DIFFERENCE BETWEEN CANCER-CELLS AND THE CORRESPONDING NORMAL TISSUE IN VIEW OF STEREOSELECTIVE HYDROLYSIS OF SYNTHETIC ESTERS

This study has aimed at taking information necessary for design of ant icancer prodrugs modified with chiral acyl group, especially about the effect of chirality of the acyl group on its enzymic removal in speci fic cells. Thus, 13 species of chiral esters were synthesized and ster eoselectivity in their enzymic hydrolysis was investigated with six ca ncer cell lines, solid tumors, and the corresponding normal tissues. C ultured cancer cells from rat liver, pancreas, and muscle hydrolyzed t he R enantiomer of (+/-)-ethyl 2-methoxy-2-phenylacetate (3c) more pre ferentially than its antipode, whereas this stereoselectivity was reve rsed in the reaction by homogenate of the corresponding normal tissue of rat. The difference in stereoselectivity between cancer cells and n ormal tissue was also found in the hydrolysis of other esters includin g those of actual anticancer agents, p-hydroxyaniline mustard and 5-fl uorouridine. The investigation was expanded to real tumor to show that the degree of stereoselectivity or the hydrolytic activity was signif icantly different between a human brain tumor and its surrounding norm al tissue for such substrates as (+/-)-ethyl 2-phenoxypropanoate and N -trifluoroacetylphenylalaninate. The esterases of rat liver cancer cel ls (Anr4) and normal rat liver gave different band patterns in active staining after gel electrophoresis. The enzymes were fractionated by i on exchange column chromatography and then tested on their stereoselec tivity against (+/-)-3c. Comparison of the results and electrophoretog rams of the fractions suggests that esterases with different stereosel ectivity are expressed in different ways by normal and cancer cells. T hese results show that stereoselectivity in enzymic hydrolysis of some synthetic chiral esters is different between cancer and normal cells, leading to the possibility that specific activation of ester-type ant icancer prodrugs in cancer cells would be controlled by the chiral str ucture of the acyl group.