Influence of tumor size on the main drug-metabolizing enzyme systems in mouse colon adenocarcinoma Co38.
Mouse colon adenocarcinoma Co38 is widely used as a screening model for human colon tumors. To understand better the influence of tumor size on the main drug-metabolizing enzyme systems, we tested 15 mouse Co38 tumors at different sizes. The average weight was 917 +/- 444 mg (range, 300-1,400 mg). Cytochromes P-450 (1A1/1A2, 2B1/B2, 2C8-10, 2E1, 3A4), epoxide hydrolase (EH), and glutathione-S-transferases (GST-alpha, -mu, and -pi) were assayed by immunoblotting. The activities of the following enzymes or cofactors were determined by spectrophotometric or fluorometric assays: 1-chloro-2,4-dinitrobenzene-GST (CDNB-GST), selenium-independent glutathione peroxidase (GPX), 3,4-dichloronitrobenzene-GST (DCNB-GST), ethacrynic acid-GST (EA-GST), total glutathione (GSH), uridine diphosphate-glucuronosyltransferase (UDP-GT), beta-glucuronidase (beta G), sulfotransferase (ST), and sulfatase (S). Our results showed the absence of all probed P-450s and EH in Co38 tumors. No relationship was found between the Co38 tumor weights and GPX, GST-alpha, and EA-GST (regression analysis). However, a significant correlation was found between the tumor weights and all other enzymes investigated. For certain enzymes or cofactors, a linear decrease (P < 0.05) was observed as a function of tumor weight (CDNB-GST, DCNB-GST, GST-mu, GST-pi, GSH, and beta G). Other enzymatic activities (UDP-GT, S, and ST) were found to decrease in medium-size tumors and to increase in large tumors (P < 0.05; quadratic correlation). These data demonstrate that the expression of many drug-metabolizing enzyme systems is altered during tumor growth and suggest that tumoral response to chemotherapy could be altered as a function of tumor size.
Massaad
L
L
Département de Pharmaco-toxicologie et de Pharmacogénétique (CNRS URA 147), Institut Gustave-Roussy, Villejuif, France.
Chabot
G G
GG
Toussaint
C
C
Koscielny
S
S
Morizet
J
J
Bissery
M C
MC
Gouyette
A
A
D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008297:Male; D051379:Mice; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D013429:Sulfatases / Q000378:metabolism; D015238:Sulfotransferases / Q000378:metabolism; D014532:Uridine Diphosphate Glucose / Q000378:metabolism
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; D015238:Sulfotransferases; D013429:Sulfatases; D004851:Epoxide Hydrolases; D005978:Glutathione; D014532:Uridine Diphosphate Glucose