Cytotoxicity and mode of action of 1-(1-cyclohexenyl) and 1-unsubstituted 3,5-pyrazolidinediones in human Molt4 T cell leukemia.
The 3,5-pyrazolidinediones proved to be potent cytotoxic agents against the growth of a number of murine and human tumor cell lines, e.g. human THP-I monocytic leukemia, Hut-78 lymphoma, MCF-7 breast effusion, A549 lung carcinoma, U87MG glioma, Hela uterine and A431 epidermoid skin cancer. In human Tmolt4 cell leukemia, the agents substantially suppressed DNA and RNA syntheses after 60 min at 100 microM. The de novo purine biosynthetic pathway appeared to be the major target of the agents with the inhibition of both PRPP-amido transferase and IMP dehydrogenase (IMPDH) activities. Suppression of IMPDH activity was due to the inhibition of both the Type I and II isoforms through an uncompetitive mechanism; however, the Type II isoform was preferentially inhibited at lower concentrations of compounds tested (>50-150 microM). Therefore IMPDH Type II activity, which predominates in cancer cells, was selectively inhibited over the Type I isoform (208-312 microM). The activities of other enzymes examined were inhibited which added to the overall suppression of DNA synthesis, i.e., ribonucleotide reductase, dihydrofolate reductase and nucleoside kinases. The agents caused Tmolt4 DNA strand scission but the DNA molecule itself did not appear to be a target of the compounds since there was no induced cross-linking of the DNA, intercalation between base pairs or alkylation of the DNA bases.
Barnes
B J
BJ
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, Chapel Hill, North Carolina 27599-7360, USA.
Izydore
R A
RA
Hall
I H
IH
D000582:Amidophosphoribosyltransferase / Q000037:antagonists & inhibitors; D000818:Animals; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D020128:Inhibitory Concentration 50; D007700:Kinetics; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D008956:Models, Chemical; D010653:Phenylbutazone / Q000494:pharmacology*; D020033:Protein Isoforms; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D011994:Recombinant Proteins; D004247:DNA; D007168:IMP Dehydrogenase; D000582:Amidophosphoribosyltransferase; D010653:Phenylbutazone