2024年6月25日 (二) 15:26的版本

Treatment of canine hemangiosarcoma: 2000 and beyond

https://doi.org/10.1892/0891-6640(2000)014%3C0479:tochab%3E2.3.co;2

1 摘要

犬血管肉瘤 （HSA） 是一种侵袭性恶性肿瘤，预后严重。手术和化疗在延长 HSA 狗狗的生存时间和提高生活质量方面的成功有限。肿瘤内科的进步正在提高兽医癌症患者的生存率和生活质量。对转移机制的理解导致了旨在延缓或抑制肿瘤扩散的新疗法的开发。有前途的新治疗选择包括新型给药系统（吸入或腔内化疗）;使用免疫调节剂，如脂质体封装的胞壁酰三肽-磷脂酰乙醇胺;抗转移药物，如血管生成抑制剂（干扰素、沙利度胺）、基质金属蛋白酶抑制剂和米诺环素;饮食调整;和基因治疗。血管生成抑制剂似乎是安全的，并且与传统化疗不同，不会引起耐药性。尽管许多较新的方法仍在开发和审查中，但使用结合创新治疗方式的多模式疗法可能为受 HSA 影响的狗提供最佳治疗选择。

Canine hemangiosarcoma (HSA) is an aggressive and malignant neoplasia with a grave prognosis. Surgery and chemotherapy have limited success in prolonging survival times and increasing quality of life in dogs with HSA. Advances in medical oncology are resulting in increased survival rates and a better quality of life for veterinary cancer patients. An understanding of mechanisms of metastasis has led to the development of new treatments designed to delay or inhibit tumor spread. Promising new treatment options include novel delivery systems (inhalation or intracavitary chemotherapy); use of immunomodulators such as liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine; antimetastatic agents such as inhibitors of angiogenesis (interferons, thalidomide), matrix metalloproteinase inhibitors, and minocycline; dietary modifications; and gene therapy. Inhibitors of angiogenesis seem to be safe and, unlike conventional chemotherapy, do not induce drug resistance. Although many of the newer approaches are still under development and review, the use of multimodality therapy incorporating innovative treatment modalities may offer the best therapeutic option for dogs affected with HSA.

2 概述

血管肉瘤 （HSA） 是一种高度恶性的内皮细胞肿瘤，在狗中比任何其他家养物种更频繁地发生，其特点是病死率高[1-4]。据报道，总患病率为狗所有肿瘤的 0.3-2.0%[1,2]。受影响的狗在诊断时的平均年龄为 9-12 岁[1-4]。HSA 几乎影响每个犬种。然而，德国牧羊犬、金毛猎犬、拉布拉多猎犬和雪纳瑞犬是易感的[1-4]。尽管许多报告显示雄性患病率增加，但尚未证实性别偏好[1-4]。HSA 的病因尚不清楚，尽管强烈的品种关联表明遗传或家族易感性。在人类中，暴露于二氧化钍或砷或氯乙烯化合物与HSA的发展有关[5]。皮肤HSA通常存在于浅色素沉着的狗中，这表明可能与紫外线暴露有关[6]。另一个假设的狗HSA形成因素是局部辐射[7]。

HSA 有可能影响身体的任何组织，3 个常见的原发部位是脾脏 （28-50%）、右心房和耳廓 （3-50%），以及皮肤或皮下组织 （13%）[1,8-10]。其他原发部位包括肝脏、肾脏、膀胱、前列腺、腹膜、肺、肺动脉、主动脉、肌肉、骨骼、口腔、舌头、椎体、 和中枢神经系统[2,10-17]。转移和局部浸润发生在疾病早期。肝脏、网膜和肺是最常见的转移部位[1-4]。可发生血行性转移或在肿瘤破裂后通过局部播种转移 (Metastasis may occur hematogenously or via local seeding after tumor rupture)。高达 25% 的脾肿瘤有相应的心脏肿瘤（右心房和耳廓）[1,2]。最初，心脏肿瘤被认为是转移性的。然而，这些现在通常被认为是 2 个独立的原发性肿瘤[12]。皮肤 HSA 往往具有较低的转移率，显然肿瘤越深，转移的可能性就越大。在患有晚期 HSA 的狗中，通常无法确定原发部位。

