Mechanism of activation of triciribine phosphate (TCN-P) as a prodrug form of TCN.
The tricyclic nucleotide triciribine phosphate (TCN-P) was synthesized as a water-soluble derivative of the tricyclic nucleoside TCN (L. B. Townsend et al, INSERM 81:37, 1978). Growth of L1210 cells in vitro was inhibited equally by TCN and TCN-P. A requirement for adenosine kinase activity for activation of both TCN and TCN-P was established by the observation that growth inhibition by either compound was decreased 200-fold by the adenosine kinase inhibitor 5-iodotubercidin and greater than 5000-fold in L1210/T, an adenosine kinase-deficient subline. The TCN/TCN-P resistance of L1210/T cells was correlated with lack of formation of intracellular TCN-P from either TCN or TCN-P. Thus, it appeared that TCN-P was hydrolyzed to TCN and then rephosphorylated intracellularly. Both the horse serum-containing culture medium and the intact cells possessed nucleotide phosphatase activity, which may contribute to the hydrolysis of TCN-P to TCN in the L1210 cell cultures. The requirement for hydrolysis of TCN-P to TCN for formation of intracellular TCN-P from exogenous TCN-P was also shown directly by the observation that human erythrocytes, which lack ectophosphatases, readily formed intracellular TCN-P from TCN but not from TCN-P when incubated in buffer.
L L
LL
Wotring
G W
GW
Crabtree
N L
NL
Edwards
R E
RE
Parks
L B
LB
Townsend
D000073:Acenaphthenes; D000248:Adenosine Kinase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D001711:Biotransformation; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007939:Leukemia L1210 / Q000378:metabolism; D051379:Mice; D009711:Nucleotides / Q000096:biosynthesis; D012265:Ribonucleotides / Q000378:metabolism* / Q000494:pharmacology
D000073:Acenaphthenes; D000970:Antineoplastic Agents; D009711:Nucleotides; D012265:Ribonucleotides; C014205:triciribine phosphate; D000248:Adenosine Kinase