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.


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


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