本文的目标有 3 个方面：第一，简要概述 HSA 的治疗方案。第二，检查最近的治疗方案。第三，提供对当前几个项目的一瞥，这些项目可能对未来的HSA治疗有希望。

Hemangiosarcoma (HSA) is a highly malignant tumor of endothelial cells that occurs more frequently in dogs than any other domestic species and is characterized by a high case fatality rate.1–4 The overall prevalence is reported to be 0.3–2.0% of all tumors in dogs.1,2 The mean age of affected dogs at the time of diagnosis is 9–12 years.1– 4 HSA affects almost every dog breed; however, German Shepherd Dogs, Golden Retrievers, Labrador Retrievers, and Schnauzers are predisposed.1–4 No sex predilection has been proven, although many reports have shown an increased prevalence in males.1–4 The etiology of HSA is unknown, although the strong breed association suggests an inherited or familial predisposition. In humans, exposure to thorium dioxide or arsenical or vinyl chloride compounds has been linked to the development of HSA.5 Cutaneous HSA is generally found in lightly pigmented dogs, suggesting a possible correlation with ultraviolet light exposure.6 Another hypothesized contributory factor to HSA formation in dogs is local irradiation.7

HSA has the potential to affect any tissue in the body, with the 3 common primary sites being the spleen (28– 50%), right atrium and auricle (3–50%), and skin or subcutaneous tissue (13%).1,8–10 Other primary sites include liver, kidney, bladder, prostate, peritoneum, lung, pulmonary artery, aorta, muscle, bone, oral cavity, tongue, vertebral body, and central nervous system.2,10–17 Metastasis and local infiltration occur early in disease. The liver, omentum, and lung are the most common sites of metastasis.1–4 Metastasis may occur hematogenously or via local seeding after tumor rupture. Up to 25% of splenic tumors have a corresponding cardiac tumor (right atrial and auricular).1,2 Initially, the cardiac tumor was thought to be metastatic; however, these now generally are accepted to be 2 separate primary tumors.12 Cutaneous HSA tends to have a lower metastatic rate, and apparently the deeper the tumor, the greater the likelihood of metastasis. In dogs with advanced HSA, determining the primary site often is not possible.

The goals of this article are 3-fold: 1st, to provide a brief historical overview of treatment options for HSA; 2nd, to examine more recent treatment options; and 3rd, to offer a glimpse into several current projects that may hold promise for the future treatment of HSA.

3 传统疗法 (Traditional Therapy)

从历史上看，手术一直是 HSA 的首选治疗方法，尽管它对改善总体生存时间几乎没有作用.4,18,19 三项对仅通过手术治疗的脾脏 HSA 狗的研究报告称，中位生存时间为 2-3 个月[4,18,19]。心脏 HSA 的手术切除也产生了不令人满意的结果，中位生存时间从 3 到 5 个月不等[20-22]。皮肤 HSA 通常与更长的生存时间有关[23]。由于手术的局限性[11]，据报道，基于多柔比星的各种方案，无论是否添加长春新碱和环磷酰胺，都具有最佳生存时间[2,3,24-27]。已发表的方案包括单药阿霉素（30 mg/m^2，静脉注射，每 3 周一次，最多 5 个周期）；多柔比星和环磷酰胺（阿霉素作为单药方案，在每 3 周周期的第 3-6 天静脉注射环磷酰胺 50-75 mg/m^2）；和长春新碱、多柔比星和环磷酰胺（多柔比星作为单药方案，环磷酰胺在每 3 周周期的第 1 天静脉注射 100 mg/m^2，长春新碱在每个周期的第 8 天和第 15 天静脉注射）[1-3,24-26]。据报道，各种基于多柔比星的方案的生存时间从 140 到 202 天不等， 虽然没有任何一个方案明显更好。

