Oral recombinant methioninase (o-rMETase) is superior to injectable rMETase and overcomes acquired gemcitabine resistance in pancreatic cancer

Cancer Lett. 2018 Sep 28;432:251-259. doi: 10.1016/j.canlet.2018.06.016. Epub 2018 Jun 18.

Abstract

Recombinant methioninase (rMETase) was previously administered as an injectable drug to target methionine dependence of cancer. Recently, we observed that rMETase could be administered orally (o-rMETase) in a patient-derived orthotopic xenograft (PDOX) mouse model of melanoma. Here, we determined the efficacy of o-rMETase on a pancreatic cancer PDOX model. Forty pancreatic cancer PDOX mouse models were randomized into four groups of 10 mice each. o-rMETase was significantly more effective than i.p.-rMETase, but the combination of both was significantly more effective than either alone. Acquired gemcitabine resistance is a major factor in the recalcitrance of pancreatic cancer. We tested a human pancreatic cancer cell line, which has acquired >100-fold GEM-resistance (PK-9R) than its parental cell line PK-9. In contrast to GEM, both cell lines were very sensitive to rMETase. In orthotopic nude mouse models of PK-9 and PK-9R, GEM inhibited tumor growth in PK-9 but not PK-9R. In contrast, o-rMETase could inhibit both tumors. The combination of GEM + o-rMETase could regress the PK-9 tumor and inhibit PK-9R tumor growth. The present study shows that o-rMETase is effective and overcomes acquired GEM resistance in pancreatic cancer and demonstrates the clinical potential of this strategy.

Keywords: Acquired resistance; Gemcitabine; Methionine dependence; Oral administration; PDOX; Pancreatic cancer.

MeSH terms

  • Administration, Oral
  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Apoptosis
  • Carbon-Sulfur Lyases / administration & dosage*
  • Cell Proliferation
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Drug Resistance, Neoplasm*
  • Humans
  • Injections, Intraperitoneal
  • Mice
  • Mice, Nude
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Recombinant Proteins / administration & dosage*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antimetabolites, Antineoplastic
  • Recombinant Proteins
  • Deoxycytidine
  • gemcitabine
  • Carbon-Sulfur Lyases
  • L-methionine gamma-lyase