Dipyridamole enhancement of toxicity to L1210 cells by deoxyadenosine and deoxycoformycin combinations in vitro.
The combination of 2'-deoxyadenosine and deoxycoformycin is known to be markedly toxic to T-lymphocyte cell lines relative to B-cell lines, and this difference appears to be related to the capacity of the cells to accumulate deoxyadenosine triphosphate (dATP). In the presence of dipyridamole and 2'-deoxyadenosine and when adenosine deaminase was inhibited with deoxycoformycin, the L1210 leukemia cell which is a non-T-, non-B-cell type accumulated dATP like a T-cell type. The intracellular L1210 concentration of dATP using the triple combination (1.1 microM deoxycoformycin-40 microM deoxyadenosine-10 microM dipyridamole) reached 400 microM at which concentration ribonucleotide reductase specific activity was reduced by 80%. While this degree of enzyme may be significant, complete inhibition might have been expected, since 400 microM dATP is approximately 40 times the concentration to give 50% inhibition in some purified systems.
D000818:Animals; D000970:Antineoplastic Agents; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003070:Coformycin / Q000031:analogs & derivatives / Q000627:therapeutic use*; D003838:Deoxyadenine Nucleotides / Q000378:metabolism; D003839:Deoxyadenosines / Q000627:therapeutic use*; D004176:Dipyridamole / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D015649:Pentostatin; D012263:Ribonucleosides / Q000627:therapeutic use*; D012264:Ribonucleotide Reductases / Q000378:metabolism
D000970:Antineoplastic Agents; D003838:Deoxyadenine Nucleotides; D003839:Deoxyadenosines; D012263:Ribonucleosides; D003070:Coformycin; D015649:Pentostatin; D004176:Dipyridamole; D012264:Ribonucleotide Reductases; C026600:2'-deoxyadenosine triphosphate