Historically, surgery has been the treatment of choice for HSA, although it does little to improve overall survival times.4,18,19 Three studies of dogs with splenic HSA treated by surgery alone reported median survival times of 2–3 months.4,18,19 Surgical excision for cardiac HSA also yields unsatisfactory results, with median survival times ranging from 3 to 5 months.20–22 Cutaneous HSA is generally associated with longer survival times.23 Because of the limitations of surgery, chemotherapy has evolved into a principal component of therapy.11 Various protocols based on doxorubicin with and without the addition of vincristine and cyclophosphamide have been reported to have the best survival times.2,3,24–27 Published protocols include single-agent doxorubicin (30 mg/m2 intravenously every 3 weeks for up to 5 cycles); doxorubicin and cyclophosphamide (doxorubicin as for single-agent protocol, with cyclophosphamide incorporated at 50–75 mg/m2 intravenously on days 3–6 of every 3-week cycle); and vincristine, doxorubicin, and cyclophosphamide (doxorubicin as for single-agent protocol, with cyclophosphamide incorporated at 100 mg/m2 intravenously on day 1 of every 3-week cycle, and vincristine at 0.75 mg/m2 intravenously on days 8 and 15 of each cycle).1–3,24–26 Survival times ranging from 140 to 202 days have been reported for the various doxorubicin-based protocols, although no protocol is clearly superior [3,24-27].

NOTES:

Protocol 1:
单药阿霉素（30 mg/m^2，静脉注射，每 3 周一次，最多 5 个周期）
Single-agent doxorubicin (30 mg/m^2 intravenously every 3 weeks for up to 5 cycles)

Protocol 2:
多柔比星和环磷酰胺（阿霉素作为单药方案，在每 3 周周期的第 3-6 天静脉注射环磷酰胺 50-75 mg/m^2）
doxorubicin and cyclophosphamide (doxorubicin as for single-agent protocol, with cyclophosphamide incorporated at 50–75 mg/m^2
 intravenously on days 3–6 of every 3-week cycle)

Protocol 3:
长春新碱、多柔比星和环磷酰胺 联用（多柔比星作为单药方案，环磷酰胺在每 3 周周期的第 1 天静脉注射 100 mg/m^2，长春新碱在每个周期的第 8 天和第 15 天静脉注射）
vincristine, doxorubicin, and cyclophosphamide (doxorubicin as for single-agent protocol, with cyclophosphamide incorporated at 100 mg/m^2
 intravenously on day 1 of every 3-week cycle, and vincristine at 0.75 mg/m2 intravenously on days 8 and 15 of each cycle)

4 新型输送系统 (Novel Delivery Systems)

对 HSA 转移行为的理解促使设计了针对预防转移的方案。许多患有 HSA 的狗死于肺部和腹腔内转移性疾病。针对常见转移部位的额外局部化疗可能有可能延缓转移并延长生存期28。

An understanding of the metastatic behavior of HSA has prompted the design of protocols tailored to the prevention of metastases. Many dogs with HSA die of pulmonary and intra-abdominal metastatic disease. Additional locally delivered chemotherapy aimed at common metastatic sites may have the potential to retard metastasis and prolong survival.28

吸入化疗是旨在抑制肺部微转移的一种策略。吸入化疗的疗效和安全性研究已在几只患有脾脏 HSA 的狗中进行.28 脾切除术后，狗每 3 周接受 4 个周期的多柔比星和环磷酰胺以及吸入阿霉素。吸入式阿霉素是一种新开发的制剂，通过专门设计的气溶胶装置给药。在第 4 个周期完成后进行 X 光检查和腹部超声检查，此后每 2 个月进行一次。对数据的中期分析表明，该方案可能是有效的，并且没有注意到由于同时全身性多柔比星化疗而增加的毒性28。

