Oral recombinant methioninase (o-rMETase) is superior to injectable rMETase and overcomes acquired gemcitabine resistance in pancreatic cancer

Author:

Kawaguchi, Kei

Miyake, Kentaro

Han, Qinghong

Li, Shukuan

Tan, Yuying

Igarashi, Kentaro

Kiyuna, Tasuku

Miyake, Masuyo

Higuchi, Takashi

Oshiro, Hiromichi

Zhang, Zhiying

Razmjooei, Sahar

Wangsiricharoen, Sintawat

Bouvet, Michael

Singh, Shree Ram

Unno, Michiaki

Hoffman, Robert M
Author Address

AntiCancer, Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA; Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan., AntiCancer, Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA., AntiCancer, Inc., San Diego, CA, USA., Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA. Electronic address: singhshr@mail.nih.gov., Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan. Electronic address: m_unno@surg1.med.tohoku.ac.jp., AntiCancer, Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA. Electronic address: all@anticancer.com.,

Abstract:

Recombinant methioninase (rMETase) was 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 combination of both was significantly more effective. 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. Copyright © 2018. Published by Elsevier B.V.

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