CELL-CULTURE ASSAYS FOR CHEMICALS WITH TUMOR-PROMOTING OR TUMOR-INHIBITING ACTIVITY-BASED ON THE MODULATION OF INTERCELLULAR COMMUNICATION

The ability of chemicals with tumor-promoting or tumor-inhibiting acti vity to modulate gap junctional intercellular communication is reviewe d. The two most extensively used types of assays for screening tests a re (1) metabolic cooperation assays involving exchange between cells o f precursors of nucleic acid synthesis and (2) dye-transfer assays tha t measure exchange of fluorescent dye from loaded cells to adjacent ce lls. About 300 substances of different biological activities have been studied using various assays. For tumor promoters/epigenetic carcinog ens, metabolic cooperation assays have a sensitivity of 62% and dye-tr ansfer assays 60%. Thirty percent of DNA-reactive carcinogens also pos sess the ability to uncouple cells. The complete estimation of the pre dictive power of these assays could not be made because the majority o f the substances studied for intercellular communication effects in vi tro have not yet been studied for promoting activity in vivo. Both met abolic cooperation assays and dye transfer assays respond well to the following classes of substances: phorbol esters, organochlorine pestic ides, polybrominated biphenyls, promoters for urinary bladder, some bi ological toxins, peroxisome proliferators, and some complex mixtures. Results of in vitro assays for such tumor promoters/nongenotoxic carci nogens, such as some bile acids, some peroxides, alkanes, some hormone s, mineral dusts, ascorbic acid, okadaic acid, and benz(e)pyrene, do n ot correlate with the data of in vivo two-stage or complete carcinogen esis. Enhancement of intercellular communication was found for 18 chem icals. Among these, cAMP, retinoids, and carotenoids have demonstrated inhibition of carcinogenesis. We examine a number of factors that are important for routine screening, including the requirement for biotra nsformation for some agents to exert effects on gap junctions. We also discuss the mechanisms of tumor promoter and tumor inhibitor effects on gap junctional permeability, including influences of protein kinase activation, changes in proton and Ca2+ intracellular concentrations, and effects of oxy radical production.