Directed enzyme prodrug therapy (DEPT) uses enzymes artificially introduced into the body to convert
prodrugs
A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
, which have no or poor biologically activity, to the active form in the desired location within the body. Many
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
drugs for cancer lack tumour specificity and the doses required to reach therapeutic levels in the tumour are often toxic to other tissues. DEPT strategies are an experimental method of reducing the systemic toxicity of a drug, by achieving high levels of the active drug only at the desired site. This article describes the variations of DEPT technology.
Antibody-directed enzyme prodrug therapy (ADEPT)
ADEPT is a strategy to overcome the problems of lack of
tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
selectivity. An antibody designed/developed against a tumor
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
is linked to an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
and injected to the blood, resulting in selective binding of the enzyme in the tumor. When the discrimination between tumor and normal tissue enzyme levels is sufficient, a
prodrug
A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
is administrated into the blood circulation, which is converted to an active cytotoxic drug by the enzyme, only within the tumor. Selectivity is achieved by the tumor specificity of the antibody and by delaying prodrug administration until there is a large differential between tumor and normal tissue enzyme levels.
ADEPT has shown antitumor activity in animal tumor models of human
choriocarcinoma
Choriocarcinoma is a malignant, trophoblastic cancer, usually of the placenta. It is characterized by early hematogenous spread to the lungs. It belongs to the malignant end of the spectrum in gestational trophoblastic disease (GTD). It is also cl ...
and colonic and
breast carcinoma
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipple, ...
.
ADEPT history
The first pilot-scale clinical trial of ADEPT was carried out at
Charing Cross Hospital
Charing Cross Hospital is an acute general teaching hospital located in Hammersmith, London, United Kingdom. The present hospital was opened in 1973, although it was originally established in 1818, approximately five miles east, in central Lond ...
,
London
London is the capital and largest city of England and the United Kingdom, with a population of just under 9 million. It stands on the River Thames in south-east England at the head of a estuary down to the North Sea, and has been a majo ...
, using an anti-CEA F(ab′)2 antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2).
The antibody used in the first ADEPT clinical trial was of murine origin and the enzyme was bacterial. Host antibodies to both components of the AEC were present in the blood of all non-immunosuppressed patients by day 10 after AEC infusion. Several patients received
ciclosporin
Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, ...
since it had been shown in rabbits that this could delay the appearance of host antibodies to soluble proteins.
A subsequent, small-scale trial at the
Royal Free Hospital
The Royal Free Hospital (also known simply as the Royal Free) is a major teaching hospital in the Hampstead area of the London Borough of Camden. The hospital is part of the Royal Free London NHS Foundation Trust, which also runs services at Barn ...
, London, used the same agents as in the Charing Cross Hospital trial but the protocol was modified to provide additional pharmacokinetic data and most patients received only a single course of treatment.
Gene-directed enzyme prodrug therapy (GDEPT)
GDEPT is a
suicide gene
In the field of genetics, a suicide gene is a gene that will cause a cell to kill itself through the process of apoptosis (programmed cell death). Activation of a suicide gene can cause death through a variety of pathways, but one important cellu ...
therapy in which the enzyme required for prodrug conversion is produced within the target cell, using a gene delivered to it by gene therapy. When an