Inhalation chemotherapy is 1 strategy aimed at inhibiting pulmonary micrometastasis. Efficacy and safety studies with inhalation chemotherapy have been performed in several dogs with splenic HSA.28 After splenectomy, dogs received 4 cycles of doxorubicin and cyclophosphamide every 3 weeks in conjunction with inhaled doxorubicin. The inhaled doxorubicin was a newly developed formulation that was administered via a specially designed aerosol device. Radiographs and abdominal ultrasound were performed after the completion of the 4th cycle and every 2 months thereafter. Interim analysis of data suggests that this protocol may be efficacious and no increase in toxicity due to concurrent systemic doxorubicin chemotherapy has been noted.28

空间稳定脂质体是含有一小部分膜糖脂或其他表面稳定剂的脂质体，可作为硬脂屏障外膜.29 该制剂导致单核细胞吞噬系统的摄取减少，从而延长了肿瘤对药物的暴露.29 聚乙二醇化脂质体包封的多柔比星是一种独特的多柔比星递送系统.29 Doxil 已在患有多种恶性肿瘤的狗中进行了评估， 包括HSA，与阿霉素相比，具有增强的杀瘤作用、降低的心脏毒性和持续的药物血液水平29,30。

Sterically stabilized liposomes are liposomes containing a small fraction of membrane glycolipid or other surface stabilizer that acts as a stearic barrier outer membrane.29 This formulation results in decreased uptake by the monocytic phagocytic system thereby prolonging tumor exposure to the drug.29 Pegylated liposomal-encapsulated doxorubicina is a unique doxorubicin delivery system.29 Doxil has been evaluated in dogs with a variety of malignancies, including HSA, and has enhanced tumoricidal effects, decreased cardiotoxicity, and sustained drug blood levels compared to doxorubicin.29,30

腹腔是 HSA 患者转移性肿瘤扩散的另一个常见部位.31 腹腔转移的一种方法是腔内给予化疗药物，如顺铂或卡铂。32 正在研究腹腔内卡铂对明显腹腔转移性 HSA 狗的疗效（后，个人交流）。然而，由于卡铂的组织扩散和渗透能力低于顺铂，因此卡铂不太可能提高对HSA的疗效33,34。

The abdominal cavity is another common site of metastatic tumor spread in HSA patients.31 One approach to abdominal metastases is the intracavitary administration of chemotherapeutic agents such as cisplatin or carboplatin. The use of intracavitary cisplatin has been described in dogs with various intra-abdominal tumors.32 The efficacy of intra-abdominal carboplatin in dogs with overt abdominal metastatic HSA is being investigated (Post, personal communication). However, because carboplatin has less tissue diffusion and penetration ability than cisplatin, carboplatin is unlikely to have improved efficacy against HSA.33,34

5 免疫调节剂 (Immunomodulators)

与化疗联合使用的生物反应调节剂可有效治疗犬HSA[35,36] 胞壁基三肽磷脂酰乙醇胺（MTP-PE）是胞壁基二肽（MDP）的亲脂性衍生物，MDP 是一种合成分子，类似于各种细菌的肽聚糖细胞壁的片段。MDP 和 MTP-PE 都可以非选择性地将巨噬细胞谱系的细胞激活到杀瘤状态，并且两者都可以封装在脂质体中以达到最佳药物递送状态。

脂质体包封的 MTP-PE（L-MTP-PE）与化疗一起给药时，可增加犬骨肉瘤患者的无病间隔和生存时间[35] LMTP-PE 也已与 HSA 狗的化疗联合评估[35] 在 1 项研究中，32 只患有脾 HSA 的狗，脾切除患者被分为 2 个治疗组[35] 一组每隔 3 周给予阿霉素和环磷酰胺（AC），进行 4 次治疗，以及每周两次的 L-MTP-PE，持续 8 周。对照组接受 AC 和安慰剂（空脂质体）。AC 和 LMTP-PE 联合治疗组的中位生存时间为277天，明显优于仅接受 AC 治疗的组（143 天）。使用 AC 和 L-MTP-PE 组合的生存时间也与先前报道的长春新碱、多柔比星和环磷酰胺（187 天）或 AC（178 天）等方案的生存时间相比有利[24,25] L-MTP-PE 在受 HSA 影响的狗中几乎没有发表额外的研究。对 L-MTP-PE 缺乏持续的研究兴趣可能是由于用于兽医的特定脂质体系统的供应有限以及产品的高成本。在未来几年内，可能会有更新、更具成本效益的脂质体递送系统问世。

