查看犬血管肉瘤的治疗：2000 年及以后的源代码

== 基质金属蛋白酶抑制剂 (Matrix Metalloproteinase Inhibitors) ==

基质金属蛋白酶是至少 26 种膜结合或分泌的锌内肽酶的家族[41,59–64] 这些酶可以降解细胞外基质的许多成分，包括原纤维和非原纤维胶原、纤连蛋白、层粘连蛋白和基底膜糖蛋白[39,59,63–65] 基质金属蛋白酶在正常生理条件下起着重要作用，例如伤口愈合、怀孕和其他涉及组织重塑的过程[59，60,65] 基质金属蛋白酶的组织抑制剂也存在，可维持细胞外基质破坏和形成之间的平衡。在健康动物中，细胞分裂、基质形成和基质降解之间存在微妙的平衡。

细胞外基质是肿瘤生长和转移能力的主要障碍.66恶性肿瘤有时可以利用基质金属蛋白酶来克服这种细胞外屏障[59,66] 基质金属蛋白酶不仅与促进肿瘤侵袭血液或淋巴管有关，还与调节原发性和继发部位的增殖以及产生和维持使肿瘤生长的局部环境有关[60,63,65,66] 在人类癌症患者中记录了基质金属蛋白酶活性的增加，并且与某些患者的存活率低有关[59,60,63,66] 据报道，与正常狗相比，患有肿瘤的狗的基质金属蛋白酶活性增加[62]

大多数基质金属蛋白酶是由基质细胞而不是由肿瘤细胞合成的，这表明肿瘤细胞与直接环境中的细胞之间存在相互作用[59,66] 基质金属蛋白酶受体存在于基质细胞上，也必须存在于肿瘤细胞上，以便发生基质金属蛋白酶的结合和激活[59,66] 在癌症状态下， 基质金属蛋白酶和基质金属蛋白酶的组织抑制剂之间可能存在不平衡。天然存在的基质金属蛋白酶组织抑制剂在实验系统中抑制了肿瘤诱导的血管生成[59,64] 由于其在体内的生物半衰期短，天然存在的基质金属蛋白酶组织抑制剂不适合临床研究。因此，已经开发出具有药理增强活性的合成基质金属蛋白酶抑制剂。例子包括 Marimastat、Bay 12–9566、AG3340、CGS27023A、COL-3 和 BMS-275291[40] 在实验研究中，基质金属蛋白酶抑制剂降低了原发性肿瘤生长速率、局部扩散和远处转移[63] 当这些药物与细胞毒性药物联合使用时，观察到累加效应。几种合成基质金属蛋白酶抑制剂已进入 III 期人体临床试验，用于治疗肺癌、乳腺癌、卵巢癌、胰腺癌和前列腺癌[63-67]。

在兽医学中，基质金属蛋白酶与肿瘤之间的关系尚不完全清楚。研究的重点是识别基质金属蛋白酶并确定与各种恶性肿瘤的关联[62,65,68-71]此类研究的临床应用有望导致用于辅助治疗的特异性基质金属蛋白酶抑制剂的设计。用于治疗各种恶性肿瘤的基质金属蛋白酶抑制剂的初步研究正在进行中（Ogilvie，个人通讯）。


The matrix metalloproteinases are a family of at least 26 membrane-bound or secreted zinc-endopeptidases.41,59–64 These enzymes can degrade many components of the extracellular matrix, including fibrillar and nonfibrillar collagens, fibronectin, laminin, and basement membrane glycoproteins.39,59,63–65 The matrix metalloproteinases play an important role in normal physiologic conditions such as wound healing, pregnancy, and other processes involving tissue remodeling.59,60,65 Tissue inhibitors of matrix metalloproteinases also exist that maintain a balance between extracellular matrix destruction and formation. In the healthy animal, a delicate balance exists between cell division, matrix formation, and matrix degradation.

The extracellular matrix constitutes a major barrier to tumor growth and metastatic ability.66 Malignant tumors can sometimes utilize matrix metalloproteinases to overcome this extracellular barrier.59,66 Matrix metalloproteinases are implicated not only in the promotion of tumor invasion of blood or lymphatic vessels but also in the regulation of proliferation at primary and secondary sites and the production and maintenance of a local environment that will enable tumor growth.60,63,65,66 Increased matrix metalloproteinase activity has been documented in human cancer patients and has been associated with poor survivability in some patients.59,60,63,66 Dogs with neoplasia reportedly have increased matrix metalloproteinase activity compared to normal dogs.62

Most matrix metalloproteinases are synthesized by stromal cells rather than by neoplastic cells, suggesting an interaction between neoplastic cells and cells within the immediate environment.59,66 Matrix metalloproteinase receptors are present on stromal cells and must also be present on tumor cells in order for binding and activation of matrix metalloproteinases to occur.59,66 In cancer states, an imbalance may exist between matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. Naturally occurring tissue inhibitors of matrix metalloproteinases have inhibited tumor-induced angiogenesis in experimental systems.59,64 Because of their short biologic half-life in vivo, naturally occurring tissue inhibitors of matrix metalloproteinases are not suitable for clinical studies. Therefore, synthetic matrix metalloproteinase inhibitors with pharmacologically enhanced activity have been developed; examples include Marimastat, Bay 12–9566, AG3340, CGS27023A, COL-3, and BMS-275291.40 In experimental studies, matrix metalloproteinase inhibitors have reduced primary tumor growth rates, localized spread, and distant metastasis.63 Additive effects were observed when these agents were used in combination with cytotoxic drugs. Several synthetic matrix metalloproteinase inhibitors have entered phase III human clinical trials for treatment of lung, breast, ovarian, pancreatic, and prostate cancers.63–67

In veterinary medicine the relationship between matrix metalloproteinases and neoplasia is not completely understood. Research is centered on identifying matrix metalloproteinases and determining associations with various malignancies.62,65,68–71 The clinical application of such studies will hopefully lead to the design of specific matrix metalloproteinase inhibitors for adjuvant treatment. Preliminary investigation of matrix metalloproteinase inhibitors for the treatment of a variety of malignant neoplasms is underway (Ogilvie, personal communication).

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