Distribution of pimonidazole and RSU 1069 in tumour and normal tissues

Abstract

Summary The tritium-labelled analogues of pimonidazole and RSU 1069 were injected into mice bearing the KHT murine sarcoma which has a hypoxic cell fraction of 1-0%. The distribution of activity at 24 h was recorded using autoradiography and measurement of tissue activity. Autoradiographs with both drugs showed high activity in particular cells within tumour, eye (melanin-associated cells), eyelid (Meibomian gland), liver (centrilobular area), skin (sebaceous gland and melanin), stomach (squamous area), footpad, oesophagus, labial gland, Zymbal's gland, preputial gland, parotid gland (intralobular ducts) and airway epithelium. These tissues had previously been identified as sites of binding of misonidazole. The measurement of total tissue radioactivity showed significantly higher activity in liver, eyelid (Meibomian gland), oesophageal lining, kidney and labial gland than was found in the tumour.Misonidazole (1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol; MISO) sensitises hypoxic tumour cells to ionising radiation (Asquith et al., 1974). This radiosensitisation is associated with the electron affinity of, MISO and is a fast (subsecond) free-radical process. MISO can also be involved in a separate, slower, enzyme dependent process in which, in the presence of the appropriate reductase(s), the nitro group is reduced yielding cytotoxic species (Varghese et al., 1976;Rauth, 1984). This second process is favoured by a hypoxic environment -such as occurs in parts of many tumoursand this leads to locally enhanced retention. The concept of the preferential retention of reactive bioreduced metabolites in tumours has generated two lines of research. One is directed towards tumour therapy (bioreductive drug therapy). In this, drugs are being developed which, as with MISO, on reduction in the hypoxic milieu of the tumour, form cytotoxic metabolites(s) that bind to critical macromolecules such as DNA. The other line of research is in the field of imaging and spectroscopy.

Dynamics of Tumor Hypoxia Measured with Bioreductive Hypoxic Cell Markers

“…Also, the patterns of pimonidazole detected with immunohistochemistry were comparable to autoradiography of misonidazole (140). These studies indicate that those markers have similar oxygen dependences.…”

“…Several 2-nitroimidazoles can be used as hypoxia markers and provide an inverse and indirect measurement of tumor oxygenation. Some of the features of the most commonly used 2-nitroimidazoles such as CCI-103F (135,136), misonidazole (137)(138)(139), pimonidazole (132,140) and EF5 (133,141) are listed in Table 1. The latter three are approved for clinical use, and several methods are available for detection of these markers.…”

Reductive metabolism of the hypoxia marker pimonidazole is regulated by oxygen tension independent of the pyridine nucleotide redox state

“…These results demonstrated that the pattern of pimonidazole binding in liver was determined by grafirst used to measure low oxygen in animal [4] and human [5] tumors as an index of the resistance to radiation [6]. Hypoxia dients of oxygen, not by the distribution of nitroreductases which predominate in pericentral regions of the hepatic lobule markers are reductively activated and bind to macromolecules at [9]. Thus, hypoxia in liver tissue can be measured at the cellular may be a critical early step in alcoholic liver injury.…”

Upregulation of Hypoxia-Inducible Factors in Normal and Psoriatic Skin

“…Distler et al (2004) and Bedogni et al (2005) demonstrated nuclear HIF-1a in the epidermis of humans and mice. Cobb et al (1990) found accumulation of tritiumlabeled pimonidazole in sebaceous glands. Bedogni et al (2005) also showed accumulation of EF5 (a bioreductive agent like pimonidazole) in the epidermis and hair follicles of normal mice.…”