Enzyme-catalyzed therapeutic agent (ECTA) design: activation of the antitumor ECTA compound NB1011 by thymidylate synthase

The in vivo administration of enzyme-inhibiting drugs for cancer and infect ious disease often results in overexpression of the targeted enzyme. We hav e developed an enzyme-catalyzed therapeutic agent (ECTA) approach in which an enzyme overexpressed within the resistant cells is recruited as an intra cellular catalyst for converting a relatively non-toxic substrate to a toxi c product. We have investigated the potential of the ECTA approach to circu mvent the thymidylate synthase (TS) overexpression-based resistance of tumo r cells to conventional fluoropyrimidine [i.e., 5-fluorouracil (5-FU)] canc er chemotherapy. (E)-5-(2-Bromovinyl)-2'-deoxy-5'-uridyl phenyl L-methoxyal aninylphosphoramidate (NB1011) is a pronucleotide analogue of (E)-5-(2-brom ovinyl)-2'-deoxyuridine (BVdU), an antiviral agent known to be a substrate for TS when in the 5'-monophosphorylated form. NB1011 was synthesized and f ound to be at least 10-fold more cytotoxic to 5-FU-resistant, TS-overexpres sing colorectal tumor cells than to normal cells. This finding demonstrates that the ECTA approach to the design of novel chemotherapeutics results in compounds that are selectively cytotoxic to tumor cell lines that overexpr ess the target enzyme, TS, and therefore may be useful in the treatment of fluoropyrimidine-resistant cancer. (C) 2001 Elsevier Science Inc. All right s reserved.