Abstract
The toxicity and metabolism of 9-β-D-arabinofuranosyl-2-fluoroadenine (F-ara-A), an adenosine deaminase-resistant nucleoside analog, have been compared to those of 9-β-D-arabi-nofuranosyladenine (ara-A) in the presence of the adenosine deaminase inhibitor, deoxycoformycin. Equal concentrations of F-ara-A and ara-A plus deoxycoformycin produced similar inhibition of growth of CCRF-CEM human lymphobiastoid cells. 9-β-D-Arabinofuranosyl-2-fluoroadenine 5́-triphosphate (F-ara-ATP) and 9-β-D-arabinofuranosyladenine 5́-triphosphate (ara-ATP), were concentratively accumulated intracellularly and exerted their major inhibitory effect on DNA synthesis. Two approaches were used to compare the effect of these nucleotide analogs on the DNA-synthetic capacity of whole cells. (a) The concentrations of F-ara-ATP and ara-ATP in cells incubated with the respective nucleosides were determined directly at the same time that the DNA-synthetic capacity of the cells in each culture was measured by incorporation of [3H]thymidine into DNA. Neither compound significantly affected the specific activity of cellular [3H]deoxythymidine triphosphate, (b) The rates of disappearance of F-ara-ATP and ara-ATP from cells washed free of the nucleosides were determined. These values were used to calculate the cellular concentration of each nucleotide analog in cells in which DNA-synthetic capacity was monitored after incubation with F-ara-A or ara-A plus deoxycoformycin and washed into fresh media. These determinations indicated that the rates of accumulation of F-ara-ATP and ara-ATP differed and were related to the concentration of the exogenous nucleoside. F-ara-ATP disappeared from cells in drug-free media at several times the rate of the disappearance of ara-ATP. However, at equal cellular concentrations, F-ara-ATP was slightly more inhibitory to the processes measured by thymidine incorporation than was ara-ATP. We conclude that F-ara-ATP and ara-ATP share a similar mechanism of action and potency of inhibition of DNA synthesis. The fact that F-ara-A retains its cytotoxic efficacy in the absence of inhibitors of adenosine deaminase provides a rationale for investigating its antitumor properties further.
Original language | English (US) |
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Pages (from-to) | 2349-2355 |
Number of pages | 7 |
Journal | Cancer Research |
Volume | 40 |
Issue number | 7 |
State | Published - Jul 1 1980 |
ASJC Scopus subject areas
- Oncology
- Cancer Research