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Clostridial-directed enzyme prodrug therapy (CDEPT) is the use of Clostridia to convert prodrugs into active drug agents. It is comparable to a more popular strategy, called ADEPT.1
The CDEPT strategy
Perhaps the most challenging issue in cancer treatment is how to reduce the side effects of the injected anti-cancer agents, which are of a high cytotoxicity potential. A widely used solution is to use enzymes which are able to convert a relatively non-toxic prodrug precursor into the active drug form(s). Clostridial-directed enzyme prodrug therapy (CDEPT)2 is one of the possible approaches.
Solid tumors, in contrast to normal tissues, grow rapidly. As a result, the cancerous tissues may suffer from inadequate blood and oxygen supply.3 Therefore, clostridia can grow in tumor and destroy it specifically.4 (Originally, Parker and co-workers5 showed that the injection of Clostridium histolyticum spores to the transplanted sarcomas of mice results in significant tumour lysis. Soon after, it was shown that a direct injection is not necessary, and that tumour colonization was readily obtained after intravenous administration of spores6).
In CDEPT, a prodrug-converting enzyme expressed by a clostridial expression plasmid converts a prodrug into an active drug form within the tumor. While the prodrug is the inactive form and can be administrated to the blood, the products of the prodrug cleavage are highly cytotoxic and show their effect only in the vicinity of tumor cells.
Difficulties in the engineering of clostridial strains have restricted the application of other enzyme prodrug systems. So far, two enzymes have been applied in CDEPT: cytosine deaminase and nitroreductase.7 It has been recently suggested that β-lactamases, which are naturally found in Clostridia, can facilitate the application of the method significantly.8
References
- ^ Bagshawe KD. "Antibody-directed enzyme prodrug therapy (ADEPT) for cancer." Expert Rev Anticancer Ther. 2006; 6(10): 1421-1431.Entrez Pubmed 17069527
- ^ Minton NP, Mauchline ML, Lemmon MJ, Brehm JK, Fox M, Michael NP, et al. "Chemotherapeutic tumour targeting using clostridial spores." FEMS Microbiol Rev 1995;17:357–64. Entrez Pubmed 7576773
- ^ Nuyts S, Van Mellaert L, Theys J, Landuyt W, Lambin P, Anne J. "Clostridium spores for tumor-specific drug delivery." Anti-Cancer Drug 2002;13:115–25. Entrez Pubmed 11901303
- ^ Brown JM, Wilson WR. "Exploiting tumour hypoxia in cancer treatment." Nat Rev Cancer. 2004; 4(6): 437-447.Entrez Pubmed 15170446
- ^ Parker RC, Plumber HC, Siebenmann CO, Chapman MG. "Effect of histolyticus infection and toxin on transplantable mouse tumours." Proc. Soc. Exp. Biol. Med. 1947; 66: 461−465.
- ^ Malmgren RA, Flanigan CC. "Localization of the vegetative form of Clostridium tetani in mouse tumours following intravenous spore administration." Cancer Res. 1955; 15: 473−478.Entrez Pubmed 13240693
- ^ Minton NP. "Clostridia in cancer therapy." Nat Rev Microbiol. 2003;1:237–42.Entrez Pubmed 15035028
- ^ Tirandaz H, Hamedi J, Marashi SA. "Application of beta-lactamase-dependent prodrugs in clostridial-directed enzyme therapy (CDEPT): A proposal." Med Hypotheses. 2006; 67: 998-999.Entrez Pubmed 16797858
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