Cellular pharmacology of MTA: a correlation of MTA-induced cellular toxicity and in vitro enzyme inhibition with its effect on intracellular folate and nucleoside triphosphate pools in CCRF-CEM cells.
The mechanism of action of an antifolate may be investigated using a variety of experimental methods. These include experiments in a cell culture setting to observe possible protection against drug effects afforded by the end products of metabolic pathways, assessing the activity of purified target enzymes in the presence of the antifolate, and, finally, the measurement of drug effects on intracellular folate and nucleoside triphosphate pools. The current discussion is focused on studies using CCRF-CEM leukemia cells that were designed to compare and contrast mechanisms of action of the antifolates methotrexate, which is primarily a dihydrofolate reductase inhibitor, raltitrexed, a thymidylate synthase inhibitor, LY309887, a glycinamide ribonucleotide formyltransferase inhibitor, and MTA (multitargeted antifolate), which is a novel antifolate antimetabolite. The results of these studies support the hypothesis that MTA affects multiple enzymatic targets and has a distinct mechanism of action from methotrexate, raltitrexed, and LY309887.
Chen
V J
VJ
Division of Cancer Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA.
Bewley
J R
JR
Andis
S L
SL
Schultz
R M
RM
Iversen
P W
PW
Shih
C
C
Mendelsohn
L G
LG
Seitz
D E
DE
Tonkinson
J L
JL
D017766:Acid Anhydride Hydrolases / Q000187:drug effects* / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D003854:Deoxyribonucleotides / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005492:Folic Acid / Q000187:drug effects / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D009701:Nucleoside-Diphosphate Kinase / Q000378:metabolism; D043583:Nucleoside-Triphosphatase; D000068437:Pemetrexed; D011799:Quinazolines / Q000494:pharmacology; D012265:Ribonucleotides / Q000378:metabolism; D013763:Tetrahydrofolates / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D013942:Thymine Nucleotides / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C105065:6R-2',5'-thienyl-5,10-dideazatetrahydrofolic acid; D000964:Antimetabolites, Antineoplastic; D003854:Deoxyribonucleotides; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D005971:Glutamates; D011799:Quinazolines; D012265:Ribonucleotides; D013763:Tetrahydrofolates; D013876:Thiophenes; D013942:Thymine Nucleotides; D000068437:Pemetrexed; D006147:Guanine; D005492:Folic Acid; D013940:Thymidylate Synthase; D009701:Nucleoside-Diphosphate Kinase; D017766:Acid Anhydride Hydrolases; D043583:Nucleoside-Triphosphatase; C068874:raltitrexed; C024157:thymidine 5'-triphosphate; D008727:Methotrexate