Disease relevance of Misonidazole

• The antitumor efficacy of adding the nitroimidazole radiosensitizing drugs misonidazole and etanidazole or hyperthermia (43 degrees C for 30 min) to Fluosol-DA/carbogen (95% O2/5% CO2) and irradiation was tested in the FSaIIC tumor system [1].
• Toxicity, radiation sensitivity modification, and combined drug effects of ascorbic acid with misonidazole in vivo on FSaII murine fibrosarcomas [2].
• Covalent binding of misonidazole adducts to cellular macromolecules is enhanced by hypoxia [3].
• Misonidazole is known to be selectively toxic for hypoxic cells, and a high dose of misonidazole gave a small increase in antitumor effects of ADR without increased toxicity [4].
• We studied eight patients with carcinoma of the pharynx and larynx (five cases) or lungs (three cases) who, during treatment with the radiosensitizing drug misonidazole, developed peripheral neuropathy dominated by severe sensory symptoms and signs mainly localized to the lower extremities [5].

High impact information on Misonidazole

• The effect of pretreating the C3H/He mouse MBT-2 tumor with diethyl maleate (DEM), buthionine-S R-sulfoximine (BSO), or misonidazole (MISO) before administration of cyclophosphamide (CTX) was studied with the use of tumor volume-doubling time delay as an endpoint [6].
• The highest number of chromosome aberrations and alterations, including an increase in heteroploidy, was also noticed in the bone marrow cells of the mice whose tumors were treated simultaneously with MIS + delta + X [7].
• Misonidazole radiosensitized the leg-implanted tumor as measured both by cell survival and regrowth delay [8].
• Autoradiographs of liver from mice treated with radiolabeled misonidazole demonstrated enhanced binding of adducts within hepatocytes surrounding hepatic veins [3].
• Misonidazole binding in murine liver tissue: a marker for cellular hypoxia in vivo [3].

Chemical compound and disease context of Misonidazole

• The influence of metronidazole, misonidazole, and desmethylmisonidazole on the induction of lung adenomas in the strain A mouse was examined [9].
• One hundred patients with non-small cell lung cancer were entered by members of the Northern California Oncology Group into a randomized Phase II trial of i.v. melphalan versus i.v. melphalan with concomitant oral misonidazole [10].
• In advanced Lewis lung carcinoma, misonidazole enhanced the antitumor activity of cyclophosphamide but not 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitrosourea [11].
• The influence of tumor size on the ability of S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) or misonidazole (MISO) to alter cyclophosphamide (CY) antitumor activity was investigated, using a chemically induced fibrosarcoma (FSA) and a spontaneous fibrosarcoma (NFSA) in C3Hf/Kam mice [12].
• The ability of three nitroimidazoles [SR-2508, misonidazole (MISO), and benznidazole] with differing octanol-water partition coefficients to enhance the cytotoxicity of the nitrosourea 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) was evaluated in two mouse tumors (the KHT sarcoma and the SCC VII/St carcinoma) [13].

Biological context of Misonidazole

• Whereas strand breaks with thymidine 5'-aldehyde at the 5' end and released thymine are the main DNA damage products in O2, under anaerobic conditions misonidazole causes a marked increase in the release of thymine and in the formation of breaks with 5'- phosphate ends [14].
• Hypoxic Chinese hamster V-79 cells were examined for light-microscope morphology, progression through the cell cycle, chromosomal aberrations, and viability, after incubation with the 2-nitroimidazole, misonidazole [1-(2-nitro-1-imidazolyl)-3 methoxy-2-propanol] [15].
• Combined effects of misonidazole, microwave hyperthermia, and X-rays on the in vivo sister chromatid exchanges and chromosomal abnormalities of the dbrB tumor and on the survival of its host [16].
• Forty-two hr after a 5.5-hr treatment with 5 mM misonidazole, the majority of cells contained heteropyknotic nuclei, whereas less than 3% had progressed into mitosis [15].
• Kinetics of misonidazole enantiomers [17].

