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

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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.

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Data availability

All data and materials are available.

Code availability

Data of the present manuscript are stored on Microsoft office and GraphPad Prism.

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Acknowledgements

This paper is dedicated to the memory of A. R. Moossa, M.D., Sun Lee, M.D., Professor Li Jiaxi, and Masaki Kitajima, M.D.

Funding

The study was funded in part by the Robert M. Hoffman Foundation for Cancer Research.

Author information

Authors and Affiliations

Authors

Contributions

NS and RMH: Project development. NS, CH, and TM: Data collection. NS, TH, QH, CH, JY, YT, HN, KK, MB, TM, MU, and RMH: Analysis and interpretation of data. NS and RMH: Writing, review, and revision of the manuscript.

Corresponding authors

Correspondence to Norihiko Sugisawa, Michiaki Unno or Robert M. Hoffman.

Ethics declarations

Conflict of interest

The authors declare that there are no potential conflicts of interest. AntiCancer, Inc. uses PDOX mouse models for contract research. QH is an employee of AntiCancer, Inc. NS, TH, JY, YT, HN, and RMH are or were unsalaried associates of AntiCancer, Inc.

Ethical approval

The mouse experiments were carried out under an AntiCancer, Inc. Institutional Animal Care and Use Committee (IACUC) approved protocol using guidelines of the National Institutes of Health Guide for the Care and Use of Animals, under Assurance Number A3873-1.

Consent to participate

Written informed consent was provided by the patient as a part of an approved protocol by the Institutional Review Board (IRB) of Kawasaki Medical School.

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All authors agree with the contents of the present manuscript and for submission to Cancer Chemotherapy and Pharmacology.

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Sugisawa, N., Higuchi, T., Han, Q. et al. 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 88, 61–67 (2021). https://doi.org/10.1007/s00280-021-04261-x

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