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

Norihiko Sugisawa, Takashi Higuchi, Qinghong Han, Chihiro Hozumi, Jun Yamamoto, Yoshihiko Tashiro, Hiroto Nishino, Kei Kawaguchi, Michael Bouvet, Takuya Murata, Michiaki Unno, Robert M. Hoffman

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)61-67
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume88
Issue number1
DOIs
Publication statusPublished - 2021 Jul

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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