Antineoplastic effect of the combination of 2,3-dihydro-1H-pyrazole[2,3a]imidazole plus deoxyadenosine/erythro-9-(2-hydroxyl-3-nonyl)adenine in mice with L1210 leukemia cells.
Administration of 2,3-dihydro-1H-pyrazole[2,3a]imidazole (IMPY, 150 mg/kg) followed 8 hr later by injection of deoxyadenosine/erythro-9-(2-hydroxyl-3-nonyl)adenine (dAdo/EHNA, 175 mg/17.5 mg/kg) on days 2, 3, 6, and 7 increased the mean survival time of L1210 tumor bearing mice (210%). The sequential treatment was more efficacious than the simultaneous administration of these drugs. Administration of IMPY or dAdo/EHNA, alone, at the same doses as in the combination, did not prolong the life-span of tumor bearing mice. To determine the basis for the increased survival due to the sequential treatment with IMPY and dAdo/EHNA, cell cycle analysis and deoxyribonucleoside triphosphate concentrations were measured. Cytotoxicity of IMPY and dAdo/EHNA is known to be achieved through the inhibition of ribonucleotide reductase. IMPY is a specific inhibitor of the nonheme-iron subunit of ribonucleotide reductase, whereas deoxyadenosine in the presence of the adenosine deaminase inhibition, EHNA, is converted to deoxyadenosine 5'-triphosphate (dATP), which is a specific inhibitor of the effector-binding-subunit of ribonucleotide reductase. Our studies showed that L1210 cells accumulated in early S-phase, whereas intracellular dATP and deoxyguanosine triphosphate (dGTP) pools were depleted 8 hr after IMPY administration. dAdo/EHNA administration 8 hr after IMPY injection caused an increase in the intracellular concentration of dATP while maintaining the depletion of the dGTP pool and prolonged the S-phase as compared to the administration of IMPY alone.
Matsumoto
M
M
Department of Internal Medicine, University of South Florida College of Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa 33612.
Weckbecker
G
G
Cory
J G
JG
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D003839:Deoxyadenosines / Q000008:administration & dosage / Q000627:therapeutic use*; D003854:Deoxyribonucleotides / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D003839:Deoxyadenosines; D003854:Deoxyribonucleotides; D011720:Pyrazoles; C010192:9-(2-hydroxy-3-nonyl)adenine; D000225:Adenine; C000971:2,3-dihydro-1H-imidazo(1,2-b)pyrazole