title: The advantageous use of hypoxic tumour cells in cancer therapy: identical chemosensitization by metronidazole and misonidazole at moderately elevated temperatures.
abstract: Chemosensitization by two nitroimidazoles (NIs), metronidazole (METRO) and misonidazole (MISO), of the anti-tumour effect of alkylating agents was studied at three different temperatures: room temperature (RT), 37 and 41.5 degrees C. Three alkylating agents, cyclophosphamide (CY), 1,3 bis(2-chloroethyl)-N-nitrosourea (BCNU) and melphalan (L-PAM) were tested when the tumours reached an average diameter of 4 mm. Tumours were 4th generation isotransplants of a spontaneous fibrosarcoma, FSa-II. Treatment at 37 or 41.5 degrees C was given by immersing the tumour-bearing foot for 60 min in a water bath set at these temperatures. The test agents were injected ip immediately before immersing the foot in the water bath, whereas METRO or MISO (2.5 mmol/kg) was given ip 30 min before the injection of a test agent. Following treatment the tumour growth (TG) time, i.e. the time required for one-half of treated tumours to reach 1000 mm3 after the treatment day, was studied. For CY, MISO was a better sensitizer than METRO at RT and 37 degrees C, but the magnitude of the chemosensitization by MISO and METRO became identical at 41.5 degrees C. Notably, the chemosensitization was substantially enhanced at 41.5 degrees C, whereas neither 41.5 degrees C-heat, NIs or combined NI and heat prolonged the TG time. Although no chemosensitization was observed for BCNU at RT, both METRO and MISO equally enhanced the effect of BCNU at 41.5 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Radiation Medicine, University of Kentucky Medical Center, Lexington 40536-0084, USA.
authors.forename: M
authors.initials: M
authors.lastname: Urano
authors.forename: K H
authors.initials: KH
authors.lastname: Wong
authors.forename: R
authors.initials: R
authors.lastname: Reynolds
authors.forename: J
authors.initials: J
authors.lastname: Begley
mesh_terms: D000818:Animals; D002330:Carmustine / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000494:pharmacology; D005260:Female; D006979:Hyperthermia, Induced; D008558:Melphalan / Q000494:pharmacology; D008795:Metronidazole / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000494:pharmacology*; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy*
chemical_list: D008795:Metronidazole; D008920:Misonidazole; D003520:Cyclophosphamide; D008558:Melphalan; D002330:Carmustine