Misonidazole

Similarly, reaction of 2-nitroimidazole with l,2-epoxy-3-methoxypropane in the presence of potassium carbonate gives misonidazole This agent also has the interesting and... 

Strobel et al. (101) reported a unique approach to delivery of anticancer agents from lactide/glycolide polymers. The concept is based on the combination of misonidazole or adriamycin-releasing devices with radiation therapy or hyperthermia. Prototype devices consisted of orthodontic wire or sutures dip-coated with drug and polymeric excipient. The device was designed to be inserted through a catheter directly into a brain tumor. In vitro release studies showed the expected first-order release kinetics on the monolithic devices. 

Nitroimidazoles (such as metronidazole and misonidazole) can enhance the porphyrin sensitized Type I photooxidations83 that is, electron transfer from the sensitizer to the oxygen molecule is facilitated to give more of the superoxide ion (Scheme 6). The Type II mechanism operates by energy transfer from the sensitizer to afford the singlet oxygen84. 

Several studies have reported the influence of nitroimidazole derivatives on biological systems. Thus the influence of Misonidazole, l-(2-nitro-l-imidazoyl)-3-methoxy-propan-2-ol, on strand breaking in calf thymus DNA under ionizing radiation conditions has been assessed70. Pulse-radiolysis studies of nitroheterocyclic compounds have examined... 

Misonidazole [27 l-methoxy-3-(2-nitroimidazol-l-yl)-2-propanol] and the model compound l-methyl-2-nitroimidazole have been used as radiosensitizers in the treatment of certain types of human tumors. One important property of these compounds is that they are more toxic to hypoxic cells than to aerobic cells, indicating that reductive metabolism of the drug is involved in the toxicity. Results of a number of studies suggest that intracellular thiols play a significant role in the hypoxic cell toxicity, and it was found that reduction products formed stable thio ethers with GSH (for literature see References 181-183). The reaction mechanism of thio ether formation has not been fully established. It has been suggested that the 4-electron reduction product was involved in thio ether formation181,184,185, and that the hydroxylamine rather than the nitroso derivative was the reactant. On the other hand, an intermediate nitroso derivative is expected to give a sulfenamide cation (see Scheme 1) which easily allows thio ether formation. 

The antifungal agent griseofulvin in plasma (318) in plasma concentrations of 50 ng/ml could be measured using 10-ftl samples. The bac-teriostat, 3,4,4 -trichk>rocarbanilide, and its metabolic products have been determined subsequent to a single-step sample cleanup 1319). The trichomonacide metronidazole, misonidazole, and their metabolites have been analyzed from serum and urine samples with similar sensitivity (320). 

Metabolism and pharmacokinetics of piprozolin were studied by RPC without prior clean-up of the urine sample (565). Misonidazole, metronidazole, and their metabolites have been analyzed using a ternary solvent system containing methanol-acetonitrile-5 mAf KH1PO4, pH 4, at volume ratios 4 3 93. The results facilitated the determination of the respective serum levels in a particular regimen of chemotherapy (364). The sig-... 

Fig. 1. Radiosensitization of hypoxic V79 cells by 5 pM cisplatin compared to 1 mM misonidazole. The enhancement ratio for the cisplatin (5 iiM) in this experiment was 1.15. Adapted from Stratford et al. (153).

Stratford IJ, Williamson C, Adams GE. Combination studies with misonidazole and a cis-platinum complex cytotoxicity and radiosensitization in vitro. BrJ Cancer 1980 41 517-522. 

Fulton DS, Urtasun RC, Shin KH, et al. Misonidazole combined with hyperfractionation in the management of malignant glioma. Int J Radiat Oncol Biol Phys 1984 10 1709-1712. 

Although flaws in these studies of hydroxyurea left their results open to question, the GOG was convinced that the weight of the evidence supported inclusion of hydroxyurea in the control arms of future trials. In the early 1980s, 308 patients with stages IIB-IVA cervical cancer were randomly assigned to receive radiation therapy with concurrent hydroxyurea or radiation therapy with concurrent misonidazole. A preliminary review... 

Stehman FB, Bundy BN, Keys H, et al. A randomized trial of hydroxyurea versus misonidazole adjunct to radiation therapy in carcinoma of the cervix. A preliminary report of a Gynecologic Oncology Group study. Am J Obstet Gynecol 1988 159 87-94. 

