Study of Differentiation Therapy for Salivary Gland Cancer

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1. Treatment by hexamethylene bisacetamide (HMBA) or 8-chloroadenosine 3' : 5' -cyclic monophosphate (8-Cl-cAMP) of human salivary gland cancer cells (HSG and HSY), which were grown in vitro and as xenograft in nude mouse, resulted in marked growth inhibition. 2. We have already found that be treatment of HSG cells with 5-azacytidine results in the differentiation into myoepithelial cells (HSG-AZA1) and acinar cells (HSG-AZA3). In the present study, we have found that differentiation into the neuron-like cells of HSG-AZA1 cells occurs in growth medium containing 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine(H-7), an inhibitor of protein kinase C.When the isoenzymic patterns of protein kinase C in HSG-AZA1 cells were analyzed, expression of all the 3 types of isoenzyme was found in the cells ; however, decreased expression of type II protein kinase C was observed in the HSG-AZA1 cells treated with H-7, as compared with untreated cells. In addition, we have found that treatment of HSG-AZA1 cells with dibutyryl cAMP results in the differentiation into neuron-like cells. 3. Treatment of HSG cells with HuIFN-a significantly decreased the number of EGF receptors/cell. 4. Treatment of HSG or HSG-AZA1 cells with HMBA resulted in the differentiation into glial cells, which was accompanied by the appearance of DNA hypomethylation and decreased expression of type II protein kinase C in the treated cells. 5. It has been suggested that selective binding of 8-Cl-cAMP to cAMP-dependent protein kinase A receptor present in HSG or HSY cells caused marked growth inhibition. 6. The cultivation of HSG cells in the presence of etoposide, an inhibitor of DNA topoisomerse II, resulted in the emergence of cells with a smooth muscle cell phenotype, such as expression of a-smooth muscle actin and myofilaments, which was accompanied by decreased expression of ras oncogene product as compared with the untreated cells. 7. We have prepared the metastasizing HSG cells (mHSG) by treating non-met