CDEPT
Encyclopedia
Clostridial-directed enzyme prodrug therapy (CDEPT) is the use of Clostridia
to convert prodrug
s into active drug agents. It is comparable to a more popular strategy, called ADEPT
.
potential. A widely used solution is to use enzyme
s which are able to convert a relatively non-toxic prodrug precursor into the active drug form(s). Clostridial-directed enzyme prodrug therapy (CDEPT) is one of the possible approaches.
Solid tumor
s, in contrast to normal tissues, grow rapidly. As a result, the cancerous tissues may suffer from inadequate blood
and oxygen
supply. Therefore, clostridia can grow in tumor and destroy it specifically. (Originally, Parker and co-workers 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 spores).
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
. It has been recently suggested that β-lactamases, which are naturally found in Clostridia, can facilitate the application of the method significantly.
Clostridia
The Clostridia are a class of Firmicutes, including Clostridium and other similar genera. They are distinguished from the Bacilli by lacking aerobic respiration. They are obligate anaerobes and oxygen is toxic to them. Species of the genus Clostridium are all Gram-positive and have the ability to...
to convert prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
s into active drug agents. It is comparable to a more popular strategy, called ADEPT
ADEPT
ADEPT is a strategy to overcome the problems of lack of tumor selectivity. An antibody designed/developed against a tumor antigen is linked to an enzyme and injected to the blood, resulting in selective binding of the enzyme in the tumor...
.
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 cytotoxicityCytotoxicity
Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are a chemical substance, an immune cell or some types of venom .-Cell physiology:...
potential. A widely used solution is to use enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s which are able to convert a relatively non-toxic prodrug precursor into the active drug form(s). Clostridial-directed enzyme prodrug therapy (CDEPT) is one of the possible approaches.
Solid tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s, in contrast to normal tissues, grow rapidly. As a result, the cancerous tissues may suffer from inadequate blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
and oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
supply. Therefore, clostridia can grow in tumor and destroy it specifically. (Originally, Parker and co-workers 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 spores).
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
Cytosine deaminase
In enzymology, a cytosine deaminase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are cytosine and H2O, whereas its two products are uracil and NH3....
and nitroreductase
Nitroreductase
Nitroreductases are a family of evolutionarily related proteins involved in the reduction nitrogen containing compounds including those containing the nitro functional group...
. It has been recently suggested that β-lactamases, which are naturally found in Clostridia, can facilitate the application of the method significantly.