S. Increased plasma levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in lung and breast cancer are altered during chest radiotherapy. Int J Radiat Oncol Biol Phys. 2003; 56: 1161-9.
68.Hovdenak N WJ, Sung CC, Kelly T, Fajardo LF, Hauer JM. Clinical significance of increased gelatinolytic activity in the rectal mucosa during external beam radiation therapy of prostate cancer. Int J Radiat Oncol Biol Phys. 2002; 53: 919-27.
69.Donnahoo KK, Meng X, Ayala A, Cain MP, Harken AH, Meldrum DR. Early kidney TNF-alpha expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion. Am J Physiol. 1999; 277: R922-9.
70.Sasanelli R, Boccarelli A, Giordano D, Laforgia M, Arnesano F, Natile G, Cardellicchio C, Capozzi MA, Coluccia M. Platinum complexes can inhibit matrix metalloproteinase activity: platinum-diethyl[(methylsulfinyl)methyl]phosphonate complexes as inhibitors of matrix metalloproteinases 2, 3, 9, and 12. J Med Chem. 2007; 50: 3434-41.
71.Mysliwiec AG, Ornstein DL. Matrix metalloproteinases in colorectal cancer. Clin Colorectal Cancer. 2002; 1: 208-19.
72.Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, Jiang RS. Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med. 2004; 350: 2461-70.