查看犬血管肉瘤的治疗：2000 年及以后的源代码

== 抑制血管生成 (Inhibition of Angiogenesis) ==

血管生成是'''从现有的微血管形成新的血管'''。'''这是转移的重要组成部分'''，提供了肿瘤细胞离开原发肿瘤部位并进入循环的主要途径[37] 假设肿瘤无限期存在而没有新生血管形成，直到肿瘤内的细胞“转换”为血管生成表型[38] 肿瘤可以通过血管生成因子的过度表达改变局部环境来诱导血管生成， 募集局部细胞并诱导其释放血管生成因子，从细胞外基质中动员血管生成蛋白，或减少抗血管生成组织因子的释放[38]相反，肿瘤也可以通过激活血管生成抑制剂来抑制血管生成，这些抑制剂可以调节原发肿瘤和转移部位的新血管形成。血管生成抑制剂的丢失可以解释在患有骨肉瘤和 HSA 的狗中观察到的原发肿瘤切除后有时可见的肺转移增殖。

已知至少有 15 种蛋白质可激活内皮细胞生长和运动，包括成纤维细胞生长因子、血管内皮生长因子、血管生成素、转化生长因子、肿瘤坏死因子 α、表皮生长因子、血小板衍生的内皮细胞生长因子、胎盘生长因子、白细胞介素-8、粒细胞刺激因子和增殖素[38] 血管内皮生长因子和碱性成纤维细胞生长因子由许多肿瘤表达并起作用直接在内皮细胞上，而转化生长因子和血小板衍生的生长因子吸引并激活炎症细胞或结缔组织细胞，进而控制血管生成。

一般来说，用于设计抗血管生成剂的 4 种主要策略是阻断刺激新血管形成的因子、利用血管生成的天然抑制剂、阻断允许新形成的血管侵入周围组织的分子，以及使新分裂的内皮细胞丧失能力。一些已知的血管生成抑制剂包括血管生长抑制素、内皮抑素、血管抑制类固醇、干扰素、白细胞介素-12、视黄酸和基质金属蛋白酶-1 和 -2的组织抑制剂[38-40]. 血管生成抑制剂不会产生不良反应，例如通常与化疗药物相关的骨髓抑制和胃肠道症状，并且似乎不会诱导多药耐药性[41] 目前正在评估大约 20 种血管生成抑制剂在I期或II期人体临床试验中，3 项已进入III期试验[38,39,42]。

Angiogenesis is the formation of new vessels from existing microvessels. This is an essential component of metastasis, providing the principal route by which tumor cells leave the primary tumor site and enter the circulation.37 Tumors are hypothesized to exist for an indefinite period of time without neovascularization until cells within the tumor ‘‘switch’’ to an angiogenic phenotype.38 Tumors can induce angiogenesis by altering the local environment via overexpression of angiogenic factors, recruitment of local cells and induction of their release of angiogenic factors, mobilization of angiogenic proteins from the extracellular matrix, or reduction of the release of antiangiogenic tissue factors.38 Conversely, tumors may also inhibit angiogenesis by activating angiogenic inhibitors that can modulate new vessel formation both at the primary tumor and at meta-static sites. Loss of angiogenic inhibitors may explain the proliferation of lung metastasis sometimes seen after removal of the primary tumor observed in dogs with osteosarcoma and HSA.

At least 15 proteins are known to activate endothelial cell growth and movement, including fibroblastic growth factor, vascular endothelial growth factor, angiogenin, transforming growth factors, tumor necrosis factor alpha, epidermal growth factor, platelet-derived endothelial cell growth factor, placental growth factor, interleukin-8, granulocyte-stimulating factor, and proliferin.38 Vascular endothelial growth factor and basic fibroblastic growth factor are expressed by many tumors and act directly on endothelial cells, whereas transforming growth factor and platelet-derived growth factor attract and activate inflammatory cells or connective tissue cells, which in turn control angiogenesis.

In general, the 4 primary strategies used to design antiangiogenic agents are blockade of the factors that stimulate the formation of new vessels, utilization of natural inhibitors of angiogenesis, blockade of the molecules that allow newly formed vessels to invade surrounding tissue, and incapacitation of newly dividing endothelial cells. Some of the known inhibitors of angiogenesis include angiostatin, endostatin, angiostatic steroids, interferons, interleukin-12, retinoic acid, and tissue inhibitor of matrix metalloproteinase-1 and -2.38–40 Angiogenesis inhibitors do not produce adverse effects such as the bone marrow suppression and gastrointestinal symptoms commonly associated with chemotherapeutic agents and do not seem to induce multidrug resistance.41 Approximately 20 angiogenesis inhibitors are currently being evaluated in phase I or phase II human clinical trials and 3 have entered phase III trials.38,39,42


'''干扰素 (Interferons)'''

干扰素（α 和 β）是人类医学中最受认可的血管生成抑制剂之一，对治疗患有血管瘤的儿童有效[43-46] 干扰素治疗可以诱导以前对其他疗法无反应的血管瘤完全消退[47]. 干扰素 α-2a 似乎通过抑制碱性成纤维细胞生长因子和血管内皮生长因子的产生来抑制血管生成。碱性成纤维细胞生长因子是儿童血管瘤过度表达的蛋白质之一，而血管内皮生长因子血清水平在患有另一种血管肿瘤血管肉瘤的人类中升高[38,48] 碱性成纤维细胞生长因子的尿液浓度在患有移行细胞癌的狗中增加，但在患有 HSA 的狗中尚未报告[49]

