Research Papers:

Temozolomide combined with irinotecan regresses a cisplatinum-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) precision-oncology mouse model

Kentaro Igarashi, Kei Kawaguchi, Tasuku Kiyuna, Kentaro Miyake, Masuyo Miyake, Yunfeng Li, Scott D. Nelson, Sarah M. Dry, Arun S. Singh, Irmina A. Elliott, Tara A. Russell, Mark A. Eckardt, Norio Yamamoto, Katsuhiro Hayashi, Hiroaki Kimura, Shinji Miwa, Hiroyuki Tsuchiya, Fritz C. Eilber and Robert M. Hoffman _

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Oncotarget. 2018; 9:7774-7781. https://doi.org/10.18632/oncotarget.22892

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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

Correspondence to:

Robert M. Hoffman, email: all@anticancer.com

Fritz C. Eilber, email: fceilber@mednet.ucla.edu

Hiroyuki Tsuchiya, email: tsuchi@med.kanazawa-u.ac.jp

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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