ABSTRACT
Potential cytotoxic compounds (spindle poisons) are being designed for the treatment of prostatic carcinoma, using the structural requirements of the substrates for prostatic acid phosphatase (PAP). Colchicine has been modified in ring C to give colchiceinamides of substituted ethanolamines and ethanolaminephosphates. Another new series of compounds modifying ring B of thiocolchicine have been prepared. Three O-phosphates of the thiocolchicine series have also been made. One has been examined for its specificity toward PAP. Some toxicity data of these compounds in mice have also been reported. Colchiceinamide-(L)-ephedrinephosphate has been examined in stumptail monkeys and some preliminary results are reported here.
Subject(s)
Acid Phosphatase/metabolism , Prostate/enzymology , Prostatic Neoplasms/drug therapy , Animals , Chemical Phenomena , Chemistry , Colchicine/analogs & derivatives , Colchicine/pharmacology , Enzyme Activation/drug effects , Ephedrine/analogs & derivatives , Ephedrine/pharmacology , Ethanolamines/pharmacology , Haplorhini , Kidney/enzymology , Macaca , Male , Organophosphorus Compounds/pharmacology , Phosphorylcholine/pharmacologyABSTRACT
Prostatic acid phosphatase (PAP), an acid phosphatase specific to the prostate gland, is demonstrated cytochemically for both light and electron microscopy with a new substrate phosphorylcholine. Lead ion is used as capture agent for liberated phosphate ion in a modified Gomori medium. PAP is demonstrated in the tubuloaveolar epithelial secretory cells of the rat ventral prostate gland. In the apical portion of the cell it is found in secretory granules and in the matrix of multivescular bodies. In the Golgi area it is localized in Golgi cisternae, Golgi related vacuoles and multivescular bodies. Evidence is presented that PAP is not a lysosomal enzyme, as are other acid phosphatases, and that phosphorylcholine is a highly specific substrate for PAP. As based on the role of pentavalent nitrogen on substrate structure, it is apparent that PAP is to other acid phosphatases what the cholinesterases are to other esterases.
Subject(s)
Acid Phosphatase/metabolism , Choline , Phosphorylcholine , Prostate/enzymology , Animals , Choline/analogs & derivatives , Epithelial Cells , Epithelium/enzymology , Epithelium/ultrastructure , Histocytochemistry , Male , Microscopy, Electron , Prostate/ultrastructure , RatsABSTRACT
By taking advantage of the structural requirements of the substrates for prostatic acid phosphatase (PAP), which consist of steric hindrance and the presence of basic nitrogen in the molecule, potential cytotoxic agents (spindle poisons) are being designed that will become enzyme activated specifically by PAP. Colchicine has been converted to colchiceinamides of substituted ethanolamines and o-phosphoethanolamines. The rate of hydrolysis of the latter by human prostatic tissue as compared to the rate of hydrolysis by human kidneys (P/K ratio) is given and indicates a significant degree of specificity for PAP. Some preliminary toxicity data in mice are also given. New thiocolchicine derivatives with phosphates on ring B are also being prepared for study and some preliminary toxicity data are given. The observation in biochemical experiments that phosphorylcholine is a very specific substrate for PAP has led us to develop specific cytochemical methods for PAP for both light and electron microscopy. Preliminary observations are given and good evidence is provided that PAP is not a lysosomal enzyme, unlike other acid phosphatases. Furthermore, PAP is to other acid phosphatases what the cholinesterases are to other esterases. Since the acid phosphatase that is able to hydrolyze phosphorylcholine is characteristic of prostatic epithelium, this is the acid phosphatase that is referred to be the designation of PAP. Other acid phosphatases (both lysosomal and nonlysosomal) in prostatic epithelial cells are not demonstrated by this substrate and hence are not included in this designation.
