| One of the major problems with current cancer cheniotherapies is the lack specificity of treatment, which leads to harmful side effects in normal tissues, especially the gut lining and bone marrow. Current research is thus focused on the development of more selective methods for the delivery of toxic compounds to cancer cells. In an attempt to circumvent these problems, investigators have expected to deliver cytotoxic drugs to cancer cells via monoclonal antibodies (mAbs) that bind to tumorselective antigens. Cytotoxic drugs have been coupled to monoclonal antibodies, and the resulting conjugates are more selectively delivered to tumor cells than are drugs alone. However, low drug delivery is a problem generally associated with this approach. It is compromised by (1) the limitation caused by the number of drug molecules that can be aftached to the antibody. (2) antigen density, (3) the limited difflisibility of conjugates due to differences in their sizes, (4) immunogenicity of antibody-drug conjugates. Antibody-directed enzyme prodrug therapy (ADEPT) has attracted considerable interest since the concept was first described in 1987. This technology involves selectively delivering an activating enzyme to the tumor site by conjugating it to a targeting antibody. This activating enzyme is then used to convert systemically administered prodrug to drug at the tumor site. The catalytic potential of a targeted enzyme and the high potential prodrug concentration may overcome the low drug delivery problem. A little amounts of antibody-enzyme conjugations can convert a large amounts of prodrug to drug which can kill tumor cells. Huennekens and co-workers conjugate monoclonal antibody KS 1/4 to carboxypeptidase A(CPA), and get the product of KS 1/4-CPA conjugation. They developed an in vitro ADEPT approach using MTX prodrugs in which MIX was modified at the glutamate moiety with one of several natural amino acids. These prodrugs were relatively nontoxic in cell culture but could be activated by bovine CPA or carboxypeptidase B to form MIX. The most successful of these prodrugs was MTX-Phe, which was found to be an excellent substrate for bovine CPA. These system was effective under cell culture conditions where the 1C50 of MTX-Phe against L1210 cells changed from 2.2>( 106mo1/L to 6.3 X 108mo1/L. We have been doing basic research on ADEPT, and synthesized two kinds prodrugs( MIX- a -Phe , MIX- a -Arg), from which carboxypeptidase A cleaves the a -carboxyl phenylalamne residue to yield methotrexate. In anti-tumor studies using the human PC-3 prostate cancer xenograft model in nude mice, the combination of anti-human Y -seminoprotein monoclonal antibody (E4B7McAb) -CPA conjugate with MIX- a -Phe resulted in a tumor inhibition rate of over 85%. An important decision that needs to be made with this type of therapy is what types of prodrugs and enzymes are to be employed. Enzymes that have been considered for ADEPT include both endogenous and nonendogenous types. onendogenous enzymes. This type enzymes, which are most used for ADEPT, have immunogenicity and may generate an immune response that would interfere with multiple rounds of therapy. Some strategies have achieved some success results by using immune inhibitors, but these inhibitors have only effects in 2-3 rounds for ADEPT. ndogenous enzymes. This type enzyme has lower immunogenicity, but may result in the hydrolysis of prodrugs at sites distal to the tumor site, t... |
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