Temozolomide combined with irinotecan regresses a cisplatinumresistant 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, Robert M. Hoffman

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)7774-7781
Number of pages8
JournalOncotarget
Volume9
Issue number8
DOIs
Publication statusPublished - 2018
Externally publishedYes

Keywords

  • Irinotecan
  • Nude mice
  • Osteosarcoma
  • PDOX
  • Temozolomide

ASJC Scopus subject areas

  • Oncology

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