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.
Cancer Lett. 2018 Sep 28;432:251-259. doi: 10.1016/j.canlet.2018.06.016. Epub 2018 Jun 18.
Recombinant methioninase (rMETase) was previously 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 the combination of both was significantly more effective than either alone. 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.
重组蛋氨酸酶（rMETase）以前作为一种注射用药物被用于针对癌症对蛋氨酸的依赖性。最近，我们观察到 rMETase 可以在黑色素瘤患者来源的原位异种移植（PDOX）小鼠模型中口服给药（o-rMETase）。在这里，我们确定了 o-rMETase 在胰腺癌 PDOX 模型中的疗效。40 只胰腺癌 PDOX 小鼠模型随机分为四组，每组 10 只。o-rMETase 比 i.p.-rMETase 更有效，但两者的联合使用比单独使用任何一种都更有效。获得吉西他滨耐药是胰腺癌顽固不化的主要因素。我们测试了一种人胰腺癌细胞系，其对吉西他滨的耐药性（PK-9R）比其亲本细胞系 PK-9 高 100 倍以上。与 GEM 相反，两种细胞系对 rMETase 都非常敏感。在 PK-9 和 PK-9R 的原位裸鼠模型中，GEM 抑制 PK-9 中的肿瘤生长，但不抑制 PK-9R。相比之下，o-rMETase 可以抑制两种肿瘤。GEM+o-rMETase 的联合使用可以使 PK-9 肿瘤消退并抑制 PK-9R 肿瘤生长。本研究表明，o-rMETase 有效并克服了胰腺癌中的获得性 GEM 耐药性，并证明了该策略的临床潜力。
