利用5TGM1细胞系及多发性骨髓瘤同基因小鼠模型对硼替佐米进行体外与体内评价

Multiple myeloma (MM) is the second most prevalent hematologic cancer, originating from plasma cells (differentiated B-cells) and accounting for approximately 2% of cancer-related deaths. Clinical manifestations often include bone pain due to osteolytic lesions, pathologic fractures, and hypercalcemia. MM typically exhibits a low proliferative index and relies heavily on its surrounding microenvironment, making it resistant to conventional chemotherapy. However, these same characteristics present opportunities for emerging therapies, such as stroma-targeting agents and immunotherapies. The success of these novel strategies depends on robust preclinical models that accurately reflect both immune function and the tumor microenvironment. To support the relevance of the syngeneic 5TGM1 murine model in drug development, we evaluated the sensitivity of 5TGM1 cells to bortezomib both in vitro and in vivo . In vitro , 5TGM1 cells were cultured for six days, and cell viability was assessed using the CellTiter-Glo assay on days 0, 3, and 6. The EC50 value for bortezomib was determined, confirming its cytotoxic effect on 5TGM1 cells. In vivo , female C57Bl/KaLwRij mice (6-8 weeks old) were intravenously inoculated with 5TGM1 cells. Bortezomib treatment was initiated one day post-inoculation and administered intraperitoneally. The study included an untreated control group, a group receiving bortezomib twice weekly, and a group receiving bortezomib thrice weekly. Additionally, untreated satellite animals were included to evaluate disease progression and were sacrificed on day 35, prior to the termination of the main study. Mice were monitored daily for clinical condition, with body weight recorded twice a week. Sacrifice criteria included ≥20% weight loss or paraplegia. Serum IgG2b levels, which indicate disease progression, were measured from samples collected before inoculation, on day 21, day 35, and at sacrifice. Gross necropsy was performed to assess metastases, and ex vivo microCT scans of both tibias were conducted to analyze osteolytic lesions. Bortezomib was well tolerated, with no significant differences in body weight between groups. The termination day was determined based on disease progression in the vehicle control group; 40% of the vehicle group was sacrificed on day 41, and the remaining animals were sacrificed the following day. IgG2b levels were reduced in treated groups, particularly in the thrice-weekly regimen. However, bortezomib did not prevent the progression of bone lesions, which increased notably in the final week of the study. These findings support the use of bortezomib as a reference compound in vitro and in vivo in the 5TGM1 model, demonstrating its efficacy in reducing tumor burden as indicated by IgG2b levels. However, its protective effect on bone integrity remains limited.