Oral recombinant methioninase combined with paclitaxel arrests recalcitrant ovarian clear cell carcinoma growth in a patient-derived orthotopic xenograft (PDOX) nude-mouse model

Cancer Chemother Pharmacol. 2021 Jul;88(1):61-67. doi: 10.1007/s00280-021-04261-x. Epub 2021 Mar 25.


Purpose: Advanced ovarian clear cell carcinoma (OCCC) is a recalcitrant disease, often resistant to the first-line platinum-based therapy. Using a novel patient-derived orthotopic xenograft (PDOX) nude-mouse model of OCCC, we tested whether oral-recombinant methioninase (o-rMETase) could enhance the efficacy of paclitaxel (PTX).

Methods: The OCCC PDOX model was established and passaged in nude mice. The OCCC PDOX models were randomized into 5 groups. G1: untreated control; G2: paclitaxel (PTX) (20 mg/kg, intraperitoneal (i.p.) injection, weekly); G3: o-rMETase (100 units, oral, daily); G4: PTX (20 mg/kg, i.p. injection, weekly) + carboplatinum (CBDCA) (40 mg/kg, i.p. injection weekly); G5: PTX (20 mg/kg, i.p. injection, weekly) + o-rMETase (100 units, oral, daily). The treatment period was 2 weeks.

Results: The combination of PTX and o-rMETase arrested OCCC tumor growth (relative tumor volume: 1.09 ± 0.63 (mean ± SD)) compared with the untreated control (relative tumor volume: 3.92 ± 1.04 (mean ± SD)) (p < 0.0001). There was no significant difference in relative tumor volume between PTX plus o-rMETase and PTX plus CBDCA (relative tumor volume: 1.39 ± 0.37 (mean ± SD)) (p = 0.93).

Conclusion: PTX plus o-rMETase arrested the OCCC tumor growth. o-rMETase is readily administered and can greatly enhance first-line therapy of a recalcitrant cancer. The novel and effective treatment strategy in the present report has future clinical potential for patients with OCCC, especially for patients who cannot well tolerate platinum-based therapy.

Keywords: Combination therapy; Methionine addiction; Oral recombinant methioninase; Ovarian clear cell carcinoma; Paclitaxel; Patient-derived orthotopic xenograft (PDOX); Tumor-growth arrest.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Carbon-Sulfur Lyases / pharmacology*
  • Carcinoma / drug therapy*
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Heterografts / drug effects
  • Humans
  • Mice
  • Mice, Nude
  • Ovarian Neoplasms / drug therapy*
  • Paclitaxel / pharmacology*
  • Recombinant Proteins / pharmacology*
  • Sarcoma, Clear Cell / drug therapy*
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays / methods


  • Antineoplastic Agents, Phytogenic
  • Recombinant Proteins
  • Carbon-Sulfur Lyases
  • L-methionine gamma-lyase
  • Paclitaxel