Metabolic control analysis aimed at the ribose synthesis pathways of tumor cells: a new strategy for antitumor drug development.
Metabolic control analysis predicts that effects on tumor growth are likely to be obtained with lower concentrations of drug, if an enzyme with a high control coefficient on tumor growth is being inhibited. Here we measure glucose-6-phosphate dehydrogenase (G6PDH) control coefficient on in vivo tumor growth using mice bearing Ehrlich ascites tumor cells. We used dehydroepiandrosterone-sulphate (DHEA-S), an uncompetitive inhibitor of this enzyme and the in situ cytochemical method to measure the enzyme activity changes that accompany changes on tumor cell growth. This method ensures that the enzyme activity determined is the one existing in the in situ conditions and enables computing a control coefficient in in situ conditions. From the data obtained on tumor cell number and the in situ enzyme activities in absence and presence of DHEA-S, a control coefficient of 0.41 for G6PDH on tumor cell growth was computed. This value is approximately the half of the transketolase control coefficient value of 0.9 previously reported. Moreover, the use of in situ methods to assess enzyme activities, applied for first time for the calculation of control coefficients in this study, opens new avenues to the use of uncompetitive inhibitors for the measurement of in situ control coefficients.
Boren
Joan
J
Department of Biochemistry and Molecular Biology, University of Barcelona, Catalonia, Spain.
Montoya
Antonio Ramos
AR
de Atauri
Pedro
P
Comin-Anduix
Begoña
B
Cortes
Antonio
A
Centelles
Josep J
JJ
Frederiks
Wilma M
WM
Van Noorden
Cornelis J F
CJ
Cascante
Marta
M
D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008433:Mathematics; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D012266:Ribose / Q000096:biosynthesis*; D014174:Transketolase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D019314:Dehydroepiandrosterone Sulfate; D012266:Ribose; D005954:Glucosephosphate Dehydrogenase; D014174:Transketolase