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Requirements for and Kinetics of Growth Arrest of Neoplastic Cells by Confluent 10T Fibroblasts Induced by a Specific Inhibitor of Cyclic Adenosine 3':5'-Phosphodiesterase¹

Grace Cancer Drug Center, Roswell Park Memorial Institute, Buffalo, New York 14263

This study was conducted to further characterize the previously described phenomenon of growth inhibition of neoplastically transformed C3H/10T cells (T10T) by nontransformed C3H/10T clone 8 mouse embryo fibroblast (10T) cells in the presence of inhibitors of cyclic adenosine 3':5'-monophosphate (cAMP) phosphodiesterase. The cAMP phosphodiesterase inhibitor di-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO20-1724) was shown to be completely nontoxic to T10T cells at 10^-4 M. yet when added to mixed cultures of T10T cells and postconfluence growth-arrested 10T cells, colony formation and [³H]thymidine incorporation into T10T cells were virtually eliminated. This effect was dose dependent and was reversible upon drug withdrawal. In 10T cells, RO20-1724 caused a dose-dependent increase in cAMP levels from about 5 to 150 pmol/10⁶ cells; in T10T cells, 10^-4 M drug treatment caused a 5-fold elevation in cAMP without a clear dose dependency. Cyclic guanosine 3':5'-monophosphate levels in 10T cells fell by 50% with drug treatment but were unmeasurable in T10T cells. When intracellular cyclic AMP levels were elevated by the adenyl cyclase stimulator forskolin, growth inhibition of T10T cells was again induced in mixed cultures but was not observed when added to T10T cells alone. Addition of RO20-1724 to low concentrations of forskolin produced a greater than additive effect on growth inhibition. Growth inhibition of T10T cells by RO20-1724 was shown to (a) require contact with, or extremely close proximity to, a confluent monolayer of 10T cells, (b) be maximum when seeded upon a growth-inhibited monolayer and not an actively growing 10T culture, and (c) not be decreased by continuous agitation of the culture medium, indicating that readily diffusible inhibitory factors are not involved. A model is presented whereby transformed cells can respond to but cannot themselves generate growth-inhibitory signals produced by post-confluence growth-inhibited nontransformed cells. The existence of these cellular interactions may well explain problems in the quantitation of transformed foci encountered in the use of this cell line as an assay system for chemical and physical carcinogens.

¹ This investigation was supported by USPHS Grant CA 21359 and Core Grant CA 24538 awarded by the National Cancer Institute, Department of Health and Human Services.

² Present address: Cancer Research Center of Hawaii, 1236 Lauhala St., Honolulu, HI 96813.

Received 8/30/83. Revised 10/31/84. Accepted 1/24/85.

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