Anti-tumor activity of an immunotoxin (TGFα-PE38) delivered by attenuated Salmonella typhimurium
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Daejin Lim1,2, Kwang Soo Kim1,2, Hyun-Ju Kim1,2, Kyong-Cheol Ko4, Jae Jun Song4, Jong Hyun Choi4, Minsang Shin5, Jung-Joon Min2,3, Jae-Ho Jeong1,2, Hyon E. Choy1,2
1Department of Microbiology, Chonnam National University Medical School, Gwangju, Republic of Korea
2Molecular Medicine, BK21 Plus, Chonnam National University Graduate School, Gwangju, Republic of Korea
3Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea
4Applied Microbiology Research Center, Bio-Materials Research Institute, Korea Research Institute of Bioscience and Biotechnology, Jeongeup, Jeonbuk, Republic of Korea
5Department of Microbiology, Kyungpook National University Medical School, Daegu, Republic of Korea
Hyon E. Choy, email: [email protected]
Jung-Joon Min, email: [email protected]
Jae-Ho Jeong, email: [email protected]
Keywords: immunotoxin, TGFα-PE38, bacterial cancer therapy, Salmonella
Received: September 20, 2016 Accepted: April 06, 2017 Published: April 18, 2017
The anticancer strategy underlying the use of immunotoxins is as follows: the cancer-binding domain delivers the toxin to a cancer cell, after which the toxin enters and kills the cell. TGFα-PE38 is an immunotoxin comprising transforming growth factor alpha (TGFα), a natural ligand of epidermal growth factor receptor (EGFR), and a modified Pseudomonas exotoxin A (PE38) lacking N terminal cell-binding domain, a highly potent cytotoxic protein moiety. Tumor cells with high level of EGFR undergo apoptosis upon treatment with TGFα-PE38. However, clinical trials demonstrated that this immunotoxin delivered by an intracerebral infusion technique has only a limited inhibitory effect on intracranial tumors mainly due to inconsistent drug delivery. To circumvent this problem, we turned to tumor-seeking bacterial system. Here, we engineered Salmonella typhimurium to selectively express and release TGFα-PE38. Engineered bacteria were administered to mice implanted with mouse colon or breast tumor cells expressing high level of EGFR. We observed that controlled expression and release of TGFα-PE38 from intra-tumoral Salmonellae by either an engineered phage lysis system or by a bacterial membrane transport signal led to significant inhibition of solid tumor growth. These results demonstrated that delivery by tumor-seeking bacteria would greatly augment efficacy of immunotoxin in cancer therapeutics.
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