Anatomical context of Misonidazole

• PURPOSE: Long-term follow-up data of a randomized trial that compared hydroxyurea and the hypoxic-cell radiosensitizer to misonidazole as adjuncts to standard radiation therapy in locally advanced carcinoma of the cervix are reported [18].
• We have investigated the effects of misonidazole on the biosynthesis of prostaglandins (PGs) in a murine mammary adenocarcinoma cell line (No. 4526) under aerobic and hypoxic conditions in attempts to exploit modulation of PG levels under hypoxia as a means of improving therapeutic approaches for the treatment of solid tumors [19].
• Misonidazole was delivered intravenously (IV) at a dose of 3.5 g/m2 in conjunction with IORT of 1,500 to 2,000 cGy to the pancreas [20].
• Several interpretations of this result are possible, including the postulate that intermittent blood flow occurs in all 9L tumor capillaries, which results in the majority of the binding of misonidazole occurring during the periods of transient hypoxia [21].
• The clearance of misonidazole and demethylmisonidazole from the peritoneal fluid was 19.1 and 12.4 ml/min, respectively [22].

Associations of Misonidazole with other chemical compounds

• Mechanism of sensitization of Chinese hamster ovary cells to melphalan by hypoxic treatment with misonidazole [23].
• The mean serum half-life for misonidazole was 11.3 hours (range, 8.4 to 20.0) and for cyclophosphamide 8.3 hours (range, 3.2 to 15.5), both within the previously reported ranges [24].
• In order to assess the effect of oxygen on chemopotentiation by misonidazole (MISO), EMT-6/Ro tumor cells were exposed in vitro to combinations of CCNU and 1.0 mM MISO in culture medium equilibrated at various oxygen concentrations [25].
• The 2-nitroimidazole hypoxic sensitizers SR 2508 and Ro-03-8799, which are less toxic than the prototype misonidazole (Miso), are in clinical trials, and dual function molecules that include a hypoxic sensitizer and alkylating function are being developed [26].
• Time-dose relationships for simultaneous misonidazole and 1,3-bis(2-chloroethyl)-1-nitrosourea exposures in vitro [27].

Gene context of Misonidazole

• DNIE inhibited glutathione peroxidase (GSH-Px), GST, and glutathione reductase (GSSG-R) activities in hepatocytes, while misonidazole and KIH-3 did not [28].
• We have studied the effect of buthionine sulfoximine (BSO; a gamma-glutamylcysteine synthetase inhibitor) administration, either alone or combined with misonidazole (MISO), on five human tumor xenografts (three melanomas: Bell, Mall, and Nall; and two rectocolic adenocarcinomas: HT29 and HRT18) transplanted into mice [29].
• By combining MISO and BSO at doses lower than previously used for each agent alone, highly effective sensitization of subsequent CTX was obtained [6].
• Misonidazole was covalently conjugated (3-68 mol drug/mol antibody) to 19-9 monoclonal antibody directed against a colorectal carcinoma tumor-associated antigen as a method for targeting radiosensitizing agents [30].
• Misonidazole, however, selectively increased the PGE2 biosynthesis under hypoxia by 49% at 100 microM [19].

Analytical, diagnostic and therapeutic context of Misonidazole

• For each of the modalities tested, the dose-modifying effect was greater when that therapy preceded rather than followed irradiation (misonidazole 2.7 vs. 1.9, etanidazole 2.4 vs. 1.7, hyperthermia 4.0 vs. 1.7 relative to the effect of radiotherapy alone) [1].
• Recent studies in mouse tumor systems have indicated a potential therapeutic advantage in combining the radiosensitizer misonidazole (MISO) with cancer chemotherapy drugs [31].
• The regimen consisted of oral administration of misonidazole at one of two dose levels, 1 g/m2 and 2 g/m2, followed by an intravenous (IV) injection of cyclophosphamide four hours later [24].
• Misonidazole (MISO) concentration in plasma, tumor, and other tissues was also measured by high-pressure liquid chromatography [32].
• Treatment of Dunning R3327-AT rat prostate tumors with photodynamic therapy in combination with misonidazole [33].

References