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Effects of Dibutyryl Cyclic Adenosine 3':5'-Monophosphate on the Growth of Cultured Human Small-Cell Lung Carcinoma and the Specific Cellular Activity of L-Dopa Decarboxylase¹

The Oncology Center [J. F., R. T., G. D. L., S. B. B.] and The Department of Medicine, [J. F., R. T., G. D. L., S. B. B.] The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21205

³ To whom requests for reprints should be addressed, at Room 2-127, The Oncology Center, The Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Baltimore, Md. 21205.

High activity of L-dopa decarboxylase separates small (oat)-cell from non-small-cell lung cancer in cell culture. The present study investigates relationships between the specific cellular activity of this enzyme and: (a) cell growth kinetics of an established line (O-H-1) of human small cell lung carcinoma, and (b) responses of these cells to treatment with cyclic adenosine 3':5'-monophosphate and sodium butyrate. The O-H-1 cells, as for most other established small-cell lines, grow as suspended cell aggregates. During growth, the specific cellular activity of L-dopa decarboxylase parallels levels for [³H]thymidine labeling index and the ratio of cells in G₂-M to those in G₁-G₀ phases of the cell cycle. Each of these parameters is 2- to 3-fold higher during exponential versus stationary growth. Continuous treatment with dibutyryl cyclic adenosine 3':5'-monophosphate (dcAMP; 0.1 or 1 mM) and 1 mM theophylline produces simultaneous cessation of cell growth and an increase in cellular L-dopa decarboxylase activity. During this period, analyses of DNA histograms reveal an increase in the number of cells in the G₂-M phase; the rate of increase in the ratio of G₂-M to G₁-G₀ cells paralleled the rate of increase in specific activity of the enzyme. The effects of the dcAMP were promptly reversible; release of the apparent G₂-M block preceded regrowth of the cells and was accompanied by a return of L-dopa decarboxylase activity to base-line levels. The changes in enzyme activity were specific for cyclic adenosine 3':5'-monophosphate; another cyclic adenosine 3':5'-monophosphate analogue, 8-bromo adenosine cyclic 3':5'-monophosphate yielded similar increases in L-dopa decarboxylase to those seen with dcAMP, while 0.01 to 1 mM butyrate alone produced the inhibition of cell growth but no changes in specific activity of L-dopa decarboxylase or percentage of cells in the different phases of the cell cycle. We conclude that the specific activity of L-dopa decarboxylase, a key neuroendocrine marker for cultured small-cell lung carcinoma, is highest during proliferative growth and/or when these cells are in the G₂M phase of the cell cycle. The differential effects of dcAMP and sodium butyrate offer potential for exploring neuroendocrine differentiation in this important lung cancer and related endocrine neoplasms.

¹ Portions of this work were presented in abstract form to The American Association of Cancer Research, 1980 (9) and were supported by Grant R01-18404 from the National Cancer Institute and Grant PDT-108 from the American Cancer Society. The FACS II cell sorter was supported through Oncology Center Core Grant 5P30-CA06973.

² Supported by a Clinical Investigator Award K08-AM-00774 from NIH.

Received 8/ 7/81. Accepted 10/28/82.

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