Oral Recombinant Methioninase Sensitizes a Bladder Cancer Orthotopic Xenograft Mouse Model to Low-dose Cisplatinum and Prevents Metastasis

Anticancer Res. 2020 Nov;40(11):6083-6091. doi: 10.21873/anticanres.14629.

Abstract

Background/aim: The aim of the study was to determine if oral recombinant methioninase (o-rMETase) can sensitize an orthotopic bladder tumor in nude mice to low-dose cisplatinum (CDDP).

Materials and methods: The green fluorescent protein (GFP)-expressing UM-UC-3-GFP bladder cancer was surgically orthotopically implanted (SOI) to the bladder in nude mice. The treatment was initiated when the primary tumor volume reached 100 mm3 Mice were assigned to 3 groups: G1: Saline vehicle (0.1 ml per mouse, oral, twice per day); G2: low-dose CDDP (0.5 mg/kg, intraperitoneal twice per week); G3: o-rMETase + low-dose CDDP (100 units per mouse, oral, twice per day + 0.5 mg/kg, intraperitoneal twice per week, respectively). Tumor volume and body weight were measured twice per week. The expression of Ki-67 was detected by immunohistochemistry to evaluate cell proliferation.

Results: The combination of o-rMETase and low-dose CDDP increased inhibition efficacy compared to low-dose CDDP monotherapy, on primary-tumor growth (p=0.032) and metastasis (p=0.002).

Conclusion: The combination of o-rMETase with low-dose CDDP has future clinical potential for bladder cancer.

Keywords: Bladder cancer; GFP; cisplatinum; combination; efficacy; nude mice; oral recombinant methioninase; orthotopic; sensitize.

MeSH terms

  • Administration, Oral
  • Animals
  • Carbon-Sulfur Lyases / administration & dosage
  • Carbon-Sulfur Lyases / pharmacology
  • Carbon-Sulfur Lyases / therapeutic use*
  • Cell Proliferation / drug effects
  • Cisplatin / administration & dosage
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use*
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Mice, Nude
  • Neoplasm Metastasis
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use*
  • Tumor Burden / drug effects
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / pathology*
  • Xenograft Model Antitumor Assays*

Substances

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