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

  • Author(s): Igarashi, Kentaro;
  • Kawaguchi, Kei;
  • Kiyuna, Tasuku;
  • Miyake, Kentaro;
  • Miyake, Masuyo;
  • Li, Yunfeng;
  • Nelson, Scott D;
  • Dry, Sarah M;
  • Singh, Arun S;
  • Elliott, Irmina A;
  • Russell, Tara A;
  • Eckardt, Mark A;
  • Yamamoto, Norio;
  • Hayashi, Katsuhiro;
  • Kimura, Hiroaki;
  • Miwa, Shinji;
  • Tsuchiya, Hiroyuki;
  • Eilber, Fritz C;
  • Hoffman, Robert M
  • et al.
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.

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