The concentration of molecular oxygen in both normal and neoplastic tissues has important implications in disease diagnosis and prognosis. In oncology, for example, hypoxic cells in solid tumours have been associated with treatment resistance by radiation (Gray et al., 1953;Thomlinson & Gray, 1958) and some forms of chemotherapy (Tannock, 1982). The most direct technique for measuring tissue oxygen tension utilizes oxygen electrodes but measurements made by these techniques can have many limitations (Cater & Silver, 1960;Chapman et al., 1983b). Even when microelectrodes are used properly, the oxygen tension measured would necessarily be an average value for many cells (related to the volume of tissue from which oxygen diffuses to the electrode surface). Histological evaluation of solid tumours suggests that important changes in cellular pO2 can occur over dimensions of a few cell diameters (Tannock, 1968;1969). The hypoxic cell radiosensitizer, misonidazole (MISO), was shown to bind selectively to the molecules of hypoxic cells (Wong et al., 1978;Miller et al., 1982). Autoradiographic analysis of radioactive MISO has been used to identify hypoxic cells in multicellular spheroids , animal tumours (Chapman et al., 1981; Horowitz et al., 1983) and in short-term cultures of human tumour fragments (Franko & Koch, 1984). This report describes the successful extension of this technique for labelling hypoxic cells to a cancer patient.
Materials and methodsA 44-year-old male with multiple, rapidly progressing subcutaneous deposits of malignant melanoma consented to receive a dose of 29 mCi of 3H-MISO 22 h before the surgical resection of a lesion from his face. 3H-MISO was prepared according to a published procedure (Bom & Smith, 1982), dissolved in sterile physiological saline and the solution tested for both sterility and pyrogenicity. 3H-MISO is as effective a marker for hypoxic cells as is '4C-MISO (Raleigh el al., Rasey et al., 1985). A dose of 74.7mg of 3H-MISO (specific activity = 0.388 mCi mg-1) in 29 ml of sterile physiological saline was administered over 5 min into the heparin lock of an indwelling catheter. The radioactivity in blood and urine was monitored for 72 h. Over the first 24 h, 3H-MISO had a half-life in plasma of 8.7+0.4h and 66% of the administered radioactivity was excreted in the urine over the first 72 h. Twenty-two hours after drug administration, a 6 x 5 cm metastatic melanoma which was fixed to the skin and deep tissues was totally resected from the left side of the face. The tumour was cut into smaller pieces and some were processed by standard histological procedures. After fixation and embedding in wax, 4,um sections were mounted on microscopic slides, dipped in liquid emulsion (Kodak NTB3) and exposed for various times to determine the presence of 3H-MISO bound to the specimen. Other random samples from the tumour were processed for liquid scintillation counting to determine the average amount of radioactivity in the tumour at the time of resection. The remainder of the tumour specime...