Regulation of deoxycytidine kinase activity and inhibition by DFDC.
(1) Deoxycytidine kinase activity increased in a transformation- and progression-linked fashion in rat hepatomas of different proliferation rates. The activity also increased and was growth rate-linked in a series of tissue culture cell lines of human and animal tumors. (2) Deoxycytidine kinase activity was stringently linked with expression of the neoplastic proliferative program as it sharply increased in log phase in tissue culture cells of hepatoma 3924A and several human carcinoma strains. (3) Deoxycytidine kinase is subject to nutritional and hormonal regulation. On starvation the activity in liver decreased and on refeeding it returned to normal. Steroid hormone increased liver enzymic activity. Deoxycytidine kinase is substrate-inducible, since deoxycytidine injections in rat led to a 2- to 3-fold increase in hepatic enzyme activity. (4) Actinomycin or cycloheximide treatment blocked the increase in liver deoxycytidine kinase activity induced by steroid or deoxycytidine treatment. Therefore, it is assumed that the rise in deoxycytidine kinase activity requires new RNA and protein synthesis. (5) Cycloheximide treatment of rats carrying hepatomas yielded a t1/2 = 3.4 hr in the tumor for deoxycytidine kinase activity which was the shortest among the examined enzymes of purine and pyrimidine biosynthesis. (6) Actinomycin treatment of rats carrying hepatomas yielded a t1/2 of 5.8 hr for deoxycytidine kinase activity in the tumor which was one of the shortest in the examined enzymes of purine and pyrimidine biosynthesis. (7) Difluorodeoxycytidine (DFDC) is a competitive inhibitor (Ki = 7-28 microM) of deoxycytidine kinase from rat hepatoma and from human pancreatic carcinoma and ovarian carcinoma cells in culture.
Weber
G
G
Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5200.
Singhal
R L
RL
Abonyi
M
M
Prajda
N
N
Hata
Y
Y
Szekeres
T
T
Yeh
A
A
Look
K Y
KY
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011742:Pyrimidine Nucleotides / Q000096:biosynthesis; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D011742:Pyrimidine Nucleotides; D003841:Deoxycytidine; D003609:Dactinomycin; D003513:Cycloheximide; D003842:Deoxycytidine Kinase; D000093542:Gemcitabine