The cytostatic- and differentiation-inducing effects of cyclopentenyl cytosine on neuroblastoma cell lines.
This paper describes the effects of cyclopentenyl cytosine (CPEC) on the proliferation and cell-cycle distribution of the SK-N-BE(2)c and SK-N-SH neuroblastoma cell lines, as well as their ability to recover from treatment with CPEC. The IC50 value of SK-N-BE(2)c for CPEC, determined after 48 hr was 80 nM. SK-N-BE(2)c cells showed a time- and concentration-dependent accumulation in the S-phase of the cell cycle after 2 and 3 days of incubation with 50-250 nM CPEC, followed by a G0/G1-phase arrest after 4 days. After incubation with 50 nM CPEC for 2 days, SK-N-BE(2)c cells fully recovered and resumed logarithmic proliferation. In contrast, a complete and persistent growth arrest occurred when SK-N-BE(2)c cells were incubated for 2 days with 100 or 250 nM CPEC. The IC50 value of SK-N-SH, determined after 48 hr, for CPEC was > or =1 microM. SK-N-SH cells incubated with 250 nM or 1 microM CPEC showed a time-dependent accumulation in the S-phase of the cell cycle, followed by an accumulation in the G0/G1-phase, which reached a maximum of 84.1% after 7 days of incubation with 1 microM CPEC. SK-N-SH cells did not resume proliferation after removal of the drug. In addition, CPEC strongly induced differentiation in SK-N-SH cells. After 48 hr incubation with 250 nM CPEC, 90% of the cell population was differentiated. Both neuronal type and Schwannian type cells were observed. We conclude that at very low concentrations, CPEC has profound cytostatic- and differentiation-inducing effects on the neuroblastoma cells studied.
Bierau
J
J
Academic Medical Center, University of Amsterdam, Emma Children's Hospital and Department of Clinical Chemistry, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands.
van Gennip
A H
AH
Helleman
J
J
van Kuilenburg
A B
AB
D000970:Antineoplastic Agents / Q000494:pharmacology*; D019731:Carbon-Nitrogen Ligases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D003562:Cytidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D003570:Cytidine Triphosphate / Q000378:metabolism; D006801:Humans; D009447:Neuroblastoma / Q000473:pathology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003562:Cytidine; D003570:Cytidine Triphosphate; C045911:cyclopentenyl cytosine; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase