This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huang, M.-C. Articles by Blakley, R. L. Search for Related Content PubMed PubMed Citation Articles by Huang, M.-C. Articles by Blakley, R. L.

Effects of Cytotoxicity of 2-Chloro-2'-deoxyadenosine and 2-Bromo-2'-deoxyadenosine on Cell Growth, Clonogenicity, DNA Synthesis, and Cell Cycle Kinetics¹

Divisions of Biochemical and Clinical Pharmacology and Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101

The cytotoxic effects of the adenosine deaminase resistant analogues 2-bromo-2'-deoxyadenosine (2-BrdAdo) and 2-chloro-2'-deoxyadenosine (2-CldAdo) have been compared with those of deoxyadenosine (dAdo). Like 2-CldAdo, 2-BrdAdo is highly effective in inhibiting the growth of many T-lymphoblastoid, B-lymphoblastoid, and myeloid cell lines in culture. Concentrations required to inhibit growth of CCRF-CEM human T-lymphoblastoid cells by 50% (IC₅₀) are: 2-CldAdo, 0.045 µM; 2-BrdAdo, 0.068 µM; dAdo, 0.9 µM in the presence of 5 µM erythro-9-(2-hydroxy-3-nonyl)adenine. Like dAdo, 2-BrdAdo causes a much greater decrease in DNA synthesis than in RNA and protein synthesis. For each of the nucleosides the concentration required to cause 50% inhibition of DNA synthesis (as measured by thymidine incorporation) in an 18-h exposure is very similar to the IC₅₀ for growth and to the concentration required to decrease viability (clonogenicity) over 18 h by 50% (EC₅₀).

A fraction of CCRF-CEM cells (30%) is resistant to killing by exposure to 2-BrdAdo or 2-CldAdo for 4 h at concentrations 100 times the EC₅₀, but 3% of cells are resistant to exposure for 4 h to a concentration of dAdo 3 times the EC₅₀.

Each of the three nucleosides causes accumulation of cells in S phase, the accumulation becoming more marked with longer periods of exposure and with higher concentrations of nucleoside. During exposures for 18–24 h at a concentration of nucleoside near the EC₅₀ most cells accumulate in S, with most in early S, whereas exposure to concentrations >EC₉₅ accumulates cells at the G₁/S border. This suggests that loss of viability is associated with a blockade of some process specifically occurring at the initiation of S phase. At an optimum dosage schedule, 2-BrdAdo and 2-CldAdo have similar therapeutic effects against L1210 in vivo, both producing over 99% cell kill, but the optimum dosage of 2-CldAdo is lower.

¹ Supported by USPHS CORE Center Grant P30-CA 21765 from the National Cancer Institute and by American Lebanese Syrian Associated Charities.

² To whom requests for reprints should be addressed.

Received 6/11/85. Revised 11/18/85. Accepted 1/30/86.

This article has been cited by other articles:

				S. Cardoen, E. Van Den Neste, C. Smal, J.-F. Rosier, A. Delacauw, A. Ferrant, G. Van den Berghe, and F. Bontemps Resistance to 2-Chloro-2'-deoxyadenosine of the Human B-cell Leukemia Cell Line EHEB Clin. Cancer Res., November 1, 2001; 7(11): 3559 - 3566. [Abstract] [Full Text] [PDF]

				P. Hentosh and M. Tibudan 2-Chloro-2'-deoxyadenosine, an Antileukemic Drug, Has an Early Effect on Cellular Mitochondrial Function Mol. Pharmacol., April 1, 1997; 51(4): 613 - 619. [Abstract] [Full Text]