Similar changes were induced by Cladribine and by gemcitabine, in the deoxypyrimidine salvage, during short-term treatments.
Short term treatments (1-2 hrs) of human tonsillar lymphocytes by Cladribine (2-Chloro-deoxyadenosine, CdA) have suggested a new target for CdA, the inhibition of dCMP deaminase (Sasvári et al. 1994; BBRC 203, 1378). Further investigations have shown, that the dCMP-deaminase activity could be inhibited by 2-Cl-dAMP in cell free extracts of lymphocytes. The pool size of dUMP (measured by an antibody against dUMP) was also decreased in WiDr colon cancer cells by CdA. The new antimetabolite against solid tumours, Gemcitabine (2',2'-difluoro-deoxycytidine, dFdC), had similar effects on the salvage of thymidine (dThd) and deoxycytidine (dCyd) as CdA. The Ki values for 3H-dThd and 3H-dCyd incorporation into DNA were 0.16 uM and 1.0 uM dFdC, respectively. The labeling of the TTP pool increased 6-7 times, while of dCTP pool only 1.5-1.7 times, suggesting a decrease of the size of corresponding pools. Similarly to CdA, the labeling as well as the concentration of dUMP was also decreased by dFdC. Both analogues are able to increase the deoxycytidine kinase activity, necessary for their phosphorylation and therapeutic action in cells. The target(s) for the two different drugs seems to be common.
Csapó
Z
Z
Semmelweis Medical, University, Department Med. Chem., Molecular Biology, and Pathobiochemistry Budapest, Hungary.
Keszler
G
G
Sasvári-Székely
M
M
Smid
K
K
Noordhuis
P
P
Peters
G J
GJ
Staub
M
M
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002460:Cell Line; D017338:Cladribine / Q000494:pharmacology*; D003844:DCMP Deaminase / Q000037:antagonists & inhibitors*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000378:metabolism; D003856:Deoxyuracil Nucleotides / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005468:Fluorodeoxyuridylate / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D014066:Palatine Tonsil; D013936:Thymidine / Q000378:metabolism*; D013937:Thymidine Kinase / Q000378:metabolism; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003856:Deoxyuracil Nucleotides; D004791:Enzyme Inhibitors; D003841:Deoxycytidine; D005468:Fluorodeoxyuridylate; D017338:Cladribine; C007267:2'-deoxyuridylic acid; D013937:Thymidine Kinase; D003842:Deoxycytidine Kinase; D003844:DCMP Deaminase; D013936:Thymidine; D000093542:Gemcitabine