2024年7月13日 (六) 09:01的版本

Chemotherapeutic Management of Hemangiosarcoma in Canines – An Update

Division of Surgery, ICAR-Indian Veterinary Research Institute, India

Published: May 30, 2019

1 Abstract

血管肉瘤是一种累及犬科动物的恶性血管内皮肿瘤。它通常影响老年动物，并且还具有某些品种偏好的特征。脾脏是犬科动物最常受影响的器官，但皮肤相关的血管肉瘤较少见。血管肉瘤等恶性肿瘤的治疗应基于多模式疗法，该疗法结合了手术切除、化疗、放疗和免疫疗法等不同技术。尽管几种化疗药物可以单独使用或联合使用，但它在产生预期的生存期增加方面是无效的。发现紫杉醇和白藜芦醇等较新的药物在体外对血管肉瘤细胞系有效。但需要进一步的研究来评估这种化疗药物的体内效应。应进行进一步的研究，以确定有效的化疗药物，如紫杉醇和白藜芦醇，这些药物可用于临床治疗犬血管肉瘤，而没有任何副作用。

Hemangiosarcoma is a malignant vascular endothelial tumor affecting canines. It commonly affects older animals and is also characterized by certain breed predilection. Spleen is the most commonly affected organ in canines but skin associated hemangiosarcomas are less frequent. Management of malignant tumors like hemangiosarcoma should be based on multimodal therapy that combines different techniques like surgical excision, chemotherapy, radiation therapy, and immunotherapy. Even though several chemotherapeutic agents are used alone or as in combinations, it was ineffective in producing a desirable increase in the survival period. Newer agents like Paclitaxel and Resveratrol was found to be effective against hemangiosarcoma cell lines in-vitro. But further studies are required for evaluating the in-vivo effects of such chemotherapeutic agents. Further research should be directed to identify effective chemotherapeutic agents like Paclitaxel and Resveratrol that can be used to manage canine hemangiosarcoma clinically without any side effects.

2 Introduction

血管肉瘤是一种起源于血管内皮的恶性肿瘤。与其他兽医物种相比，它主要出现在犬科动物中。它主要发生在老年动物中，也被发现与某些品种有关：德国牧羊犬、金毛猎犬、拉布拉多猎犬、拳击师、伯尔尼山犬、德国短毛指针犬和平毛猎犬 [1]。Sabattini和Bettini [2]，（2009）报告说，德国牧羊犬品种是血管瘤和血管肉瘤受影响最大的品种。Lamerato-Kozicki[3]评估了关于犬血管肉瘤起源的两种假说，并得出结论，它们是由转化的血管母细胞干细胞引起的。这排除了血管肉瘤起源于突变导致的分化血管内皮细胞的假设。一项类似的研究报告称，血管肉瘤起源于多能祖细胞，该祖细胞具有分化为多个谱系的能力，这是适应过程的一部分[4]。Benjamin等[5]报道，通过将狗暴露于高水平的电离辐射，可以在狗身上进行实验性地发展血管肉瘤。犬血管肉瘤通常会累及脾脏。皮肤相关性血管肉瘤在犬科动物中较少见[6]。皮肤血管肉瘤根据其组织学位置分为三个阶段：真皮、皮下和深部。其中，皮肤（I期）皮肤血管肉瘤被发现不那么严重，与其他阶段相比，生存时间更长。皮下注射（II期）和深层（III期）的生存期较短。在深部（III.期）皮肤血管肉瘤中，皮肤下方的肌肉层也受累[7]。

