在裸鼠模型中使用蛋氨酸限制联合异环磷酰胺协同根除具有获得性异环磷酰胺耐药性的纤维肉瘤

Synergistic Eradication of Fibrosarcoma With Acquired Ifosfamide Resistance Using Methionine Restriction Combined With Ifosfamide in Nude-mouse Models.

作者信息

Morinaga Sei, Han Qinghong, Mizuta Kohei, Kang Byung Mo, Bouvet Michael, Yamamoto Norio, Hayashi Katsuhiro, Kimura Hiroaki, Miwa Shinji, Igarashi Kentaro, Higuchi Takashi, Tsuchiya Hiroyuki, Demura Satoru, Hoffman Robert M

机构信息

AntiCancer Inc., San Diego, CA, U.S.A.

Department of Surgery, University of California, San Diego, CA, U.S.A.

出版信息

In Vivo. 2025 Jan-Feb;39(1):120-126. doi: 10.21873/invivo.13809.

DOI:10.21873/invivo.13809

PMID:39740911

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11705138/

Abstract

BACKGROUND/AIM: Ifosfamide is used clinically with doxorubicin as first-line chemotherapy for soft-tissue sarcoma. However, ifosfamide efficacy for soft-tissue sarcoma is limited due to frequent occurence of ifosfamide resistance and thus more effective therapy is needed. The present study aimed to determine the synergy of recombinant methioninase (rMETase) plus ifosfamide against HT1080 human fibrosarcoma cells in vitro. Additionally, the present study also investigated the efficacy of a methionine-restricted diet combined with ifosfamide in nude-mouse models of ifosfamide-resistant HT1080 (IR-HT1080).

MATERIALS AND METHODS

Cell viability for HT1080 human fibrosarcoma cells was determined in four groups in vitro: No treatment control; ifosfamide alone; rMETase alone; and a combination of ifosfamide plus rMETase. HT1080 tumors were established in nude mice subcutaneously. The HT1080 tumor models were treated by administering ifosfamide by intraperitoneal injection twice a week, for a total of 11 doses. Surviving tumors were considered ifosfamide resistant (IR-HT1080). Four groups of IR-HT1080 nude-mouse models were subsequently established: Group 1 was a no-treatment control, Group 2 received ifosfamide, Group 3 was given a methionine-restricted diet (MR), and Group 4 received ifosfamide plus MR. Additionally, two groups of nude mice with parental HT1080 subcutaneous tumors were included: Group 5 was a no-treatment control, and Group 6 received ifosfamide for comparison.

RESULTS

The 50% inhibitory concentration (IC) for ifosfamide against HT1080 cells was 0.38 mM. The IC for rMETase was 0.75 U/ml for HT1080 cells (data from [4]). The combination of rMETase (0.75 U/ml) plus ifosfamide (0.38 mM) was synergistic against HT1080 fibrosarcoma cells in vitro. The combination of ifosfamide plus MR eradicated the IR-HT1080 tumors in nude-mouse models, while each treatment alone achieved limited tumor inhibition.

CONCLUSION

The present results suggest the combination of MR and ifosfamide has promising potential for overcoming ifosfamide resistance in future clinical applications.

摘要

背景/目的：异环磷酰胺在临床上与多柔比星联合用作软组织肉瘤的一线化疗药物。然而，由于异环磷酰胺耐药性频繁发生，其对软组织肉瘤的疗效有限，因此需要更有效的治疗方法。本研究旨在确定重组蛋氨酸酶（rMETase）加异环磷酰胺对HT1080人纤维肉瘤细胞的体外协同作用。此外，本研究还在异环磷酰胺耐药的HT1080（IR-HT1080）裸鼠模型中研究了蛋氨酸限制饮食联合异环磷酰胺的疗效。

材料与方法

体外将HT1080人纤维肉瘤细胞分为四组测定细胞活力：未处理对照组；单独使用异环磷酰胺组；单独使用rMETase组；异环磷酰胺加rMETase联合组。将HT1080肿瘤皮下接种于裸鼠体内。通过每周两次腹腔注射异环磷酰胺治疗HT1080肿瘤模型，共注射11剂。存活的肿瘤被认为是异环磷酰胺耐药（IR-HT1080）。随后建立四组IR-HT1080裸鼠模型：第1组为未处理对照组，第2组接受异环磷酰胺治疗，第3组给予蛋氨酸限制饮食（MR），第4组接受异环磷酰胺加MR治疗。此外，纳入两组接种亲本HT1080皮下肿瘤的裸鼠：第5组为未处理对照组，第6组接受异环磷酰胺治疗以作比较。

结果

异环磷酰胺对HT1080细胞的50%抑制浓度（IC）为0.38 mM。rMETase对HT1080细胞的IC为0.75 U/ml（数据来自[4]）。rMETase（0.75 U/ml）加异环磷酰胺（0.38 mM）的联合用药在体外对HT1080纤维肉瘤细胞具有协同作用。异环磷酰胺加MR的联合用药根除了裸鼠模型中的IR-HT1080肿瘤，而单独使用每种治疗方法仅实现了有限的肿瘤抑制。