Oral recombinant methioninase (o-rMETase) is superior to injectable rMETase and overcomes acquired gemcitabine resistance in pancreatic cancer
Oral recombinant methioninase (o-rMETase) is superior to injectable rMETase and overcomes acquired gemcitabine resistance in pancreatic cancer
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DOI：
10.1016/j.canlet.2018.06.016
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Hoffman, Robert M.
中科院分区：
文献类型：
--
作者：
Kawaguchi, Kei;Miyake, Kentaro;Hoffman, Robert M.
重组蛋氨酸酶（rMETase）以前作为注射药物用于治疗癌症的蛋氨酸依赖性。最近，我们观察到 rMETase 可以在患者来源的原位异种移植 (PDOX) 黑色素瘤小鼠模型中口服给药 (o-rMETase)。在这里，我们确定了 o-rMETase 对胰腺癌 PDOX 模型的功效。 40 只胰腺癌 PDOX 小鼠模型被随机分为四组，每组 10 只。 o-rMETase 明显比 i.p.-rMETase 更有效，但两者组合比单独使用任一者更有效。获得性吉西他滨耐药是胰腺癌难治的主要因素。我们测试了人类胰腺癌细胞系，该细胞系获得的 GEM 抗性 (PK-9R) 是其亲本细胞系 PK-9 的 100 倍以上。与 GEM 相比，两种细胞系对 rMETase 都非常敏感。在 PK-9 和 PK-9R 原位裸鼠模型中，GEM 抑制 PK-9 中的肿瘤生长，但不抑制 PK-9R 中的肿瘤生长。相反，o-rMETase 可以抑制这两种肿瘤。 GEM + o-rMETase 的组合可以消退 PK-9 肿瘤并抑制 PK-9R 肿瘤生长。目前的研究表明，o-rMETase 是有效的，并且克服了胰腺癌的获得性 GEM 耐药性，并证明了该策略的临床潜力。
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.