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Conversion to the Terminally Differentiated State during Treatment of NG108-15 Neural Tumor Cells with 1-ß-D-Arabinofuranosylcytosine in Defined Medium¹

Department of Biochemistry, Biophysics, and Genetics, University of Colorado Health Sciences Center, Denver, Colorado 80206

Differentiation of cells of the neural tumor hybrid cloned cell line NG108-15 begins stochastically upon transfer to a serum-free defined medium (A. Krystosek, J. Cell. Physiol., 125: 319–329, 1985). Such cultures in N2 medium contain both proliferating and neurite-forming cells (which are not mutally exclusive subpopulations). Addition of 1-ß-D-arabinofuranosylcytosine (ara-C) to NG108-15 cells in N2 medium yielded cultures with a highly differentiated appearance. Investigation of the nature of this effect revealed that ara-C did not increase the probability that cells would enter the differentiation pathway; it did, however, completely abolish proliferation. The early kinetics of neurite formation were similar in control and treated cultures. This was followed by a phase in which ara-C-treated cells underwent continuous rapid maturation including normalization of nucleolar features.

Loss of proliferative potential of treated cells was tested in a drug-free serum challenge protocol. Permanently postmitotic cells (i.e., cells which failed to divide even once) were shown to accumulate with time of ara-C pretreatment; this represented 59% of total cells at day 3 and 94% at day 7 of treatment. Thus, the bulk of the population can commit to terminal differentiation. Even among the minority of cells capable of 1–2 rounds of division in the challenge incubation, cessation of proliferation was more likely than continuous colonial growth, suggesting that a profound phenotypic alteration had occurred.

The results show that advanced morphological maturation and the step(s) of terminal neuronal differentiation can be achieved in this cell line in response to a cancer chemotherapeutic agent and that this drug is a more complete inducer than compounds which modulate the cyclic AMP system.

¹ This study was supported by Grant R23-CA32260 from the USPHS awarded by the National Cancer Institute.

² To whom requests for reprints should be addressed. Present address: Eleanor Roosevelt Institute for Cancer Research, 1899 Gaylord Street, Denver, CO 80206.

Received 9/ 3/87. Revised 6/27/88. Accepted 9/26/88.