Targeting Folates by Carboxypeptidase G2: Potential Applications in Anticancer Therapy

Abstract

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.

Neoglycoenzymes

“…393 CNBr-activated dextran was also employed by Sherwood and co-workers to modify carboxypeptidase G2 (EC 3.4.17.11), 71,394 an enzyme with potential application in cancer therapy. 395 Artificial glycosylation resulted in a 5-fold and 2.5fold increase in plasma persistence of the enzyme in healthy and tumor bearing mice, respectively. The conjugate was also more resistant to proteolysis by trypsin and α-chymotrypsin.…”

Akute lymphatische Leukämie des Erwachsenen Diagnostik, Risikogruppen und Therapie

“…In Einzelfällen kommt es nach der Gabe von HDM zu einer verzögerten MTX-Ausscheidung oder zu einem progredienten Nierenversagen. Hier hat sich eine interventionelle Behandlung mit Carboxypeptidase als effektiv erwiesen [29].…”