Biologic response modifiers used in combination with chemotherapy are efficacious in the treatment of canine HSA.35,36 Muramyl tripeptide-phosphatidylethanolamine (MTP-PE) is a lipophilic derivative of muramyl dipeptide (MDP), a synthetic molecule that resembles a fragment of the peptidoglycan cell wall of various bacteria. Both MDP and MTP-PE can nonselectively activate cells of macrophage lineage into a tumorcidal state, and both can be encapsulated in liposomes for optimal drug delivery.

Liposome-encapsulated MTP-PE (L-MTP-PE), when given with chemotherapy, increases disease-free interval and survival time in canine osteosarcoma patients.35 LMTP-PE has also been evaluated in conjunction with chemotherapy in dogs with HSA.35 In 1 study of 32 dogs with splenic HSA, splenectomized patients were divided into 2 treatment groups.35 One group was administered doxorubicin and cyclophosphamide (AC) at 3-week intervals for 4 treatments as well as L-MTP-PE twice weekly for 8 weeks. The control group received AC and placebo (empty liposomes). The median survival time for the AC and LMTP-PE combination group was 277 days, which was significantly better than for the group receiving only AC (143 days). Survival times using AC and L-MTP-PE in combination also compared favorably to previously reported survival times with protocols such as vincristine, doxorubicin, and cyclophosphamide (187 days) or AC (178 days).24,25 Little additional research with L-MTP-PE in dogs affected with HSA has been published. The lack of ongoing research interest in L-MTP-PE may be due to the limited supply of the specific liposome system for veterinary use and the high cost of the product. Newer and more cost-effective liposomal delivery systems may become available within the next few years.

6 抗转移药物 (Antimetastatic Agents)

转移性“级联”是一个逐步的过程，肿瘤细胞通过该过程生长并扩散到身体的其他部位（图1）。简而言之，级联反应的阶段包括转化、血管生成、运动和侵袭、栓塞和进入循环、在毛细血管床中停留、粘附毛细血管壁、外渗到器官实质、适应局部微环境、肿瘤细胞增殖，然后进一步血管生成。了解转移所涉及的过程，可以生产和使用旨在控制转移级联反应中特定步骤的药物。

下一节将讨论几种能够通过影响血管生成（干扰素、沙利度胺）、预防基质分解（基质金属蛋白酶抑制剂、米诺环素）和饮食调整来改变转移的药物。下面讨论的许多药物已经或正在接受犬 HSA 治疗的检查。

The metastatic ‘‘cascade’’ is a step-wise process by which neoplastic cells grow and spread to other locations in the body (Fig 1). Briefly, the stages of the cascade include transformation, angiogenesis, motility and invasion, embolism and entrance into circulation, lodgment in capillary beds, adherence to capillary walls, extravasation into organ parenchyma, adjustment to local microenvironment, tumor cell proliferation, and then further angiogenesis. An understanding of the processes involved in metastasis allows for the production and use of agents designed to control specific steps within the metastatic cascade.

The following section will discuss several agents capable of altering metastasis through effects on angiogenesis (interferon, thalidomide), prevention of matrix breakdown (matrix metalloproteinase inhibitors, minocycline), and dietary modifications. Many of the agents discussed below have either been or are in the process of being examined for treatment of canine HSA.

7 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.

8 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).

