Abstract
Tiazofurin, a C-nucleoside, and acivicin, a glutamine antagonist, are targeting against de novo guanylate synthesis and are under clinical trials as anticancer drugs. To elucidate the mechanisms of the recovery of the activities of the target enzymes after inhibition by these drugs, hepatoma 3924A cells were incubated either with 100 uM tiazofurin or 10 uM acivicin for three hours and the enzyme activities in cells after replacement with fresh medium were measured. IMP dehydrogenase, inhibited by 86% with tiazofurin, recovered to the control level within two hours. The addition of 6.7 uM cycloheximide did not affect this recovery. GMP synthase activity, which acivicin completely inhibited, recovered to 82% within 36 hours and cycloheximide blocked this return. These results suggest that in tissue culture system the recovery of GMP synthase activity after acivicin treatment is due to the newly synthesized enzyme protein. By contrast, under these in vitro conditions, inhibition of IMP dehydrogenase by tiazofurin is released by other mechanisms, e.g., dissociation of the drug from the enzyme or degradation of the drug. The applicability of the observations obtained in this in vitro system to animals and in human chemotherapy is under investigation. (Supported by Outstanding Investigator Grant CA-42510 to G.W.)
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call