The effect of hypoxic misonidazole (MISO) pretreatment on the subsequent heat sensitivity of EMT6 multicellular tumour spheroids has been investigated. Spheroids were grown in static culture and treated when either 200-300 micrometers or 650-800 micrometers in diameter. Pretreatment was carried out in glass spinner vessels containing 100 ml medium with or without 5mM MISO under conditions of hypoxia. Three-hour hypoxic pretreatment with 5mM MISO significantly enhanced the subsequent response of 200 micrometers spheroids to heat at 43 degrees C. Oxic incubation at 37 degrees C between pretreatment and heating caused progressively loss of heat sensitization with time, recovery being almost complete after 6 h. Recovery was inhibited by incubation at 0 degree C during the interval. Preheating 200 micrometers spheroids at 43 degrees C for 2 h increased their subsequent sensitivity to hypoxic MISO at 37 degrees C. These results are discussed in relation to known mechanisms of MISO metabolism.

Oestrogen (RE) and progesterone (RP) cytosolic receptors have been studied in 59 clinically inflammatory tumours of the human breast. The results were compared to those obtained in a series of 496 operable tumours. A single saturating dose of oestradiol for RE and R 5020 for RP was used and the cut-off between negative and positive tumours was 100 fmol/g tissue. A significant difference was seen (P less than 0.02) between the 2 classes of patients: (RE-, RP-) tumours were commoner among clinically inflammatory tumours (48%) than among operable ones (28%), independently of menopause. Concerning the histological type (based on an assessment of differentiation) and the histological grading (Scarff and Bloom) there was a significant difference (P less than 0.001) between the 2 populations of tumours. No significant difference was found in the distribution of RE and RP among the 3 histological types, whereas a significant correlation existed between histological grading and RE (P less than 0.02). Finally, patients with RE+ clinically inflammatory tumours constitute a lower risk group, especially when they are free of metastases at the time of diagnosis. The presence of RE therefore seems to indicate, as in the operable tumour group, a favourable prognosis.

Immune-suppressed mice carrying xenografts of several different types of human germ-cell tumours were injected with a radiolabelled monoclonal antibody (LICR LON/HT13) raised against membrane components of a human germ-cell tumour (HX39). Subsequent assessment of radioactivity in excised organs and tumours showed a selective accretion of antibody in the tumour. Quantitative autoradiography supported the results of radiolocalization observed in vivo in different tumours, and also showed that the antibody localized to viable tumour cells and in close association with their cell membrane. The vascular architecture of tumours was found to be an important factor governing antibody distribution. No localization occurred with radiolabelled normal mouse IgG. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4

Overnight exposure of Chinese hamster cells (V79-753B) to 5 x 10(-5) M flurbiprofen (2-(2-fluoro-4-biphenyl)propionic acid) in vitro reduced the cytotoxic effects of misonidazole, 1-methyl-4-nitro-5-phenoxysulphonylimidazole (NSC 38087) and nitrofurantoin, both in air and in hypoxia at 37 degrees C. Flurbiprofen did not alter the cells' uptake of 14C-misonidazole, nor did it affect the radiosensitivity of aerobic or anaerobic cells, or the degree of hypoxic-cell radiosensitization produced by the sensitizers. When flurbiprofen-treated cells were exposed to melphalan there was no protection against cytotoxicity. These data suggest that flurbiprofen may inhibit the catabolism of radiosensitizers to toxic products and indicate the need to examine whether it will protect against misonidazole-induced toxicity in vivo.

An electrolytic reduction system has been developed to model the cytotoxic action of a range of nitroimidazole drugs against DNA hypoxic cells or anaerobic microorganisms. THe degree of damage induced by these drugs (measured as the release of [14C]-dT from DNA) and their relative rates of reduction have been correlated with their redox potentials. The results show that the correlation of drug-induced damage and electron affinity is related to the amount of drug reduced, and supports the hypothesis that at the molecular level the cytotoxic mechanism of reduced nitroimidazoles is identical in hypoxic mammalian cells, bacteria and protozoa.

The urinary excretion patterns of oestrogen metabolites, including unusual metabolites, were determined by gas chromatography and mass spectrometry for 63 women with advanced breast cancer and 39 normal postmenopausal women. The concentration of total unusual metabolites excreted was found to be an excellent discriminant between breast-cancer patients and controls (P less than 0.0001). Discrimination between responders and non-responders to endocrine therapy was attempted, using several different indices. Of these, the ratio of Classical Oestrogens to Unusual Metabolites (CE/UM) proved a fair discriminant, but the product of this ratio and the oestriol ratio (CE/UM x E3R) was much the best discriminant. This product, termed a Pattern Index, has considerable potential, not only as a discriminant for selecting therapy, but also as a rapid index of patient response to that therapy.

The hybrid cell line BH2 was derived by fusion between an AKR thymoma BW5147 (HGPRT-) and C57BL thymoma EL-4R (TK-). The hybrid cells showed a near-tetraploid modal number of chromosomes, in contrast to the near-diploid stem-lines of both parental cell populations; most of the BH2 hybrid cells acquired marker chromosomes from both parental cell lines. Inoculation of the parental and hybrid cells into C57BL and AKR mice revealed that the possible admixture of revertant parental cells in the hybrid cell population was less than 10(-4). Anodic electrophoretic mobilities (AEM) of the mouse thymoma lines and their hybrids were compared with each other and with normal mouse lymphoid cells. The AEM of the parental and hybrid T-cell lines was slower than that of mouse T LNC and comparable with AEM of some thymocyte subsets. The mean AEM of parental and hybrid cell lines was 0.69 micrometers/sec/V/cm for BW5147 cells, 0.96 for EL-4R cells and 0.83 for BH2 cells, the mean AEM of the hybrid cell population being identical with the mean of the parental AEM values. The mean AEM was found to be a relatively stable characteristic of each cell line. Images Fig. 1

This report compares the results at 36 months for 121 patients treated with radiotherapy alone (R) and 115 with radiotherapy followed by 3-drug chemotherapy (RC) for small-cell carcinoma of the lung of "limited" extent. The RC patients had an increased survival (P = 0.009 by log-rank test). The median survival was 25 weeks for the R patients and 43 weeks for the RC patients, but at 36 months, only 4 (3%) of the R patients and 5 (4%) of the RC patients were still alive. There was evidence of recurrence of the primary cancer in 41 (35%) of the 117 R and 35 (32%) of the 110 RC patients who died. Distant metastases were more frequent in the R series, being reported in 99 (82%) compared with 82 (71%) of the RC patients (P less than 0.05 by log-rank test). The numbers of R patients alive and considered free of metastases were 10 (8%) at 12 months, 3 (2%) at 24 months and 3 (2%) at 36 months; the corresponding figures for the RC patients being 30 (26%), 9 (8%), and 4 (3%).