9 四环素衍生物 (Tetracycline Derivatives)

米诺环素是四环素的半合成衍生物，具有抗血管生成和基质金属蛋白酶抑制特性，已成为多项人类癌症研究的焦点。米诺环素似乎抑制局部胶原酶活性，从而阻止血管生成。这种机制是由于基质金属蛋白酶的抑制还是通过基质金属蛋白酶非依赖性机制尚不清楚[72] 米诺环素在涉及人类患者颅内胶质瘤和实验室动物胰岛细胞癌和刘易斯肺癌的研究中是有效的[73-75] 一项研究显示，患有 HSA 的狗单独接受化疗（AC 方案）或化疗和米诺环素，并未显示生存时间的显着差异[76] 然而，米诺环素可能对病情较轻的狗有益[76]。

Minocycline, a semisynthetic derivative of tetracycline that has both antiangiogenic and matrix metalloproteinase inhibitory properties, has become the focus of several human cancer studies. Minocycline seems to inhibit local collagenase activity, thereby preventing angiogenesis. Whether this mechanism is due to inhibition of matrix metalloproteinases or via a matrix metalloproteinase–independent mechanism is unknown.72 Minocycline has been efficacious in studies involving intracranial glioma in human patients and islet cell carcinoma and Lewis lung carcinoma in laboratory animals.73–75 One study in which dogs with HSA received either chemotherapy (AC protocol) alone or chemotherapy and minocycline did not demonstrate a significant difference in survival times.76 However, minocycline may provide benefit in dogs with less advanced disease[76]

10 饮食调整 (Dietary Modifications)

最近，兽医癌症患者的营养方面受到了很多关注[77-84]。许多代谢异常与肿瘤有关。用于描述这些异常的副肿瘤综合征是癌症恶病质，其特征是尽管摄入了足够的营养，但体重减轻。碳水化合物、脂质和蛋白质代谢都会对癌症患者产生不利影响。

Recently, a great deal of attention has been directed toward nutritional aspects of the veterinary cancer patient.77–84 Numerous metabolic abnormalities have been associated with neoplasia. The paraneoplastic syndrome used to describe these abnormalities is cancer cachexia, which is characterized by weight loss despite adequate nutritional intake. Carbohydrate, lipid, and protein metabolism are all adversely affected in cancer patients.

癌症相关代谢异常的临床影响导致使用饮食操纵来试图减轻癌症恶病质。简单碳水化合物含量低的饮食，适量的高生物利用度蛋白质来源，补充 omega-3 脂肪酸和特定氨基酸，如精氨酸、甘氨酸、谷氨酰胺和半胱氨酸，可能对一些癌症患者有益[77]。癌症饮食管理的关键组成部分之一是利用脂肪来源作为主要的膳食能量成分， 注意脂肪酸的类型和比例与饮食[77,84]。高脂肪饮食可能对癌症患者有 2 个主要的有益影响[77,78,80,84]。首先，肿瘤似乎在使用脂肪作为能量来源方面效率低下，与正常体细胞相比，富含脂肪衍生卡路里的饮食可能会有效地“饿死”肿瘤细胞[77,80,84]。其次，特别是 omega-3 脂肪酸已被证明具有抗血管生成特性，并在动物模型中抑制肿瘤发展[78]。二十碳五烯酸是一种 omega-3 脂肪酸，在实验性肿瘤模型中具有杀瘤作用而不会损害正常细胞[78]。最近的一项双盲随机研究评估了富含多不饱和 omega-3 脂肪酸和精氨酸的特殊饮食对代谢参数的影响[77]。在特殊饮食的患者中注意到乳酸水平降低，与对照动物相比，这些狗的无病间隔和生存时间明显更长[79]，此后开发了一种可比较的商业饮食，旨在提高犬癌患者的生存时间和生活质量（希尔肿瘤饮食 Hill’s Neoplasia [ND]）[b]。虽然ND饮食是为患有淋巴瘤的狗设计的，它在其他肿瘤中的使用似乎是合理的[85]。因为患有HSA的动物已被证明会发展为癌症恶病质，因此饮食疗法可能是一种可行的治疗方式。目前，一项兽医研究正在检查饮食操纵对患有 HSA 的狗的影响（Ogilvie，个人交流）。

