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Title: Melphalan metabolism in cultured cells

Abstract

Procedures are presented for the adaptation of reversed-phase-HPLC methods to accomplish separation and isolation of the cancer therapeutic drug melphalan (L-phenylalanine mustard) and its metabolic products from whole cells. Five major degradation products of melphalan were observed following its hydrolysis in phosphate buffer in vitro. The two most polar of these products (or modifications of them) were also found in the cytosol of Chinese hamster CHO cells. The amounts of these two polar products (shown not to be mono- or dihydroxymelphalan) were significantly changed by the pretreatment of cells with ZnC1/sub 2/, one being increased in amount while the other was reduced to an insignificant level. In ZnC1/sub 2/-treated cells, there was also an increased binding of melphalan (or its derivatives) to one protein fraction resolved by gel filtration-HPLC. These observations suggest that changes in polar melphalan products, and perhaps their interaction with a protein, may by involved in the reduction of melphalan cytotoxicity observed in ZnC1/sub 2/-treated cells. While ZnC1/sub 2/ is also known to increase the level of glutathione in cells, no significant amounts of glutathione-melphalan derivatives of the type formed non-enzymatically in vitro could be detected in ZnC1/sub 2/-treated or untreated cells. Formation of derivatives of melphalanmore » with glutathione catabolic products in ZnC1/sub 2/-treated cells has not yet been eliminated, however. 17 refs., 5 figs., 1 tab.« less

Authors:
; ; ;
Publication Date:
Research Org.:
Los Alamos National Lab., NM (USA)
OSTI Identifier:
5438539
Report Number(s):
LA-10442-MS
ON: DE85016218
DOE Contract Number:  
W-7405-ENG-36
Resource Type:
Technical Report
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; ANTINEOPLASTIC DRUGS; DECOMPOSITION; LABELLING; LIQUID COLUMN CHROMATOGRAPHY; METABOLITES; CARBON 14 COMPOUNDS; CHEMICAL PREPARATION; EXPERIMENTAL DATA; GLUTATHIONE; RADIOCHEMISTRY; TRACER TECHNIQUES; TRITIUM COMPOUNDS; ZINC CHLORIDES; CHEMICAL REACTIONS; CHEMISTRY; CHLORIDES; CHLORINE COMPOUNDS; CHROMATOGRAPHY; DATA; DRUGS; HALIDES; HALOGEN COMPOUNDS; INFORMATION; ISOTOPE APPLICATIONS; LABELLED COMPOUNDS; NUMERICAL DATA; ORGANIC COMPOUNDS; PEPTIDES; POLYPEPTIDES; PROTEINS; RADIOPROTECTIVE SUBSTANCES; SEPARATION PROCESSES; SYNTHESIS; ZINC COMPOUNDS; ZINC HALIDES; 550501* - Metabolism- Tracer Techniques

Citation Formats

Seagrave, J C, Valdez, J G, Tobey, R A, and Gurley, L R. Melphalan metabolism in cultured cells. United States: N. p., 1985. Web.
Seagrave, J C, Valdez, J G, Tobey, R A, & Gurley, L R. Melphalan metabolism in cultured cells. United States.
Seagrave, J C, Valdez, J G, Tobey, R A, and Gurley, L R. 1985. "Melphalan metabolism in cultured cells". United States.
@article{osti_5438539,
title = {Melphalan metabolism in cultured cells},
author = {Seagrave, J C and Valdez, J G and Tobey, R A and Gurley, L R},
abstractNote = {Procedures are presented for the adaptation of reversed-phase-HPLC methods to accomplish separation and isolation of the cancer therapeutic drug melphalan (L-phenylalanine mustard) and its metabolic products from whole cells. Five major degradation products of melphalan were observed following its hydrolysis in phosphate buffer in vitro. The two most polar of these products (or modifications of them) were also found in the cytosol of Chinese hamster CHO cells. The amounts of these two polar products (shown not to be mono- or dihydroxymelphalan) were significantly changed by the pretreatment of cells with ZnC1/sub 2/, one being increased in amount while the other was reduced to an insignificant level. In ZnC1/sub 2/-treated cells, there was also an increased binding of melphalan (or its derivatives) to one protein fraction resolved by gel filtration-HPLC. These observations suggest that changes in polar melphalan products, and perhaps their interaction with a protein, may by involved in the reduction of melphalan cytotoxicity observed in ZnC1/sub 2/-treated cells. While ZnC1/sub 2/ is also known to increase the level of glutathione in cells, no significant amounts of glutathione-melphalan derivatives of the type formed non-enzymatically in vitro could be detected in ZnC1/sub 2/-treated or untreated cells. Formation of derivatives of melphalan with glutathione catabolic products in ZnC1/sub 2/-treated cells has not yet been eliminated, however. 17 refs., 5 figs., 1 tab.},
doi = {},
url = {https://www.osti.gov/biblio/5438539}, journal = {},
number = ,
volume = ,
place = {United States},
year = {Sat Jun 01 00:00:00 EDT 1985},
month = {Sat Jun 01 00:00:00 EDT 1985}
}

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