Oral-recombinant Methioninase Converts an Osteosarcoma from Docetaxel-resistant to -Sensitive in a Clinically-relevant Patient-derived Orthotopic-xenograft (PDOX) Mouse Model

Anticancer Res. 2021 Apr;41(4):1745-1751. doi: 10.21873/anticanres.14939.

Abstract

Background/aim: Osteosarcoma is the most frequent malignant bone tumor. Failure of first-line therapy results in poor prognosis of osteosarcoma. In the present report, we examined the efficacy of the combination of oral recombinant methioninase (o-rMETase) and docetaxel (DOC) on an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model.

Materials and methods: Osteosarcoma-PDOX models were established by tumor insertion within the tibia of nude mice. The osteosarcoma PDOX models were randomized into four groups (4-5 mice per group): control; o-rMETae alone; DOC alone; o- rMETase combined with DOC. The treatment period was 3 weeks.

Results: The combination of o-rMETase and DOC showed significant efficacy compared to the control group (p=0.03). In contrast, there was no significant efficacy of o-rMETase alone or DOC alone (p=0.65, 0.60, respectively).

Conclusion: o-rMETase converted an osteosarcoma PDOX from DOC-resistant to -sensitive. This combination therapy may be effective against recalcitrant osteosarcoma and other recalcitrant cancers.

Keywords: Osteosarcoma; PDOX; combination therapy; docetaxel; efficacy; methioninase; methionine; nude mice.

MeSH terms

  • Administration, Oral
  • Adolescent
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / pathology
  • Carbon-Sulfur Lyases / administration & dosage*
  • Docetaxel / pharmacology*
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Osteosarcoma / drug therapy*
  • Osteosarcoma / pathology
  • Recombinant Proteins / administration & dosage
  • Tibia / drug effects*
  • Tibia / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Recombinant Proteins
  • Docetaxel
  • Carbon-Sulfur Lyases
  • L-methionine gamma-lyase