Hemangiosarcoma is a type of malignant tumor that originates from the vascular endothelium. It is mostly seen in canines when compared to other veterinary species. It occurs mainly in older animals and is also found to be related to certain breeds German Shepherd, Golden Retriever, Labrador Retriever, Boxer, Bernese Mountain dog, German Shorthaired Pointer and Flat-Coated Retriever [1]. Sabattini & Bettini [2], (2009) reported that German shepherd dog breed was the most affected breed in case of hemangioma and hemangiosarcoma. Lamerato-Kozicki [3] evaluated two hypotheses regarding the origin of hemangiosarcoma in canine and concluded that they are arising from the transformed hemangioblastic stem cells. This ruled out the hypothesis that hemangiosarcoma are originating from the differentiated vascular endothelial cells due to mutation. A similar study reported that hemangiosarcoma arises from multipotent progenitors that has the ability to differentiate into multiple lineages as a part of adaptive process [4]. Benjamin et al. [5] reported that hemangiosarcoma can be developed experimentally in dogs by exposing them to high levels of ionizing radiations. Hemangiosarcoma in canines commonly affects the spleen. Skin associated hemangiosarcomas are less frequently seen in canines [6]. Cutaneous hemangiosarcomas are classified into three stages depending on their histological location as dermal, hypodermal, and deep. Among them dermal (Stage I) cutaneous hemangiosarcoma was found to be less severe and had higher survival times when compared to other stages. Hypodermal (Stage II) and Deep (Stage III) were having only shorter survival periods. In deep (Stage III) cutaneous hemangiosarcoma, the muscle layer below the skin are also involved [7].

对死于血管肉瘤的狗的尸检显示存在多器官转移[8]。Waters等[9]报道，与没有肺转移的狗相比，有肺转移的狗发生脑转移的风险要高8倍。因此，血管肉瘤肺转移的筛查也可作为颅内病变和相关症状的指征。完全切除是非内脏血管肉瘤的治疗方法选择。手术切除非内脏血管肉瘤可以使患者在至少一年内临床正常。在这种情况下，肿瘤切除不完全将导致复发[10]。Tsuji等[11]报道了一例犬皮肤血管肉瘤病例，其特征是从肘部到手指的左前肢多发性皮肤和皮下肿块。肿瘤边界划界不清，上覆皮肤溃疡。在骨骼和肌肉血管肉瘤的情况下，如果肢体和肌肉血管肉瘤局限于单个肢体，则可以尝试截肢。放射疗法可用于姑息治疗，以管理狗的血管肉瘤。在接受放射治疗时，在受脾血管肉瘤影响的非脾脏血管肉瘤患者中观察到肿瘤大小减小[12]。

Post-mortem examination of dogs died due to hemangiosarcoma revealed presence of multi-organ metastasis [8]. Waters et al. [9] reported that the dogs having pulmonary metastasis will have eight times greater risk of having brain metastasis when compared with the dogs without pulmonary metastasis. Hence screening for lung metastasis in hemangiosarcoma can be also used as an indication of intracranial lesion and associated symptoms. Complete excision is the choice of treatment in case of non-visceral hemangiosarcoma. Surgical removal of non-visceral hemangiosarcoma can make the patient clinically normal for at least a period of one year. Incomplete removal of tumor in such cases will result in recurrence [10]. Tsuji et al. [11] reported a case of canine cutaneous hemangiosarcoma characterized by multiple cutaneous and subcutaneous masses in the left forelimb from elbow to digits. The tumor showed poor demarcation and the overlying skin was ulcerated. Amputation of the limb can be attempted in cases of hemangiosarcomas of bones and muscles if they are localized to a single limb. Radiation therapy can be used for palliative treatment in managing hemangiosarcoma in dogs. Reduction in tumor size was observed in non-splenic hemangiosarcoma affected canine patients when treated with radiation therapy [12].

