TY - JOUR
T1 - Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone; 3-AP)
T2 - An inhibitor of ribonucleotide reductase with antineoplastic activity
AU - Finch, Rick A.
AU - Liu, Mao Chin
AU - Cory, Ann H.
AU - Cory, Joseph G.
AU - Sartorelli, Alan C.
N1 - Funding Information:
This research was supported by U.S. Public Health Service Grants CA-53340 (ACS) and CA-55540 (JGC) from the National Cancer Institute. RAF is a Special Fellow of the Leukemia Society of America.
PY - 1999/7
Y1 - 1999/7
N2 - The enzyme RR catalyzes the conversion of ribonucleoside diphosphates to their deoxyribonucleotide counterparts. RR is critical for the generation of the cytosine, adenine, and guanine deoxyribonucleotide 5'-triphosphate building blocks of DNA, which are present in cells as exceedingly small intracellular pools. Therefore, interference with the function of RR might well result in an agent with significant antineoplastic activity, particularly against rapidly proliferating tumor cells. HUr is the only inhibitor of RR in clinical usage; this agent, however, is a relatively poor inhibitor of the enzyme and has a short serum halflife. Consequently, HUr is a relatively weak anticancer agent. In an effort to develop a more potent inhibitor of RR with utility as an anticancer agent, we have synthesized 3-AP and demonstrated (a) potent inhibition of LI210 leukemia cells in vitro, (b) curative capacity for mice bearing the LI210 leukemia, (c) marked inhibition of RR, and (d) sensitivity of HUr-resistant cells to 3-AP. These findings collectively demonstrate the clinical potential of 3-AP as an antineoplastic agent.
AB - The enzyme RR catalyzes the conversion of ribonucleoside diphosphates to their deoxyribonucleotide counterparts. RR is critical for the generation of the cytosine, adenine, and guanine deoxyribonucleotide 5'-triphosphate building blocks of DNA, which are present in cells as exceedingly small intracellular pools. Therefore, interference with the function of RR might well result in an agent with significant antineoplastic activity, particularly against rapidly proliferating tumor cells. HUr is the only inhibitor of RR in clinical usage; this agent, however, is a relatively poor inhibitor of the enzyme and has a short serum halflife. Consequently, HUr is a relatively weak anticancer agent. In an effort to develop a more potent inhibitor of RR with utility as an anticancer agent, we have synthesized 3-AP and demonstrated (a) potent inhibition of LI210 leukemia cells in vitro, (b) curative capacity for mice bearing the LI210 leukemia, (c) marked inhibition of RR, and (d) sensitivity of HUr-resistant cells to 3-AP. These findings collectively demonstrate the clinical potential of 3-AP as an antineoplastic agent.
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U2 - 10.1016/S0065-2571(98)00017-X
DO - 10.1016/S0065-2571(98)00017-X
M3 - Article
C2 - 10470363
AN - SCOPUS:0032832996
SN - 0065-2571
VL - 39
SP - 3
EP - 12
JO - Advances in Enzyme Regulation
JF - Advances in Enzyme Regulation
IS - 1
ER -