Recombinant methioninase in combination with doxorubicin (DOX) overcomes first-line DOX resistance in a patient-derived orthotopic xenograft nude-mouse model of undifferentiated spindle-cell sarcoma

Cancer Lett. 2018 Mar 28;417:168-173. doi: 10.1016/j.canlet.2017.12.028. Epub 2018 Jan 3.

Abstract

We have previously established a patient-derived orthotopic xenograft (PDOX) model of undifferentiated spindle cell sarcoma (USCS). Recombinant methioninase (rMETase) has previously demonstrated efficacy in PDOX mouse models of human cancers. In the present study, we determined if rMETase in combination with doxorubicin (DOX) can overcome first-line DOX resistance in a PDOX models of USCS. The USCS PDOX mouse models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks); G3, rMETase (100 units/mouse, i.p., daily, for 2 weeks); G4, DOX (3 mg/kg, i.p., weekly, for 2 weeks) combined with rMETase (100 units/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured twice a week. On day 14 after initiation, the USCS PDOX tumor sizes were (G1): 360 ± 85 mm3; DOX (G2): 355 ± 111 mm3, p = .927; rMETase (G3): 182 ± 57 mm3, p = .0003; DOX + rMETase (G4): 134 ± 29 mm3, p = .00001. These results indicate that rMETase can overcome USCS resistance to DOX, which is first line therapy for this disease. The body weight of treated mice was not significantly different in any group. The present results demonstrate the power of the PDOX model to identify effective therapy for recalcitrant cancer and the potential of rMETase to overcome DOX resistance.

Keywords: Doxorubicin; Nude mice; PDOX; Precision medicine; Recombinant methioninase; Spindle-cell sarcoma.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Body Weight / drug effects
  • Carbon-Sulfur Lyases / administration & dosage
  • Carbon-Sulfur Lyases / genetics
  • Doxorubicin / administration & dosage
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • Mice, Nude
  • Recombinant Proteins / administration & dosage
  • Sarcoma / drug therapy*
  • Sarcoma / pathology
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays*

Substances

  • Recombinant Proteins
  • Doxorubicin
  • Carbon-Sulfur Lyases
  • L-methionine gamma-lyase