Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone; 3-AP): an inhibitor of ribonucleotide reductase with antineoplastic activity.
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 half-life. 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 L1210 leukemia cells in vitro, (b) curative capacity for mice bearing the L1210 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.
Finch
R A
RA
Department of Pharmacology, Yale University School of Medicine, New Haven CT 06520, USA.
Liu
M C
MC
Cory
A H
AH
Cory
J G
JG
Sartorelli
A C
AC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006918:Hydroxyurea / Q000494:pharmacology; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D011725:Pyridines / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013882:Thiosemicarbazones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D007501:Iron; D012264:Ribonucleotide Reductases; D006918:Hydroxyurea