DNA interaction and cytostatic activity of the new liver organotropic complex 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-cell proliferation. Changes in the electrophoretic mobility of the open and covalently closed circular forms of the pUC18 plasmid DNA from Escherichia coli, a shift in the denaturation temperature of double-stranded DNA, and ethidium-bromide displacement from DNA binding, were induced by Bamet-R2 and cisplatin, but not by GC. Neutral-red retention was used to measure the number of living cells in culture after long-term (72-hr) exposure to these compounds and to evaluate the effect on cell viability after short-term (6-hr) exposure. Bamet-R2 and cisplatin, but not GC, induced significant inhibition of cell growth. This effect ranged from mild to strong, depending upon the sensitivity of the different cell types as follows: cisplatin, rat hepatocytes in primary culture < 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 approximately equal to hCC < rH. DNA synthesis was measured by radiolabeled-thymidine incorporation into DNA. Bamet-R2 and cisplatin, but not GC, significantly inhibited the rate of DNA synthesis by these cells. After short-term exposure to Bamet-R2 or GC, no acute cell toxicity was observed, except on hCC cells. By contrast, acute toxicity was induced by cisplatin for all cell types studied. The in vivo anti-tumoral effect was investigated in 3 different strains of mice following 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. However, signs of toxicity (increases in blood urea concentrations and decreases in packed blood cell volume and in liver, kidney and body weight) and a reduction in survival rate were observed only during cisplatin administration. In sum, these results indicate that this bile-acid derivative can be considered as a cytostatic drug whose potential usefulness deserves further investigation.
Marin
J J
JJ
Department of Physiology and Pharmacology, University of Salamanca, Spain. jjgmarin@gugu.usal.es
Macias
R I
RI
Criado
J J
JJ
Bueno
A
A
Monte
M J
MJ
Serrano
M A
MA
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004247:DNA / Q000737:chemistry* / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004996:Ethidium / Q000737:chemistry / Q000494:pharmacology; D006000:Glycocholic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008114:Liver Neoplasms, Experimental; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C108271:diaminneplatinum(II)-chlorocholylglycinate; D004247:DNA; D004996:Ethidium; D006000:Glycocholic Acid; D002945:Cisplatin