Selective activation of anticancer prodrugs by monoclonal antibody-enzyme conjugates.
Several recent reports have demonstrated that anticancer drugs can be generated site-selectively at solid tumors by monoclonal antibody-enzyme conjugates targeted to antigens on tumor cell surfaces. The first step in this drug targeting approach involves the delivery of the enzyme conjugate to a tumor cell population. After the conjugate has localized within the tumor and cleared from non-target tissues, a relatively non-cytotoxic drug precursor (prodrug) is administered. Upon contact with the targeted enzyme, the prodrug is converted into a toxic drug. Several examples are presented to illustrate this targeting strategy. Monoclonal antibody-beta-lactamase conjugates have been developed to activate a panel of anticancer prodrugs that are mechanistically dissimilar. The antitumor activities of the monoclonal antibody-beta-lactamase conjugate/prodrug combinations exceed those obtained by systemic drug administration, and are immunologically specific. In another example involving targeted cytosine deaminase for the generation of 5-fluorouracil, it is shown that as much as 17 times more drug can be delivered within a tumor compared to when 5-fluorouracil is administered alone. The method of using targeted enzymes for prodrug activation can be extended to include prodrugs that release very potent drugs, such as palytoxin, a marine natural product, and to treat cells that have the multidrug resistance phenotype. Some of the requirements for successful therapy with this approach for cancer therapy are discussed.
Wallace
P M
PM
Bristol Myers Squibb Pharmaceutical Research Institute, Seattle, Washington.
Senter
P D
PD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D004338:Drug Combinations; D057487:Enzyme Therapy; D004798:Enzymes / Q000378:metabolism; D006801:Humans; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011355:Prodrugs / Q000378:metabolism / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004338:Drug Combinations; D004798:Enzymes; D011355:Prodrugs