Igarashi Kentaro, Murakami Takashi, Kawaguchi Kei, Kiyuna Tasuku, Miyake Kentaro, Zhang Yong, Nelson Scott D, Dry Sarah M, Li Yunfeng, Yanagawa Jane, Russell Tara A, Singh Arun S, Tsuchiya Hiroyuki, Elliott Irmina, Eilber Fritz C, Hoffman Robert M
AntiCancer, Inc., San Diego, California, USA.
Department of Surgery, University of California, San Diego, California, USA.
Oncotarget. 2017 Jul 8;8(37):62111-62119. doi: 10.18632/oncotarget.19095. eCollection 2017 Sep 22.
In the present study, we evaluated the efficacy of trabectedin (TRAB) and temozolomide (TEM) compared to cisplatinum (CDDP) on a patient-derived orthotopic xenogrraft (PDOX) of a lung-metastasis from an osteosarcoma of a patient who failed CDDP therapy. Osteosarcoma resected from the patient was implanted orthotopically in the distal femur of mice to establish PDOX models which were randomized into the following groups when tumor volume reached approximately 100 mm: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal injection, weekly, for 2 weeks); G3, TRAB (0.15 mg/kg, intravenous injection, weekly, for 2 weeks); G4, TEM (25 mg/kg, oral, daily, for 14 days). Tumor size and body weight were measured with calipers and a digital balance, respectively, twice a week. On day 14 after initiation of treatment, TEM and TRAB, but not CDDP, significantly inhibited tumor volume compared to untreated control: control (G1): 814.5±258.8 mm; CDDP (G2): 608.6±126.9 mm; TRAB (G3): 286.6±133.0 mm; TEM (G4): 182.9±69.1 mm. CDDP vs. control, p=0.07; TRAB vs. control, p=0.0004; TEM vs. control p =0.0002; TRAB vs. CDDP, p =0.0002; TEM vs. CDDP, p =0.00003. The results of the present study show that a PDOX model of an osteosarcoma lung-metastasis that recurred after adjuvant CDDP-treatment has identified potentially, highly-effective drugs for this recalcitrant disease, while accurately maintaining the CDDP resistance of the tumor in the patient, thereby demonstrating the potential of the osteosarcoma PDOX model for precision oncology.
在本研究中，我们评估了曲贝替定（TRAB）和替莫唑胺（TEM）相较于顺铂（CDDP）对一名顺铂治疗失败的骨肉瘤患者肺转移灶的患者源性原位异种移植瘤（PDOX）的疗效。将从该患者切除的骨肉瘤原位植入小鼠股骨远端以建立PDOX模型，当肿瘤体积达到约100 mm³时，将其随机分为以下几组：G1，未治疗对照组；G2，顺铂（6 mg/kg，腹腔注射，每周一次，共2周）；G3，曲贝替定（0.15 mg/kg，静脉注射，每周一次，共2周）；G4，替莫唑胺（25 mg/kg，口服，每日一次，共14天）。每周用卡尺和电子天平分别测量两次肿瘤大小和体重。在开始治疗后的第14天，与未治疗的对照组相比，替莫唑胺和曲贝替定能显著抑制肿瘤体积，但顺铂不能：对照组（G1）：814.5±258.8 mm³；顺铂组（G2）：608.6±126.9 mm³；曲贝替定组（G3）：286.6±133.0 mm³；替莫唑胺组（G4）：182.9±69.1 mm³。顺铂与对照组相比，p = 0.07；曲贝替定与对照组相比，p = 0.0004；替莫唑胺与对照组相比，p = 0.0002；曲贝替定与顺铂相比，p = 0.0002；替莫唑胺与顺铂相比，p = 0.00003。本研究结果表明，辅助顺铂治疗后复发的骨肉瘤肺转移的PDOX模型已识别出针对这种难治性疾病的潜在高效药物，同时准确维持了患者肿瘤的顺铂耐药性，从而证明了骨肉瘤PDOX模型在精准肿瘤学中的潜力。
