Retention of misonidazole in normal and malignant tissues: interplay of hypoxia and reductases.
Tritiated misonidazole (MISO) was injected intravenously (iv) into mice bearing five different tumors. At 24 hr the tumors were removed for analysis of bound MISO, and at the same time three normal tissues were removed (liver, labial gland, and esophagus). The labial gland and esophagus were selected as representatives of sebaceous and stratified squamous tissues, respectively, tissues that in many parts of the body retain high levels of MISO. The tumors used were early transplant generations of spontaneous mouse tumors of mammary gland, lung, and liver. The levels (mean +/- SEM) of MISO at 24 hr for the five tumors and three normal tissues, expressed as percentage of the injected dose per gram of tissue were: A110 (0.03 +/- 0.007), A114 (0.103 +/- 0.04), A150 (0.09 +/- 0.005), A167 (0.037 +/- 0.012), A168 (0.122 +/- 0.0016), esophagus (0.507 +/- 0.09), labial gland (0.125 +/- 0.013), liver (0.11 +/- 0.004). Histochemical examination of the normal tissues showed reductase activity in all three. In the esophagus and labial gland, inhibition of the reaction by dicumarol indicated the likely presence of the reductase DT-diaphorase which, by 2-electron transfer, can be expected to reduce MISO to a reactive, locally-binding metabolite, even in the presence of oxygen.
Cobb
L M
LM
Division of Experimental Pathology & Therapeutics, MRC Radiobiology Unit, Didcot, Oxon, U.K.
Nolan
J
J
Hacker
T
T
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D004947:Esophagus / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008920:Misonidazole / Q000493:pharmacokinetics*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000502:physiology*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism*; D014316:Tritium
D014316:Tritium; D008920:Misonidazole; D016660:NAD(P)H Dehydrogenase (Quinone)