Targeting Folates by Carboxypeptidase G2: Potential Applications in Anticancer Therapy.
Carboxypeptidase G2 (CPG2) cleaves folates and folate analogues resulting in alternative routes of folate metabolism. CPG2 is of particular interest in anticancer therapy for several reasons. CPG2 rapidly converts methotrexate (MTX) into less toxic metabolites causing a rapid decline of MTX serum levels in animal models as well as in humans. Thus, CPG2 is a powerful rescue agent in patients receiving high-dose MTX and might circumvent life-threatening toxicity in patients with MTX intoxication. As CPG2 causes a predefined and considerable decline of MTX levels, this substance might be also attractive for MTX dose escalation studies. In addition, CPG2 has been used in antibody-directed enzyme prodrug therapy. Prodrugs have been developed which are cleaved by CPG2, resulting in a release of active cytotoxic agents. The use of these prodrugs, attached to a tumor-specific antibody-CPG2- complex, might enhance concentrations of cytotoxic drugs in tumor tissues. Finally, CPG2 has been investigated in combination with trimetrexate, as it has been shown that trimetrexate is resistant to CPG2 cleavage. In conclusion, CPG2 is a novel drug with promising properties. However, clinical experiences are limited and further studies are necessary to define the role of CPG2 in cancer therapy. Copyright 2000 S. Karger GmbH, Freiburg
Krackhardt
A.
A
Medizinische Klinik III, Hämatologie, Onkologie und Transfusionsmedizin, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin.
Schwartz
S.
S
Thiel
E.
E