Modification of ricin and its hepatotoxicity and activity against hepatocellular cancer in mice.

Abstract

AIM:To observe the effects of ricin (RT) with and without chemical modification on both hepatotoxicity of mice and activity against hepatocellular cancer (HCC), and evaluate the possibility to improve RT anticancer activity via chemical modification.METHODS:RT was modified with N-succinimidyl3(2-pyridyldithio) propionate (SPDP),a heterobifunctional cross-linker, and SPDP derivative of RT (PDP-R) was obtained.The serum glutathione-s-transferase (SGST) activity,as an index of liver damage, was determined in mice intoxicated with RT and PDP-R,at various doses and time.The tissue damage of HCC in the nude mice ip injected with PDP-R was compared with that with RT at the same dose by immunohistochemical method, the relative content of both RT and PDP-R in the HCC tissues was measured by computerized image-analysis. RESULTS:The SGST activities increased with doses or/and time intoxicated with both RT and PDP-R, and the increase in the value of RT group was more significant than that in the PDP-R group; the SGST activity of RT group was 2.8-fold (P < 0.01) of PDP-R group at a dose of 12.5&mgr;g/kg for 42h, showing the much lower toxicity of R-PDP than that of RT. Under an optical microscope, hemolysis and necrosis of massive cells in the HCC tissues of PDP-R group were observed and the ratio of necrosis mounted to 90.5% while the corresponding value of RT group only to 62.5%.With computerized image-analysis, the average relative content of RT and PDP-R in the HCC tissues,represented as greyness, was 140.06 plus minus 3.43 and 169.10 plus minus 2.74, respectively. There was significant difference between the two (P< 0.05), indicating the higher content of PDP-R in the HCC tissue than that of RT.CONCLUSION:The hepatotoxicity of PDP-R to mice may be reduced by chemical modification with SPDP, but both the affinity of PDP-R to the HCC tissues and ability to kill it may be stronger than that of RT. So this might be a valuable attempt to improve the anticancer activity of RT.