DNA INTERACTION AND CYTOSTATIC ACTIVITY OF THE NEW LIVER ORGANOTROPICCOMPLEX OF CISPLATIN WITH GLYCOCHOLIC ACID - BAMET-R2

The aim of this study was to investigate the ability of the new liver organotropic complex of cisplatin with glycocholate (GC), Bamet-R2, to interact with DNA, inhibit its replication and hence reduce tumor-cel l proliferation. Changes in the electrophoretic mobility of the open a nd covalently closed circular forms of the pUC 18 plasmid DNA from Esc herichia coil, a shift in the denaturation temperature of double-stran ded DNA, and ethidium-bromide displacement from DNA binding, were indu ced by Bamet-R2 and cisplatin, but not by GC, Neutral-red retention wa s used to measure the number of living cells in culture after long-ter m (72-hr) exposure to these compounds and to evaluate the effect on ce ll viability after short-term (6-hr) exposure. Bamet-R2 and cisplatin, but not GC, induced significant inhibition of cell growth. This effec t ranged from mild to strong, depending upon the sensitivity of the di fferent cell types as follows: cisplatin, rat hepatocytes in primary c ulture < rat hepatoma McA-RH7777 cells (rH) < human colon carcinoma LS 174T cells (hCC) < mouse hepatoma Hepa 1-6 cells (mH); Bamet-R2, rat hepatocytes < mH approximate to hCC < rH. DNA synthesis was measured b y radiolabeled-thymidine incorporation into DNA, Bamet-R2 and cisplati n, but not GC, significantly inhibited the rate of DNA synthesis by th ese cells. After short-term exposure to Bamet-R2 or CC, no acute cell toxicity was observed, except on hCC cells, By contrast, acute toxicit y was induced by cisplatin for all cell types studied. The in vivo ant i-tumoral effect was investigated in 3 different strains of mice follo wing s.c. implantation of tumor cells (mouse sarcoma S-18011 cells in Swiss and B6 mice and hCC cells in nude mice). In all 3 models, tumor growth was inhibited by Bamet-R2 and cisplatin to a similar degree. Ho wever, signs of toxicity (increases in blood urea concentrations and d ecreases in packed blood cell volume and in liver, kidney and body wei ght) and a reduction in survival rate were observed only during cispla tin administration. In sum, these results indicate that this bile-acid derivative can be considered as a cytostatic drug whose potential use fulness deserves further investigation. Int J. Cancer 78:346-352, 1998 . (C) 1998 Wiley-Liss, Inc.