MacEwen E G, Kurzman I D, Vail D M, Dubielzig R R, Everlith K, Madewell B R, Rodriguez C O, Phillips B, Zwahlen C H, Obradovich J, Rosenthal R C, Fox L E, Rosenberg M, Henry C, Fidel J
University of Wisconsin, School of Veterinary Medicine, Madison 53706, USA.
Clin Cancer Res. 1999 Dec;5(12):4249-58.
Spontaneous canine oral melanoma (COM) is a highly metastatic cancer, resistant to chemotherapy, and can serve as a model for cancer immunotherapy. Liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine (L-MTP-PE) can activate the tumoricidal activity of the monocyte-macrophage system following i.v. injection. The objective of these studies was to evaluate the therapeutic effectiveness of L-MTP-PE administered alone and combined with recombinant canine granulocyte macrophage colony-stimulating factor (rcGM-CSF) in dogs undergoing surgery for oral melanoma. Ninety-eight dogs with histologically confirmed, clinically staged, oral melanoma were entered into two randomized, double-blind, surgical adjuvant trials. In trial 1, 50 dogs were stratified based on clinical stage and randomized to once a week L-MTP-PE or lipid equivalent (control). When all of the clinical stages were combined, no difference in disease-free survival or in survival time (ST) were detected. However, within stage I, dogs receiving L-MTP-PE had a significant increase in ST compared with control, with 80% of the dogs treated with L-MTP-PE still alive at >2 years. Within each stage II and stage III, there was no difference detected between the treatment groups. In trial 2, 48 dogs were stratified on the basis of clinical stage and extent of surgery (simple resection or radical excision), treated with L-MTP-PE two times a week, and randomized to rcGM-CSF or saline (placebo) given s.c. daily for 9 weeks. Within each stage and when all of the stages were combined, there was no difference between the treatment groups. In both studies, stage I COM is associated with a better prognosis. No effect on survival was observed with regard to tumor location in the oral cavity, sex, type/extent of surgery, or age. In a subset of dogs tested, pulmonary alveolar macrophage cytotoxicity was enhanced with combined rcGM-CSF and L-MTP-PE but not in dogs treated with L-MTP-PE alone. The present study indicates that after surgery, L-MTP-PE administered alone or combined with rcGM-CSF showed no significant antitumor activity in treating advanced stage COM. In early stage COM, L-MTP-PE was shown to result in a prolongation of ST. Furthermore, this study provides additional rationale for the use of the dog model for human malignant melanoma.
自发性犬口腔黑色素瘤(COM)是一种具有高度转移性的癌症,对化疗耐药,可作为癌症免疫治疗的模型。脂质体包裹的胞壁酰三肽-磷脂酰乙醇胺(L-MTP-PE)静脉注射后可激活单核细胞-巨噬细胞系统的杀瘤活性。这些研究的目的是评估单独给予L-MTP-PE以及联合重组犬粒细胞巨噬细胞集落刺激因子(rcGM-CSF)对接受口腔黑色素瘤手术的犬的治疗效果。98只经组织学确诊、临床分期的口腔黑色素瘤犬进入两项随机、双盲、手术辅助试验。在试验1中,50只犬根据临床分期分层,随机分为每周一次的L-MTP-PE组或脂质等效物组(对照组)。当所有临床分期合并时,未检测到无病生存期或生存时间(ST)的差异。然而,在I期内,接受L-MTP-PE治疗的犬与对照组相比,ST显著增加,80%接受L-MTP-PE治疗的犬在2年以上仍存活。在每个II期和III期内,治疗组之间未检测到差异。在试验2中,48只犬根据临床分期和手术范围(单纯切除或根治性切除)分层,每周两次接受L-MTP-PE治疗,并随机分为rcGM-CSF组或生理盐水(安慰剂)组,每天皮下注射9周。在每个分期以及所有分期合并时,治疗组之间均无差异。在两项研究中,I期COM的预后较好。未观察到肿瘤在口腔中的位置、性别、手术类型/范围或年龄对生存有影响。在一部分受试犬中,rcGM-CSF和L-MTP-PE联合使用可增强肺泡巨噬细胞的细胞毒性,但单独使用L-MTP-PE治疗的犬则无此效果。本研究表明,手术后单独给予L-MTP-PE或联合rcGM-CSF在治疗晚期COM时未显示出显著的抗肿瘤活性。在早期COM中,L-MTP-PE可延长ST。此外,本研究为犬模型用于人类恶性黑色素瘤的研究提供了更多的理论依据。