ANTITUMOUR ACTIVITY OF ORGANOTIN COMPOUNDS AND MEMBRANE-MEDIATED INHIBITION OF SIGNAL TRANSDUCTION LEADING TO DNA SYNTHESIS

Yasuaki Arakawa
1994 Main Group Metal Chemistry  
In vivo, dialkyltin compounds such as dibutyltin exhibited antitumor activity towards various tumor systems such as Ehrlich ascites 'tumor, IMC-carcinoma, p-388 lymphocytic leukaemia and sarcoma 180 in descending order of activity in mice. In addition, in a two-stage mouse skin carcinogenesis system of initiation and promotion, the optimal dose of dibutyltin inhibited the promotion stage, especially the first stage of two-stage promotion system, more strongly than the initiation stage. On the
more » ... ion stage. On the other hand, in vitro, dibutyltin dramatically inhibited the proliferation of malignant cells such as thymic lymphosarcoma cells and HeLa cells, and further inhibited the initiation stage of two-stage transformation of BALB/c 3T3 cells. Further, the compound selectively inhibited phosphatidylinositol (PI) turnover and arachidonate release without affecting directly Ca 2+ entry into the cells. The compound also caused a significant increase in the membrane order of inositol phospholipids (PIP2) that are the substrate of phospholipase C. Moreover, the compound inhibited selectively the phosphorylation of lipocortin, a phospholipase A 2 inhibitory protein, whereas the compound had no direct inhibitory effect on phospholipase C, phospholipase A 2 and protein kinase C. From these results, the suppressive effects of dibutyltin on cell proliferation system appear to reflect the membrane-mediated inhibition of the signal transduction leading to DNA synthesis such as the phospholipase activation system, because an affinity of intracellular dibutyltin to the nucleus was little or no.
doi:10.1515/mgmc.1994.17.1-4.225 fatcat:msvogoxmnfgfhjpdvk2ijyni5i