干扰素α是市售的，并已进入各种人类恶性肿瘤的III期临床试验[39,42]目前的几项临床研究兽医研究正在进行中，评估干扰素α-2b 加标准化疗（AC，多柔比星）以及另一种抗血管生成药物沙利度胺（Vail和Post，个人交流）。在狗身上使用干扰素的主要潜在缺点是费用高昂和主人对每日注射的依从性差。最终可能会产生针对干扰素的中和抗体，从而限制疗效并需要使用更高剂量。然而，这还有待证实。在人类医学中，关于抗干扰素抗体是否对干扰素治疗的疗效有重大影响的争论正在进行中[50,51]。

The interferons (alpha and beta) are among the most well-recognized angiogenic inhibitors in human medicine and are efficacious in the treatment of children with hemangiomas.43–46 Interferon treatment can induce complete regression of hemangiomas previously unresponsive to other therapies.47 Interferon alpha-2a seems to inhibit angiogenesis via suppression of basic fibroblastic growth factor and vascular endothelial growth factor production. Basic fibroblastic growth factor is one of the proteins overexpressed by hemangiomas in children, whereas vascular endothelial growth factor serum levels are elevated in humans with another vascular neoplasm, angiosarcoma.38,48 Urine concentrations of basic fibroblastic growth factor are increased in dogs with transitional cell carcinoma but have yet to be reported in dogs with HSA.49

Interferon alpha is commercially available and has entered phase III clinical trials for a variety of human malignancies.39,42 Several current clinical studies veterinary studies are underway evaluating interferon alpha-2b in combination with standard chemotherapy (AC, doxorubicin) as well as with another antiangiogenic agent, thalidomide (Vail and Post, personal communication). The major potential disadvantages of interferon use in dogs are expense and poor owner compliance with daily injections. Neutralizing antibodies may eventually be produced against the interferon, thereby limiting efficacy and necessitating the use of higher doses; however, this is yet to be proven. In human medicine debate is ongoing as to whether or not anti-interferon antibodies have a significant impact on the efficacy of interferon therapy.50,51


'''沙利度胺 (Thalidomide)'''

沙利度胺是一种著名的致畸药物，是一种血管生成抑制剂[52] 沙利度胺可能抑制血管内皮生长因子、碱性成纤维细胞生长因子和肿瘤坏死因子 α，并且可能为癌症治疗提供有吸引力的替代方案，因为它能够抑制血管生成和预防肿瘤坏死因子 α 相关的恶病质[52-54] 肿瘤坏死因子 α 的抑制似乎是剂量依赖性的[52] 沙利度胺的一个潜在优势是，在非怀孕的狗中使用沙利度胺的不良反应很少[55] 沙利度胺已进入 II 期人体临床试验，用于治疗各种恶性肿瘤[39,54,56-58] 沙利度胺目前正在 I 期和 II 期兽医临床研究中作为患有多种恶性肿瘤的狗的单一药物进行检查[55] 沙利度胺目前正在几项临床兽医试验中对单独使用 HSA 或与标准化疗多柔比星联合使用的狗进行评估（Khanna、Post、Matthews 和 Meleo，个人交流）。

沙利度胺和任何血管生成抑制剂的一个潜在缺点是，明显的有益作用可能发展缓慢。因为从理论上讲，血管生成抑制剂只会损害新血管的发育，所以这些药物对预先存在的肿瘤组织可能几乎没有影响。因此，尽管血管生成抑制剂可以预防肿瘤转移，但需要额外的治疗方式来减少原有肿瘤负荷的大小。

Thalidomide, a noted teratogenic drug, is an inhibitor of angiogenesis.52 Thalidomide likely inhibits vascular endothelial growth factor, basic fibroblastic growth factor, and tumor necrosis factor alpha, and may offer an attractive alternative in cancer treatment because of its ability to inhibit angiogenesis and prevent tumor necrosis factor alpha–associated cachexia.52–54 Inhibition of tumor necrosis factor alpha seems to be dose dependent, and high doses of thalidomide may be necessary to achieve a therapeutic effect.52 One potential advantage of thalidomide is the paucity of adverse effects associated with its usage in nonpregnant dogs.55 Thalidomide has entered phase II human clinical trials for the treatment of a variety of malignancies.39,54,56–58 Thalidomide is currently being examined in a phase I and phase II veterinary clinical study as a single agent in dogs with a variety of malignancies and thus far the drug seems to be well tolerated.55 Thalidomide is also currently being evaluated in several clinical veterinary trials in dogs with HSA alone or in combination with a standard chemotherapy, doxorubicin (Khanna, Post, Matthews, and Meleo, personal communication).

One potential disadvantage of thalidomide and of any inhibitor of angiogenesis is that obvious beneficial effects may be slow to develop. Because inhibitors of angiogenesis in theory will only impair new vessel development, such drugs may have little or no effect on pre-existing tumor tissue. Therefore, although inhibitors of angiogenesis may prevent tumor metastases, additional therapeutic modalities are needed to reduce the size of the pre-existing tumor burden.

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