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Journal of Neuroscience, Vol 9, 115-124, Copyright © 1989 by Society for Neuroscience
Cytosine arabinoside kills postmitotic neurons: evidence that deoxycytidine may have a role in neuronal survival that is independent of DNA synthesis
TL Wallace and EM Johnson Jr
Center for Biotechnology, Baylor College of Medicine, The Woodlands, Texas 77381.
Cytosine arabinoside (ARA C), a competitive inhibitor of the incorporation
of 2'-deoxycytidine into DNA in other cell types, caused a
concentration-dependent inhibition of KCl- and insulin-stimulated survival
of postmitotic ciliary parasympathetic ganglion neurons, and the nerve
growth factor (NGF)-stimulated survival of postmitotic dorsal root ganglion
(DRG) sensory neurons in vitro. The IC50 for survival was 2 x 10(-8) M for
both types of neurons after 4 d under the culture conditions used. The
inhibition of DRG survival by ARA C in the presence of varying
concentrations of NGF indicated that ARA C acted as an apparent
noncompetitive antagonist of NGF. This cytotoxic effect of ARA C was
blocked by 2'-deoxycytidine, but not by cytosine, 2'- deoxyadenosine,
2'-deoxyguanosine, or 2'-deoxythymine, indicating that ARA C was
interfering with a deoxycytidine-specific survival process. Cytidine could
block ARA C toxicity, but it was 40 times less potent than
2'-deoxycytidine. The blockade of the cytotoxic effect of ARA C by
2'-deoxycytidine indicated that 2'-deoxycytidine was an apparent
competitive antagonist of ARA C toxicity. 2'-Deoxycytidine, by itself, was
not survival-promoting. Other antimitotic agents, such as adenine
arabinoside, thymine arabinoside, 5-fluorodeoxyuridine, 5-
bromodeoxycytidine, 5-azadeoxycytidine, and aphidicolin had no effect on
neuronal survival at a concentration 5000 times the EC50 of ARA C,
indicating that inhibition of DNA synthesis or repair was probably not the
mechanism by which ARA C inhibited neuronal survival and that other
2'-deoxynucleosides were not involved in the survival-promoting process.
Nitrobenzylthioinosine, an inhibitor of 2'-deoxycytidine and ARA C membrane
transport in other cell types, inhibited the cytotoxic effect of ARA C in
neurons, suggesting that ARA C entered the neurons through a similar
transport mechanism and that ARA C needed to gain access to the inside of
the neuron to be effective. These results indicate that ARA C, in addition
to being an antimitotic agent for dividing cells, is also cytotoxic for
postmitotic neurons. This inhibition of neuronal survival by ARA C is
hypothesized to be due to inhibition of a 2'-deoxycytidine-dependent
process that is independent of DNA synthesis or repair. Thus,
2'-deoxycytidine may have an important and previously unrecognized role in
cellular function that in the case of neurons is critical for survival.
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