3 化疗 (Chemotherapy)

多柔比星（阿霉素）是血管肉瘤中常用的化疗药物，既可以作为单一药物使用[13,14]，也可以与其他药物（如环磷酰胺[15]和达卡巴嗪[16]联合使用。阿霉素也被用作与环磷酰胺和长春新碱的三药联合化疗，用于治疗狗血管肉瘤[17]。U'任等[18]评价了针对犬血管肉瘤的同种异体肿瘤裂解物疫苗的安全性和有效性。研究发现，使用多柔比星对接受化疗的狗进行疫苗接种会产生强烈的体液免疫反应，平均生存期为 182 天。将免疫疗法与化疗相结合可以提高患有血管肉瘤的犬患者的平均生存期。

Doxorubicin is the chemotherapeutic agent used commonly in case of hemangiosarcoma both as a single agent [13,14] and as a combination therapy with other agents like cyclophosphamide [15] dacarbazine [16]. Doxorubicin is also used as a three-drug combination chemotherapy with cyclophosphamide and vincristine in managing hemangiosarcoma in dogs [17]. U’ren et al. [18] evaluated the safety and efficacy of allogeneic tumor lysate vaccine directed against hemangiosarcomas in canines. It was found that vaccinating the dogs undergoing chemotherapy using doxorubicin produced strong humoral immune response and had mean survival period of 182 days. Combining Immunotherapy with chemotherapy can improves the mean survival period of canine patients affected with hemangiosarcoma.

在体外评估时，发现用作水溶性纳米颗粒胶束制剂的药物紫杉醇对犬血管肉瘤细胞系有效。对血管肉瘤的作用是由于药物的凋亡启动活性[19]。研究推荐的50%抑制浓度在临床上是可以达到的。需要进一步的体内研究来评估紫杉醇对血管肉瘤的疗效。

The drug paclitaxel used as water-soluble nanoparticle micellar formulation was found to be effective against canine hemangiosarcoma cell lines when evaluated in-vitro. The action against hemangiosarcoma was due to the apoptosis initiating activity of the drug [19]. The 50% inhibitory concentration recommended by the study was found to be clinically achievable. Further in-vivo studies are required to evaluate the efficacy of paclitaxel against hemangiosarcoma.

白藜芦醇是一种天然存在的非黄酮类多酚化合物，被发现对两种血管肉瘤细胞系具有生长抑制作用，因此使其成为纳入用于治疗犬血管肉瘤的基于多柔比星的化疗方案的合适候选者。白藜芦醇与多柔比星的组合增加了多柔比星的细胞毒性作用，而没有增加其心脏毒性作用[20]。

Resveratrol, a naturally found non-flavonoid polyphenolic compound was found to be having growth-inhibitory effect on two hemangiosarcoma cell lines thus making it a suitable candidate for incorporating into doxorubicin based chemotherapeutic regimens used to manage hemangiosarcoma in canines. The combination of resveratrol with doxorubicin increased the cytotoxic effect of doxorubicin without increasing its cardio toxic effects [20].

4 Conclusion

在过去的几年中，几种抗癌药物因其对许多恶性肿瘤的疗效而被评估。造成这种趋势的主要原因主要是由于基于蒽环类药物的化疗方案无法对抗血管肉瘤等恶性肿瘤。恶性肿瘤的治疗应基于多模式治疗，该疗法结合了手术切除、化疗、放疗和免疫疗法等不同技术。与单独进行化疗相比，联合疗法是治疗犬血管肉瘤的更好选择。进一步的体内研究对于确定可以有效管理犬血管肉瘤的新药物是必要的。最近的研究为开发有效的化疗药物带来了希望，因为发现几种新的化疗药物对几种血管肉瘤细胞系有效

During the past few years several anti-cancer agents are been evaluated for its efficacy against many malignant tumors. The main reason for such a trend is mostly due to the inability of anthracycline-based chemotherapeutic regimens against malignant tumors like hemangiosarcoma. Management of malignant tumors should be based on multimodal therapy that combines different techniques like surgical excision, chemotherapy, radiation therapy, and immunotherapy. Rather than going for chemotherapy alone combination therapy can be a better option in managing canine hemangiosarcoma. Further in-vivo studies are necessary for identifying newer agents that can effectively manage canine hemangiosarcoma. Recent studies give a hope for the development of effective chemotherapeutic agent since several new chemotherapeutic agents were found to be effective against several hemangiosarcoma cell line

5 Reference

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