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

• DOI: 10.1007/s00280-021-04261-x
• Publication Date: 2021-03-25T22:57:59Z
• Authors: 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
• Keywords: Ovarian Neoplasms; Paclitaxel; Carcinoma; Mice, Nude; Antineoplastic Agents, Phytogenic; Xenograft Model Antitumor Assays; Recombinant Proteins; Tumor Burden; 3. Good health; Carbon-Sulfur Lyases; Disease Models, Animal; Mice; 03 medical and health sciences; 0302 clinical medicine; Drug Resistance, Neoplasm; Animals; Heterografts; Humans; Female; Sarcoma, Clear Cell

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).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.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).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.