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 activity to modulate gap junctional intercellular communication is reviewed. The two most extensively used types of assays for screening tests are (1) metabolic cooperation assays involving exchange between cells of precursors of nucleic acid synthesis and (2) dye-transfer assays that measure exchange of fluorescent dye from loaded cells to adjacent cells. About 300 substances of different biological activities have been studied using various assays. For tumor promoters/epigenetic carcinogens, metabolic cooperation assays have a sensitivity of 62% and dye-transfer assays 60%. Thirty percent of DNA-reactive carcinogens also possess the ability to uncouple cells. The complete estimation of the predictive power of these assays could not be made because the majority of the substances studied for intercellular communication effectsin vitro have not yet been studied for promoting activityin vivo. Both metabolic cooperation assays and dye transfer assays respond well to the following classes of substances: phorbol esters, organochlorine pesticides, polybrominated biphenyls, promoters for urinary bladder, some biological toxins, peroxisome proliferators, and some complex mixtures. Results ofin vitro assays for such tumor promoters/nongenotoxic carcinogens, such as some bile acids, some peroxides, alkanes, some hormones, mineral dusts, ascorbic acid, okadaic acid, and benz(e)pyrene, do not correlated with the data ofin vivo two-stage or complete carcinogenesis. Enhancement of intercellular communication was found for 18 chemicals. 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 biotransformation for some agents to exert effects on gap junction. 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.Abbreviations DMBA 7,12-dimethylbenz(a)anthracene - DT dye transfer - DDT 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane - HGPRT hypoxanthine-guanine phosphoribosyl-transferase - MC metabolic cooperation - PAH polycyclic aromatic hydrocarbons - PKA protein kinase A - PKC protein kinase C - TG 6-thioguanine - TPA 12-O-tetradecanoylphorbol-13-acetate