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Biochemical Pharmacology of 2-Chlorodeoxyadenosine in Malignant Human Hematopoietic Cell Lines and Therapeutic Effects of 2-Bromodeoxyadenosine in Drug Combinations in Mice¹

Department of Biochemical and Clinical Pharmacology [T. L. A., W. C. L., F. C. H., R. L. B.], Department of Hematology-Oncology [V. M. S.], and Division of Comparative Medicine [J. E. R.], St. Jude Children's Research Hospital, Memphis, Tennessee 38101, and the Department of Pharmacology, University of Tennessee College of Medicine-Memphis, Memphis, Tennessee 38163 [R. L. B.]

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 µM CldAdo, CldAdo 5'-phosphate (CldAMP) reached 0.7–14 µM and CldAdo 5'-triphosphate (CldATP) reached 0.05–6 µM 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.

¹ This study was supported in part by USPHS CORE Center Grant P30 CA 21765 and by Research Grant CA 39242 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities.

² Present address: Nucleic Acid Research Institute, ICN Plaza, Costa Mesa, CA 92626.

³ To whom requests for reprints should be addressed.

Received 2/22/89. Revised 6/ 7/89. Accepted 6/16/89.

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