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Novel multi-drugs incorporating hybrid-structured nanofibers enhance alkylating agent activity in malignant gliomas.
Ther Adv Med Oncol 2019; 11:1758835919875555TA

Abstract

Background

Malignant gliomas (MGs) are highly chemotherapy-resistant. Temozolomide (TMZ) and carmustine (BiCNU) are alkylating agents clinically used for treating MGs. However, their effectiveness is restrained by overexpression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) in tumors. O6-benzylguanine (O6-BG) is a nonreversible inhibitor of MGMT, it promotes the cytotoxicity of alkylating chemotherapy. The authors have developed a hybrid-structured nanofibrous membrane (HSNM) that sequentially delivers high concentrations of O6-BG, BiCNU, and TMZ in an attempt to provide an alternative to the current therapeutic options for MGs.

Methods

The HSNMs were implanted onto the cerebral surface of pathogen-free rats following surgical craniectomy, while the in vivo release behaviors of O6-BG, TMZ, and BiCNU from the HSNMs were explored. Subsequently, the HSNMs were surgically implanted onto the brain surface of two types of tumor-bearing rats. The survival rate, tumor volume, malignancy of tumor, and apoptotic cell death were evaluated and compared with other treatment regimens.

Results

The biodegradable HSNMs sequentially and sustainably delivered high concentrations of O6-BG, BiCNU, and TMZ for more than 14 weeks. The tumor-bearing rats treated with HSNMs demonstrated therapeutic advantages in terms of retarded and restricted tumor growth, prolonged survival time, and attenuated malignancy.

Conclusion

The results demonstrated that O6-BG potentiates the effects of interstitially transported BiCNU and TMZ. Therefore, O6-BG may be required for alkylating agents to offer maximum therapeutic benefits for the treatment of MGMT-expressing tumors. In addition, the HSNM-supported chemoprotective gene therapy enhanced chemotherapy tolerance and efficacy. It can, therefore, potentially provide an improved therapeutic alternative for MGs.

Authors+Show Affiliations

Department of Mechanical Engineering, Chang Gung University, Tao-Yuan.Division of Neurosurgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei.Division of Neurosurgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei.Department of Neurosurgery, Chang Gung Memorial Hospital-Linkuo, Chang Gung University College of Medicine, Tao-Yuan.Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei.Department of Mechanical Engineering, Chang Gung University, Tao-Yuan.Department of Mechanical Engineering, Chang Gung University, Tao-Yuan.Division of Neurosurgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, No. 291, Zhongzheng Rd., Zhonghe Dist., Taipei, 235.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31632467

Citation

Liu, Shih-Jung, et al. "Novel Multi-drugs Incorporating Hybrid-structured Nanofibers Enhance Alkylating Agent Activity in Malignant Gliomas." Therapeutic Advances in Medical Oncology, vol. 11, 2019, p. 1758835919875555.
Liu SJ, Yang ST, Chen SM, et al. Novel multi-drugs incorporating hybrid-structured nanofibers enhance alkylating agent activity in malignant gliomas. Ther Adv Med Oncol. 2019;11:1758835919875555.
Liu, S. J., Yang, S. T., Chen, S. M., Huang, Y. C., Lee, W. H., Ho, J., ... Tseng, Y. Y. (2019). Novel multi-drugs incorporating hybrid-structured nanofibers enhance alkylating agent activity in malignant gliomas. Therapeutic Advances in Medical Oncology, 11, p. 1758835919875555. doi:10.1177/1758835919875555.
Liu SJ, et al. Novel Multi-drugs Incorporating Hybrid-structured Nanofibers Enhance Alkylating Agent Activity in Malignant Gliomas. Ther Adv Med Oncol. 2019;11:1758835919875555. PubMed PMID: 31632467.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel multi-drugs incorporating hybrid-structured nanofibers enhance alkylating agent activity in malignant gliomas. AU - Liu,Shih-Jung, AU - Yang,Shun-Tai, AU - Chen,Shu-Mei, AU - Huang,Yin-Chen, AU - Lee,Wei-Hwa, AU - Ho,Jui, AU - Chen,Yin-Chun, AU - Tseng,Yuan-Yun, Y1 - 2019/09/26/ PY - 2018/12/04/received PY - 2019/08/19/accepted PY - 2019/10/22/entrez PY - 2019/10/22/pubmed PY - 2019/10/22/medline KW - O6-benzylguanine (O6-BG) KW - O6-methylguanine-DNA methyltransferase (MGMT) KW - chemoresistance KW - malignant glioma KW - nanofibrous membrane SP - 1758835919875555 EP - 1758835919875555 JF - Therapeutic advances in medical oncology JO - Ther Adv Med Oncol VL - 11 N2 - Background: Malignant gliomas (MGs) are highly chemotherapy-resistant. Temozolomide (TMZ) and carmustine (BiCNU) are alkylating agents clinically used for treating MGs. However, their effectiveness is restrained by overexpression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) in tumors. O6-benzylguanine (O6-BG) is a nonreversible inhibitor of MGMT, it promotes the cytotoxicity of alkylating chemotherapy. The authors have developed a hybrid-structured nanofibrous membrane (HSNM) that sequentially delivers high concentrations of O6-BG, BiCNU, and TMZ in an attempt to provide an alternative to the current therapeutic options for MGs. Methods: The HSNMs were implanted onto the cerebral surface of pathogen-free rats following surgical craniectomy, while the in vivo release behaviors of O6-BG, TMZ, and BiCNU from the HSNMs were explored. Subsequently, the HSNMs were surgically implanted onto the brain surface of two types of tumor-bearing rats. The survival rate, tumor volume, malignancy of tumor, and apoptotic cell death were evaluated and compared with other treatment regimens. Results: The biodegradable HSNMs sequentially and sustainably delivered high concentrations of O6-BG, BiCNU, and TMZ for more than 14 weeks. The tumor-bearing rats treated with HSNMs demonstrated therapeutic advantages in terms of retarded and restricted tumor growth, prolonged survival time, and attenuated malignancy. Conclusion: The results demonstrated that O6-BG potentiates the effects of interstitially transported BiCNU and TMZ. Therefore, O6-BG may be required for alkylating agents to offer maximum therapeutic benefits for the treatment of MGMT-expressing tumors. In addition, the HSNM-supported chemoprotective gene therapy enhanced chemotherapy tolerance and efficacy. It can, therefore, potentially provide an improved therapeutic alternative for MGs. SN - 1758-8340 UR - https://www.unboundmedicine.com/medline/citation/31632467/Novel_multi-drugs_incorporating_hybrid-structured_nanofibers_enhance_alkylating_agent_activity_in_malignant_gliomas L2 - http://journals.sagepub.com/doi/full/10.1177/1758835919875555?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -