Biochemical pharmacology of 2-chlorodeoxyadenosine in malignant human hematopoietic cell lines and therapeutic effects of 2-bromodeoxyadenosine in drug combinations in mice.
Growth of human hematopoietic cell lines showed a 100-fold range of sensitivity to inhibition by 2-chloro-2'-deoxyadenosine (CldAdo), with highly sensitive lines in all three groups: T-lymphoblastic, B-lymphoblastic, and non-T, non-B. Formation of nucleotides from [8-3H]CldAdo was investigated in ten lines. In cells exposed to 0.15 microM CldAdo, CldAdo 5'-phosphate (CldAMP) reached 0.7-14 microM and CldAdo 5'-triphosphate (CldATP) reached 0.05-6 microM in 1 h. In most cases these nucleotide concentrations at 1 h were close to the steady-state concentrations, and the latter concentrations were approximately proportional to extracellular CldAdo concentration. On removal of extracellular CldAdo, intracellular CldAMP and CldATP declined rapidly with half times of 0.56-0.9 and 0.64-1.46 h, respectively. There was no correlation between these rates of catabolism and steady-state levels. The different sensitivities of the lines to CldAdo is explained only in part by the different steady-state concentrations of CldATP, and must be more directly related to differential effects on target enzymes. Mice inoculated with L1210 leukemia were treated with 2-bromo-2'-deoxyadenosine (BrdAdo) paired with one of 18 other therapeutic agents. Eight of the drugs paired with BrdAdo gave therapeutic responses from the combination greater than the sum of the responses of members of the pair. They included alkylating agents, antimetabolites blocking deoxyribonucleotide synthesis, and DNA polymerase inhibitors. Toxic dosages of CldAdo caused damage chiefly to the hemic-lymphatic systems and the kidneys.
Avery
T L
TL
Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101.
Rehg
J E
JE
Lumm
W C
WC
Harwood
F C
FC
Santana
V M
VM
Blakley
R L
RL
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001402:B-Lymphocytes; D001711:Biotransformation; D001932:Brain Neoplasms / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D017338:Cladribine; D003839:Deoxyadenosines / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D013601:T-Lymphocytes; D014407:Tumor Cells, Cultured / Q000166:cytology* / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D003839:Deoxyadenosines; D017338:Cladribine; C050069:2-bromo-2'-deoxyadenosine