SR2508 (etanidazole) pharmacokinetics and biochemical effects in tumor and normal tissues of scid mice bearing HT-29 human colon adenocarcinoma.
Several lines of evidence implicate glutathione (GSH) depletion and/or GSH transferase inhibition in the sensitizing action of nitroimidazoles to alkylating agents. To characterize this interaction, scid mice bearing subcutaneously implanted HT-29 colon tumor (0.75 to 1.25 cm diameter) were treated with SR2508 (2 g/kg, i.p.). At intervals following treatment, samples of blood, liver, spleen, kidney and central non-necrotic tumor core and tumor periphery were obtained and analyzed for SR2508 content by high-pressure liquid chromatography. Tissues were assayed spectrophotometrically for GSH and GSH transferase. SR2508 plasma pharmacokinetics in this model were similar to those described previously (t 1/2 beta = 5.83 hr). The volume of distribution of 0.32 L/kg suggests minimal tissue binding. In tumor periphery and core samples SR2508 levels peaked at 1 hr, and declined exponentially in parallel with plasma. During the terminal phase core SR2508 levels were 10-fold and tumor periphery levels 4.3-fold those of concurrent plasma concentrations. Consistent with these data, tumor GSH levels in both periphery and core fell below 30% of control at 4 hr, and remained depressed > 12 hr. Delayed recovery of GSH content of tumor tissue may explain in part the selectivity of SR2508 for tumor (oxic or hypoxic). GSH transferase activity in tumor was inhibited both at the center and periphery to 75 and 71% of control, respectively, and it appeared that recovery occurred more slowly in the hypoxic core. The mild degree of inhibition observed does not support an important role for inhibition of GSH transferase in sensitization by SR2508 in this tumor. The pronounced selective depletion of GSH in tumor supports the further development of SR2508 in the reversal of alkylating agent resistance.
O'Dwyer
P J
PJ
Fox Chase Cancer Center, Philadelphia, PA 19111.
Panting
L
L
LaCreta
F P
FP
Clapper
M L
ML
D000230:Adenocarcinoma / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism*; D017341:Etanidazole / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D051379:Mice; D016513:Mice, SCID; D013154:Spleen / Q000378:metabolism
D017341:Etanidazole; D005982:Glutathione Transferase; D005978:Glutathione