Stehman FB, Bundy BN, Thomas G, et al. Hydroxyurea versus misonidazole with radiation in cervical carcinoma long-term follow-up of a Gynecologic Oncology Group trial. J Clin Oncol 1993 11 1523-1528. 

P. Zanzonico, J. Campa, D. Polycarpe-Holman, G. Forster, R. Finn, S. Larson, J. Humm, C. Ling, Animal-specific positioning molds for registration of repeat imaging studies Comparative microPET imaging of F18-labeled fluoro-deoxyglucose and fluoro-misonidazole in rodent tumors, Nucl. Med. Biol. 33 (2006) 65-70. 

A. Franko, C. Koch, D. Boisvert, Distribution of misonidazole adducts in gliosarcoma tumors and spheroids Implications for oxygen distribution. Cancer Res. 52 (1992) 3831-3837. 

It is interesting that in the presence of misonidazole the 5-hydroxymethyluracil yield is reduced to one quarter (Nishimoto et al. 1983a). Addition of misonidazole to the allylic radical which has no marked reductive power (note that this radical is also not oxidized by the more reactive oxidant TNM, see above) must thus give products other than 5-hydroxymethyluracil. 

OER, Oxygen enhancement ratio MER misonidazole enhancement ration Cya, cysteamine... 

The radiation response of cells from a GSH-synthetase-deficient patient and its clinically healthy brother are compared in Table 12.22. There, it is seen that the GSH deficiency results in a lower OER both of survival and SSB formation. This is largely due to a reduction of GSH, since the other non-protein sulfhy-dryls (NPSH) are not markedly suppressed in this mutant. The efficiency of GSH has been attributed to its particular spatial distribution, since exogenous thiols (here cysteamine) cannot substitute for this. Other sensitizers such as misonidazole (see below) behave similar as O2 with respect to SSB formation in these two cell lines. 

In fact, with a few exceptions, neither 02 nor nitro compounds react with free radicals by ET (as would be required for an electron affinity relationship in its proper sense) but rather undergo addition reactions. The ensuing radicals show different decay routes as is discussed in Chapter 6.3. When DNA is irradiated in deoxygenated aqueous solution in the presence of 14C-labeled mitronidazole, some of the sensitizer remains attached to DNA (Willson et al. 1974). Misonidazole and practically all other nitroimidazoles have a lower reduction potential than 02, and much higher concentrations have to administered to achieve the same effect (Whillans and Hunt 1982). 

The actual use of nitro compounds such as misonidazole in cancer treatment is largely based on their toxicity against hypoxic cells. Here, they act as biore-... 

Al-Kazwini AT, O Neill P, Fielden EM (1988) Radiation-induced luminescence from dry" and hydrated DNA and related macromolecules. Radiat Phys Chem 32 385-389 Al-Kazwini AT, O Neill P, Papworth D, Adams GE, Fielden M (1991) Comments on the estimated distance over which electrons can migrate in solid DNA before being trapped by misonidazole. Radiat Res 125 348-349... 

Denison L, Haigh A, D Cunha G, Martin RF (1992) DNA ligands as radioprotectors Molecular studies with Hoechst 33342 and Hoechst 33258. Int J Radiat Biol 61 69-81 Deschavanne PJ, Debieu D, Chavaudra N, Malaise EP (1985) Radiosensitizing and cytotoxic properties of misonidazole on glutathione synthetase deficient human fibroblasts. Int J Radiat Biol 48 213-221... 

Priyadarshy S, Risser SM, Beratan DN (1996) DNA is not a molecular wire Protein-like electron-transfer predicted for extended Ti-electron system. J Phys Chem 100 17678-17682 Purdie JW (1980) Dephosphorylation of WR-2721 to WR-1065 in vitro and effect of WR-1065 and misonidazole in combination in irradiated cells. In Brady LW (ed) Radiation Sensitizers, pp 330-333... 

Whillans DW, Hunt JW (1978) Rapid-mixing studies of the mechanisms of chemical radiosensitization and protection in mammalian cells. Br J Cancer 37 38-41 Whillans DW, Hunt JW (1982) A rapid-mixing comparison of the mechanisms of radiosensitization by oxygen and misonidazole in CHO cells. Radiat Res 90 126-141 Whillans DW, Adams GE, Neta P (1975) Electron-affinic sensitization. VI. Pulse radiolysis and ESR comparison of some 2- and 5-nitroimidazoles. Radiat Res 62 407-421... 

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