A Novel Anionic-phosphate-platinum Complex Effectively Targets a Cisplatinum-resistant Osteosarcoma in a Patient-derived Orthotopic Xenograft Mouse Model

Abstract

Background/Aim: We have previously developed a novel bone-targeting platinum compound, 3Pt, and showed that it has strong inhibitory activity against osteosarcoma cells and orthotopic cell-line xenograft mouse models. In the present report, we compared the efficacy of 3Pt to cisplatinum (CDDP) in a CDDP-resistant relapsed osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. Patients and Methods: The tumor of a patient with osteosarcoma of the distal femur was treated with CDDP-based chemotherapy followed by surgery. The surgical specimen was used to establish a PDOX model. An osteosarcoma cell line was also established from the original patient tumor. Osteosarcoma cell viability was assessed with the WST-8 assay and the IC50 values were calculated. The PDOX models were randomized into three groups: untreated control, CDDP-treated group, and 3Pt-treated group. Tumor size and body weight were measured twice a week. Results: 3Pt had a strong concentration-dependent cytocidal effect in vitro. The IC 50 value of 3Pt was significantly lower than that of CDDP. On day 14 of the treatment, 3Pt caused a significantly greater tumor growth inhibition compared to the untreated control and CDDP-treated mice. Conclusion: 3Pt is a promising clinical candidate for the treatment of recalcitrant osteosarcoma. Osteosarcoma is a rare and highly malignant mesenchymal bone tumor. The primary tumor is pathologically characterized by the formation of immature bone or osteoid. A bimodal distribution of osteosarcoma occurence has been reported, with a first peak in adolescence and a second peak in older age (1). Patients with osteosarcoma treated with chemotherapy and surgery have approximately a 70% 5-year survival rate (2-4). First-line chemotherapy for osteosarcoma includes highdose methotrexate (MTX), cisplatinum (CDDP), doxorubicin, (DCX) and ifosfamide (IFS) (5-9). However, dose escalation of these drugs has not been effective for recalcitrant osteosarcoma (6), with 5-year overall survival rates being less than 20% (6-9). We have previously developed a novel platinum complex 3Pt ([Pt(Pt(1R,2R-diaminocyclohexane)(myo-inositol-1,2,3, 4,5,6-hexakisphosphate))2]), which comprises anionic phosphate moieties (10). The cytotoxic potency of 3Pt was higher than that of CDDP in all osteosarcoma cell lines tested. 3Pt was also effective in CDDP-resistant cells (10). Mice treated with 3Pt showed no renal cell injury compared 217 This article is freely accessible online.

Efficient and Consistent Orthotopic Osteosarcoma Model by Cell Sheet Transplantation in the Nude Mice for Drug Testing

“…As such, it can be used as a novel reference model by other researchers in establishing other mouse tumor models. This contradicts the findings reported in other articles using orthotopic xenotransplantation of human osteosarcoma cell lines (Igarashi et al, 2020). There are numerous techniques for constructing a mouse tumor model.…”

Multikinase-Inhibitor Screening in Drug-resistant Osteosarcoma Patient-derived Orthotopic Xenograft Mouse Models Identifies the Clinical Potential of Regorafenib

“…These fresh tumor samples were previously transported to the laboratory on ice and established in nude mice using small tumor fragments transplanted subcutaneously (10,11,(17)(18)(19).…”

“…We developed patient-derived orthotopic xenograft (PDOX) models of all major types of malignancies, including osteosarcoma, with the technique of surgical orthotopic implantation (SOI), allowing effective and ineffective drugs to be distinguished (9)(10)(11)(12)(13). The PDOX models recapitulate human-tumor behavior better than other in vivo models due to their intact histology and correct organ-tumor microenvironment of the orthotopicallyimplanted tumor (14)(15)(16).…”

Osteosarcoma Patient-derived Orthotopic Xenograft (PDOX) Models Used to Identify Novel and Effective Therapeutics: A Review

“…Efficacy of a novel anioninc-phosphate-platinum complex on osteosarcoma PDOX. An anioninc-platinum complex, which contains 3Pt and bisphosphonates, can have high-bone and low-kidney accumulation, leading to increased anti-tumor efficacy on bone tumors and decreased nephrotoxicity compared to CDDP (39). We demonstrated that 3Pt inhibited tumor growth more effectively than CDDP in the pelvicosteosarcoma PDOX model from patient #1 (39).…”