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 infectious disease often results in overexpression of the targeted enzyme. We have developed an enzyme-catalyzed therapeutic agent (ECTA) approach in which an enzyme overexpressed within the resistant cells is recruited as an intracellular catalyst for converting a relatively non-toxic substrate to a toxic product. We have investigated the potential of the ECTA approach to circumvent the thymidylate synthase (TS) overexpression-based resistance of tumor cells to conventional fluoropyrimidine [i.e. 5-fluorouracil (5-FU)] cancer chemotherapy. (E)-5-(2-Bromovinyl)-2'-deoxy-5'-uridyl phenyl L-methoxyalaninylphosphoramidate (NB1011) is a pronucleotide analogue of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdU), an antiviral agent known to be a substrate for TS when in the 5'-monophosphorylated form. NB1011 was synthesized and found to be at least 10-fold more cytotoxic to 5-FU-resistant, TS-overexpressing 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 overexpress the target enzyme, TS, and therefore may be useful in the treatment of fluoropyrimidine-resistant cancer.
Lackey
D B
DB
NewBiotics, Inc., 11760-E Sorrento Valley Rd., San Diego, CA 92121, USA. dlackey1@newbiotics.com
Groziak
M P
MP
Sergeeva
M
M
Beryt
M
M
Boyer
C
C
Stroud
R M
RM
Sayre
P
P
Park
J W
JW
Johnston
P
P
Slamon
D
D
Shepard
H M
HM
Pegram
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D003856:Deoxyuracil Nucleotides / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000008:administration & dosage / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D003856:Deoxyuracil Nucleotides; C421011:NB1011; D011355:Prodrugs; C020235:brivudine; C007267:2'-deoxyuridylic acid; D013940:Thymidylate Synthase; D001973:Bromodeoxyuridine