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Potentiation of 1-ß-D-Arabinofuranosylcytosine Cytotoxicity to HL-60 Cells by 1,25-Dihydroxyvitamin D₃ Correlates with Reduced Rate of Maturation of DNA Replication Intermediates¹

Departments of Laboratory Medicine and Pathology [G. P. S., K. B. R., A. K. B.] and Radiology [H. Z. H.], University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103

S-phase-active cytotoxic drugs selectively damage leukemic cells, but the mechanisms of this action are not clear. We have investigated the previously reported potentiation of toxicity of 1-ß-D-arabinofuranosylcytosine (ara-C) to HL-60 cells by the differentiation-inducing steroid, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], and compared the results with the effects of other drugs which inhibit DNA synthesis. Determination of the intracellular content of the active metabolite of ara-C, ara-CTP, excluded more prolonged retention of the drug as the basis for potentiation of cytotoxicity. Alkaline elution of replicating DNA showed that 1,25(OH)₂D₃ added with or immediately after ara-C or hydroxyurea reduced the rate maturation of the replicating DNA and resulted in an increased proportion of smaller DNA fragments. However, pretreatment of the cells with 1,25(OH)₂D₃ inhibited this effect of the drugs on replication of DNA. No direct effect of 1,25(OH)₂D₃ on replicating DNA could be detected. The results suggest that the early events which initiate cell differentiation may protect an intact DNA replicative machinery from S-phase-active drugs but reduce the rate of DNA maturation once DNA integrity has been compromised by inhibitors of DNA synthesis.

¹ Supported by Grant RO1 CA44722 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Department of Laboratory Medicine and Pathology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103.

Received 12/10/90. Accepted 4/19/91.

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