Bacterial Toxins for Oncoleaking Suicidal Cancer Gene Therapy
For suicide gene therapy, initially prodrug-converting enzymes (gene-directed enzyme-producing therapy, GDEPT) were employed to intracellularly metabolize non-toxic prodrugs into toxic compounds, leading to the effective suicidal killing of the transfecte
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Abstract
For suicide gene therapy, initially prodrug-converting enzymes (gene-directed enzyme-producing therapy, GDEPT) were employed to intracellularly metabolize non-toxic prodrugs into toxic compounds, leading to the effective suicidal killing of the transfected tumor cells. In this regard, the suicide gene therapy has demonstrated its potential for efficient tumor eradication. Numerous suicide genes of viral or bacterial origin were isolated, characterized, and extensively tested in vitro and in vivo, demonstrating their therapeutic potential even in clinical trials to treat cancers of different entities. Apart from this, growing efforts are made to generate more targeted and more effective suicide gene systems for cancer gene therapy. In this regard, bacterial toxins are an alternative to the classical GDEPT strategy, which add to the broad spectrum of different suicide approaches. In this context, lytic bacterial toxins, such as streptolysin O (SLO) or the claudin-targeted Clostridium perfringens enterotoxin (CPE) represent attractive new types of suicide oncoleaking genes. They permit as pore-forming proteins rapid and also selective toxicity toward a broad range of cancers. In this chapter, we describe the generation and use of SLO as well as of CPE-based gene therapies for the effective tumor cell eradication as promising, novel suicide gene approach particularly for treatment of therapy refractory tumors. Keywords
Cancer gene therapy
Suicide gene therapy Bacterial toxin Solid tumors
J. Pahle W. Walther (&) Experimental and Clinical Research Center, Charité University Medicine Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany e-mail: [email protected] © Springer International Publishing Switzerland 2016 W. Walther (ed.), Current Strategies in Cancer Gene Therapy, Recent Results in Cancer Research 209, DOI 10.1007/978-3-319-42934-2_7
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Introduction
Finding novel and efficient therapies that target malignancies is still important as the incidence of cancer diseases is constantly increasing. Conventional treatment modalities for cancer such as surgery, radiation therapy, and chemotherapy, which are usually combined for a better treatment effect, remain the therapeutic backbone of cancer therapy. However, these therapies do have their limitations, mainly caused by tumor heterogeneity and development of therapy refractory tumor cell populations. During the last decades, anticancer therapy has been continuously improved to overcome these drawbacks, but problems with adverse effects and drug resistance still constitute a main obstacle for successful cancer treatment. Therefore, alternative treatment options are urgently required to efficiently target and eradicate tumors. Cancer gene therapy represents one such promising strategy, an approach where selective tumor cell killing and tumor growth inhibition can be achieved by introducing foreign nucleic acid (DNA or RNA) as therapeutic agent to tumor cells (Walther and
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