Hall D G, Stoica G
Department of Veterinary Pathobiology, Texas A&M University, College Station.
J Bone Miner Res. 1994 Feb;9(2):221-30. doi: 10.1002/jbmr.5650090211.
Risedronate (NE-58095) is a third-generation bisphosphonate with very potent antiresorptive activity but few toxic effects. The purpose of this work was to evaluate the effect of risedronate treatment on bone metastases produced in a rat breast cancer model. Berlin Druckrey IV rats inoculated with ENU1564 mammary adenocarcinoma cells were treated daily with risedronate or a saline placebo. Survival times, dictated by extraskeletal metastases (lung, heart, and brain), were not affected by risedronate treatment. Risedronate-treated animals had skeletal changes associated with decreased remodeling of bones undergoing endochondral ossification, most prominently affecting the appendicular skeleton. Despite the skeletal alterations induced by the treatment, the distribution of bone metastases throughout the surveyed skeletal sites was similar for treated and untreated animals. Bone metastases were enumerated in histologic sections of distal femur, spine, and skull. Tumor size was estimated from area measurements obtained from histologic lesions in distal femoral metaphyses and vertebral bodies. A greater number of treated rats had no bone metastases in any of the examined sections (30 versus 16.1% of untreated rats). Multiple bone metastases were observed less frequently in treated rats (33.3 versus 71% of untreated rats). Treated rats had fewer observed bone metastases in each examined site than untreated rats (p < or = 0.025). Mean tumor areas in femora and vertebrae were smaller in treated rats (p < or = 0.05), due to the less frequent presence of very large lesions. In untreated animals, osteoclasts appeared to be active at the tumor/bone interface and osseous structures were often completely replaced by expanding tumors. In contrast, metastases in treated animals caused less disruption of skeletal histoarchitecture. The apparent lack of osteoclastic activity and retention of bone within lesions suggested a decreased contribution of osteoclasts to the bone resorptive process. An in vivo immunohistochemical cell proliferation assay failed to reveal differences in the percentage of dividing tumor cells in bone metastatic sites in treated versus untreated animals. The results demonstrate significant effects of risedronate treatment on the incidence and size of observed skeletal metastases in this model.
利塞膦酸盐（NE - 58095）是一种第三代双膦酸盐，具有很强的抗吸收活性但毒性作用很少。这项工作的目的是评估利塞膦酸盐治疗对大鼠乳腺癌模型中产生的骨转移的影响。接种ENU1564乳腺腺癌细胞的柏林德雷IV大鼠每天接受利塞膦酸盐或生理盐水安慰剂治疗。由骨外转移（肺、心脏和脑）决定的生存时间不受利塞膦酸盐治疗的影响。接受利塞膦酸盐治疗的动物出现了与软骨内骨化的骨骼重塑减少相关的骨骼变化，最显著影响四肢骨骼。尽管治疗引起了骨骼改变，但治疗组和未治疗组动物在整个调查骨骼部位的骨转移分布相似。在远端股骨、脊柱和颅骨的组织学切片中对骨转移进行计数。根据从远端股骨干骺端和椎体的组织学病变获得的面积测量值估计肿瘤大小。更多接受治疗的大鼠在任何检查切片中都没有骨转移（30% 对未治疗大鼠的16.1%）。在接受治疗的大鼠中观察到多发骨转移的频率较低（33.3% 对未治疗大鼠的71%）。在每个检查部位，接受治疗的大鼠观察到的骨转移比未治疗的大鼠少（p≤0.025）。由于非常大的病变出现频率较低，治疗组大鼠股骨和椎骨的平均肿瘤面积较小（p≤0.05）。在未治疗的动物中，破骨细胞在肿瘤/骨界面似乎活跃，骨结构常常被扩展的肿瘤完全取代。相比之下，治疗组动物的转移对骨骼组织结构的破坏较小。病变内破骨细胞活性明显缺乏和骨的保留表明破骨细胞对骨吸收过程的贡献减少。一项体内免疫组织化学细胞增殖试验未能揭示治疗组与未治疗组动物骨转移部位分裂肿瘤细胞百分比的差异。结果表明利塞膦酸盐治疗对该模型中观察到的骨骼转移的发生率和大小有显著影响。
