肿瘤选择性细菌治疗联合鼠伤寒沙门氏菌 A1-R 与口服重组蛋氨酸酶靶向治疗在患者来源的原位异种移植模型中消退尤文肉瘤。

Combining Tumor-Selective Bacterial Therapy with Salmonella typhimurium A1-R and Cancer Metabolism Targeting with Oral Recombinant Methioninase Regressed an Ewing's Sarcoma in a Patient-Derived Orthotopic Xenograft Model.

机构信息

AntiCancer Inc., San Diego, California, USA.

Department of Surgery, University of California, San Diego, California, USA.

出版信息

Chemotherapy. 2018;63(5):278-283. doi: 10.1159/000495574. Epub 2019 Jan 23.

DOI:10.1159/000495574

PMID:30673664

Abstract

BACKGROUND

Ewing's sarcoma (ES) is a recalcitrant disease in need of transformative therapeutics.

OBJECTIVES

The aim of this study was to investigate the efficacy of tumor-selective Salmonella typhimurium A1-R combined with tumor metabolism targeting with oral administration of recombinant methioninase (o-rMETase), on an ES patient-derived orthotopic xenograft (PDOX) model.

METHODS

The ES PDOX models were previously established in the right chest wall. The ES PDOX models were randomized into 5 groups when the tumor volume reached 80 mm3: G1: untreated control; G2: doxorubicin; G3: S. typhimurium A1-R; G4: o-rMETase; G5: S. typhimurium A1-R combined with o-rMETase. All mice were sacrificed on day 15. Body weight and tumor volume were assessed twice a week.

RESULTS

S. typhimurium A1-R and o-rMETase respectively suppressed tumor growth as monotherapies (p = 0.050 and p = 0.032). S. typhimurium A1-R combined with o-rMETase regressed tumor growth significantly compared to untreated group on day 15 (p < 0.032). S. typhimurium A1-R combined with o-rMETase group was significantly more effective than S. typhimurium A1-R or o-rMETase monotherapy (p = 0.032, p = 0.032).

CONCLUSIONS

The present results suggest that the combination of S. typhimurium A1-R and o-rMETase has promise to be a transformative therapy for ES.

摘要

背景

尤因氏肉瘤（ES）是一种需要变革性治疗的难治性疾病。

目的

本研究旨在探讨肿瘤选择性鼠伤寒沙门氏菌 A1-R 与口服重组甲硫氨酸酶（o-rMETase）联合靶向肿瘤代谢对 ES 患者来源的原位异种移植（PDOX）模型的疗效。

方法

ES PDOX 模型先前在右胸壁建立。当肿瘤体积达到 80mm3 时，ES PDOX 模型随机分为 5 组：G1：未治疗对照；G2：多柔比星；G3：鼠伤寒沙门氏菌 A1-R；G4：o-rMETase；G5：鼠伤寒沙门氏菌 A1-R 联合 o-rMETase。所有小鼠均在第 15 天处死。每周两次评估体重和肿瘤体积。

结果

鼠伤寒沙门氏菌 A1-R 和 o-rMETase 分别作为单药治疗抑制肿瘤生长（p=0.050 和 p=0.032）。与未治疗组相比，鼠伤寒沙门氏菌 A1-R 联合 o-rMETase 组在第 15 天肿瘤生长明显消退（p<0.032）。鼠伤寒沙门氏菌 A1-R 联合 o-rMETase 组的疗效明显优于鼠伤寒沙门氏菌 A1-R 或 o-rMETase 单药治疗（p=0.032，p=0.032）。