Patatsos K, Shekhar T M, Hawkins C J
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
Vet Comp Oncol. 2018 Dec;16(4):544-553. doi: 10.1111/vco.12413. Epub 2018 Jul 12.
Osteosarcoma, a common malignancy in large dog breeds, typically metastasises from long bones to lungs and is usually fatal within 1 to 2 years of diagnosis. Better therapies are needed for canine patients and their human counterparts, a third of whom die within 5 years of diagnosis. We compared the in vitro sensitivity of canine osteosarcoma cells derived from 4 tumours to the currently used chemotherapy drugs doxorubicin and carboplatin, and 4 new anti-cancer drugs. Agents targeting histone deacetylases or PARP were ineffective. Two of the 4 cell lines were somewhat sensitive to the BH3-mimetic navitoclax. The proteasome inhibitor bortezomib potently induced caspase-dependent apoptosis, at concentrations substantially lower than levels detected in the bones and lungs of treated rodents. Co-treatment with bortezomib and either doxorubicin or carboplatin was more toxic to canine osteosarcoma cells than each agent alone. Newer proteasome inhibitors carfilzomib, ixazomib, oprozomib and delanzomib manifested similar activities to bortezomib. Human osteosarcoma cells were as sensitive to bortezomib as the canine cells, but slightly less sensitive to the newer drugs. Human osteoblasts were less sensitive to proteasome inhibition than osteosarcoma cells, but physiologically relevant concentrations were toxic. Such toxicity, if replicated in vivo, may impair bone growth and strength in adolescent human osteosarcoma patients, but may be tolerated by canine patients, which are usually diagnosed later in life. Proteasome inhibitors such as bortezomib may be useful for treating canine osteosarcoma, and ultimately may improve outcomes for human patients if their osteoblasts survive exposure in vivo, or if osteoblast toxicity can be managed.
骨肉瘤是大型犬种中常见的恶性肿瘤，通常从长骨转移至肺部，通常在诊断后1至2年内致命。犬类患者及其人类患者都需要更好的治疗方法，三分之一的人类患者在诊断后5年内死亡。我们比较了来自4个肿瘤的犬骨肉瘤细胞对目前使用的化疗药物阿霉素和卡铂以及4种新型抗癌药物的体外敏感性。靶向组蛋白脱乙酰酶或PARP的药物无效。4个细胞系中有2个对BH3模拟物维托拉生 somewhat敏感。蛋白酶体抑制剂硼替佐米在浓度远低于在接受治疗的啮齿动物骨骼和肺部中检测到的水平时，就能有效诱导半胱天冬酶依赖性凋亡。硼替佐米与阿霉素或卡铂联合治疗对犬骨肉瘤细胞的毒性比单独使用每种药物更大。新型蛋白酶体抑制剂卡非佐米、伊沙佐米、奥普罗佐米和德兰佐米表现出与硼替佐米相似的活性。人骨肉瘤细胞对硼替佐米的敏感性与犬细胞相同，但对新型药物的敏感性略低。人成骨细胞对蛋白酶体抑制的敏感性低于骨肉瘤细胞，但生理相关浓度具有毒性。如果这种毒性在体内重现，可能会损害青少年人骨肉瘤患者的骨骼生长和强度，但犬类患者可能可以耐受，因为犬类通常在生命后期才被诊断出来。像硼替佐米这样的蛋白酶体抑制剂可能有助于治疗犬骨肉瘤，如果其成骨细胞在体内暴露后存活下来，或者如果可以控制成骨细胞毒性，最终可能会改善人类患者的治疗结果。
