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 anticancer prodrugs modified with chiral acyl group, especially about the effect of chirality of the acyl group on its enzymic removal in specific cells. Thus, 13 species of chiral esters were synthesized and stereoselectivity in their enzymic hydrolysis was investigated with six cancer cell lines, solid tumors, and the corresponding normal tissues. Cultured cancer cells from rat liver, pancreas, and muscle hydrolyzed the R enantiomer of (+/-)-ethyl 2-methoxy-2-phenylacetate (3c) more preferentially than its antipode, whereas this stereoselectivity was reversed in the reaction by homogenate of the corresponding normal tissue of rat. The difference in stereoselectivity between cancer cells and normal tissue was also found in the hydrolysis of other esters including those of actual anticancer agents, p-hydroxyaniline mustard and 5-fluorouridine. The investigation was expanded to real tumor to show that the degree of stereoselectivity or the hydrolytic activity was significantly different between a human brain tumor and its surrounding normal tissue for such substrates as (+/-)-ethyl 2-phenoxypropanoate and N-trifluoroacetylphenylalaninate. The esterases of rat liver cancer cells (Anr4) and normal rat liver gave different band patterns in active staining after gel electrophoresis. The enzymes were fractionated by ion exchange column chromatography and then tested on their stereoselectivity against (+/-)-3c. Comparison of the results and electrophoretograms of the fractions suggests that esterases with different stereoselectivity are expressed in different ways by normal and cancer cells. These 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 anticancer prodrugs in cancer cells would be controlled by the chiral structure of the acyl group.
Yamazaki
Y
Y
National Institute of Bioscience and Human Technology, Agency of Industrial Science and Technology, Ibaraki, Japan.
Ogawa
Y
Y
Afify
A S
AS
Kageyama
Y
Y
Okada
T
T
Okuno
H
H
Yoshii
Y
Y
Nose
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism; D004952:Esters / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism; D008297:Male; D009132:Muscles / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism; D010648:Phenylacetates / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004952:Esters; D010648:Phenylacetates; C093256:ethyl-2-methoxy-2-phenylacetate