Temozolomide combined with irinotecan regresses a cisplatinum-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) precision-oncology mouse model
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Kentaro Igarashi1,2,3, Kei Kawaguchi1,2, Tasuku Kiyuna1,2, Kentaro Miyake1,2, Masuyo Miyake1,2, Yunfeng Li4, Scott D. Nelson4, Sarah M. Dry4, Arun S. Singh5, Irmina A. Elliott6, Tara A. Russell6, Mark A. Eckardt7, Norio Yamamoto3, Katsuhiro Hayashi3, Hiroaki Kimura3, Shinji Miwa3, Hiroyuki Tsuchiya3, Fritz C. Eilber6 and Robert M. Hoffman1,2
1AntiCancer, Inc., San Diego, California, USA
2Department of Surgery, University of California, San Diego, California, USA
3Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan
4Department of Pathology, University of California, Los Angeles, California, USA
5Division of Hematology-Oncology, University of California, Los Angeles, California, USA
6Division of Surgical Oncology, University of California, Los Angeles, California, USA
7Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA
Robert M. Hoffman, email: [email protected]
Fritz C. Eilber, email: [email protected]
Hiroyuki Tsuchiya, email: [email protected]
Keywords: osteosarcoma; PDOX; nude mice; temozolomide; irinotecan
Received: October 17, 2017 Accepted: November 10, 2017 Published: December 04, 2017
Relapsed osteosarcoma is a recalcitrant tumor. A patient’s cisplatinum (CDDP)-resistant relapsed osteosarcoma lung metastasis was previously established orthotopically in the distal femur of mice to establish a patient-derived orthotopic xenograft (PDOX) model. In the present study, the PDOX models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); gemcitabine (GEM) (100 mg/kg, i.p., weekly, for 2 weeks) combined with docetaxel (DOC) (20 mg/kg, i.p., once); temozolomide (TEM) (25 mg/kg, p.o., daily, for 2 weeks) combined with irinotecan (IRN) (4 mg/kg i.p., daily for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. After 2 weeks, all treatments significantly inhibited tumor growth except CDDP compared to the untreated control: CDDP: p = 0.093; GEM+DOC: p = 0.0002, TEM+IRN: p < 0.0001. TEM combined with IRN was significantly more effective than either CDDP (p = 0.0001) or GEM combined with DOC (p = 0.0003) and significantly regressed the tumor volume compared to day 0 (p = 0.003). Thus the PDOX model precisely identified the combination of TEM-IRN that could regress the CDDP-resistant relapsed metastatic osteosarcoma PDOX.
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