The clinical impact of cancer-associated metabolic abnormalities has led to the use of dietary manipulation in an attempt to lessen cancer cachexia. A diet low in simple carbohydrates with a moderate amount of a highly bioavailable protein source supplemented with omega-3 fatty acids and specific amino acids such as arginine, glycine, glutamine, and cysteine may be beneficial to some cancer patients.77 One of the key components to the dietary management of cancer is the utilization of a fat source as the major dietary energy component, with attention to the type and ratio of fatty acids with the diet.77,84 High-fat diets may have 2 major beneficial effects in cancer patients.77,78,80,84 First, tumors seem to be inefficient in using fat as an energy source, and a diet that is high in fat-derived calories may effectively ‘‘starve’’ neoplastic cells compared to normal body cells.77,80,84 Second, omega-3 fatty acids in particular have been shown to possess antiangiogenic properties, and inhibit tumor development in animal models.78 Eicosapentaenoic acid, an omega-3 fatty acid, has tumorcidal effects without damaging normal cells in experimental tumor models.78 A recent double-blind, randomized study evaluated the effect of a specialized diet high in polyunsaturated omega-3 fatty acids and arginine on metabolic parameters, chemical indices of inflammation, quality of life, and disease-free interval and survival time of dogs with lymphoma.77 Decreased levels of lactic acid were noted in patients on the special diet and these dogs had significantly longer disease-free interval and survival times compared to control animals.79 A comparable commercial diet has since been developed that is designed to enhance survival time and quality of life in canine cancer patients (Hill’s Neoplasia Diet [ND]).b Although the ND diet was designed for dogs with lymphoma, its use in other neoplasia seems plausible.85 Because animals with HSA have been shown to develop cancer cachexia, it stands to reason that dietary therapy may be a viable modality of treatment. Currently, a veterinary study is examining the effect of dietary manipulations on dogs with HSA (Ogilvie, personal communication).

根据 2015-2020 年美国人膳食指南，建议每周食用 8 至 12 盎司 (oz) 的海鲜，以获得必要的 omega-3。

美国心脏协会 (AHA) 建议每周至少食用两份鱼，以降低患心血管疾病的风险。

鱼油胶囊可能含有磷虾油或鱼肝油，但也有素食选择（藻油来自藻类）。

大多数人从他们吃的植物性食物（坚果和种子）中获得足够的 ALA。

但孕妇可能会对这些指南持谨慎态度，因为某些鱼类中存在汞的风险。

在这种情况下，孕妇仍应以每周至少 8 盎司（但少于 12 盎司）为目标，以帮助婴儿的认知和视力发育。

一定要选择汞含量较低的鱼，例如野生鲑鱼、鲱鱼、沙丁鱼、鳟鱼和大西洋或太平洋鲭鱼（但不要选择甲基汞含量高的鲭鱼）。

大多数鱼油或 omega-3 补充剂都含有 EPA 和 DHA，它们来自动物来源，[比来自植物来源的 ALA] 更具生物利用度说。

这些包括鱼类和其他海鲜，尤其是冷水、油性品种，如鲑鱼、金枪鱼、鲭鱼、鲱鱼、凤尾鱼和沙丁鱼。

核桃、奇亚籽和亚麻籽，以及它们的油和其他植物油（如菜籽油）也是 omega-3 的良好来源。

市场上的许多食品都添加了 omega-3。

当您寻找鸡蛋、牛奶、酸奶、果汁和豆浆制成的饮料时，请查看标签。

母乳和大多数婴儿配方奶粉都含有 ALA、EPA 和 DHA。

11 Reference

• Doxorubicin chemotherapy for presumptive cardiac hemangiosarcoma in dogs 2014 阿霉素化疗治疗狗的推定性心脏血管肉瘤

• Comparison of doxorubicin-cyclophosphamide with doxorubicin-dacarbazine for HSA 2017 多柔比星-环磷酰胺与多柔比星-达卡巴肼辅助治疗犬血管肉瘤的比较

• [b] Hill’s Neoplasia Diet, Hill’s Pet Nutrition, Topeka, KS

• Nutritional Management of Patients with Neoplasia 小动物肿瘤患者的营养管理