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Flavone acetic acid (FAA) was administered at a dose of 4.8 g m-2 over 1 h to patients with advanced malignant disease in combination with Interleukin II. A new high performance liquid chromatography method is described to determine both the parent compound and eight drug-related products, and the conditions required to determine these components in plasma are discussed. The half-life over the first 8 h was 2.3 h, but the terminal clearance of the drug was extremely slow. Severe (WHO Grade 4) hypotension was observed in some patients. However, incidence of this did not appear to be associated with any differences in FAA plasma concentrations, nor were there differences in FAA clearance between those patients whose tumour responded to the drug combination and those who did not.

4-Hydroxyanisole is a depigmenting agent which has been shown to have activity against malignant melanoma when given intra-arterially in man. An intravenous dose escalation study has been carried out with the aim of obtaining maximum plasma concentrations in a 5 day schedule. 8 patients entered this study which was stopped because of drug toxicity after 3 patients had been treated at the third dose escalation of 15 g/m2. 2 patients had WHO grade 4 liver and one also grade 4 renal toxicity and another had grade 4 haemoglobin toxicity. Extrapolated plateau plasma levels between 112 and 860 mumol/l were obtained, which in vitro studies suggested would be cytotoxic. Hopefully, newer analogues will have a greater specificity for the melanin pathway with less toxicity.

A high-performance liquid chromatographic method is described for the determination of tissue collagen and protein synthesis rates in vivo, together with an index of collagen degradation. The technique utilises post-column reaction with 7-chloro-4-nitrobenzofurazan (NBDCl), which shows higher reactivity towards the secondary amino acids, proline and hydroxyproline, and also exploits differences in absorbance and fluorescence spectra to avoid interference by primary amino acids, including cysteine which reacts rapidly with NBDCl. The relative benefits of using fluorescence or absorbance detection are discussed. A detailed description is given of the steps involved in sample preparation and data for five normal tissues in the mouse are presented using fluorescence detection.

We have conducted a survey in the United Kingdom in order to evaluate the prevalence of anaemia and of iron deficiency in elderly male and female patients and in female patients of child-bearing age presenting to their general practitioner. Although haemoglobin values were approximately normally distributed, there was evidence of a bimodal distribution of serum ferritin values, particularly in elderly men. A correlation between serum ferritin and haemoglobin values was found to exist, both in the elderly and in younger women. The overall prevalence of anaemia in the study population was 14.3%, although it was higher for elderly men (20.1%) than either elderly women (13.7%) or women of child-bearing age (11.9%). Iron deficiency associated with anaemia was more common in elderly men (45.2% of those anaemic) than elderly women (28.6%) or women of child-bearing age (25.6%). This survey indicates that the prevalence of anaemia among certain groups of high risk patients presenting for consultation to their general practitioner is about 1 in 7, although the prevalence is as high as 1 in 5 in elderly men.

The effect of hypoxic cell radiosensitizers is increased when mammalian cells are depleted of endogenous glutathione by buthionine sulphoximine pre-treatment in vitro; a similar gain has not been observed in tumors in vivo despite evidence of glutathione depletion in vivo following buthionine sulphoximine treatment. However, concentrations of biological reducing agents other than glutathione were not measured in the in vivo experiments. Other reducing agents found in tumors include alpha-tocopherol, which reduces the sensitizing efficiency of nitro-aromatic sensitizers in thiol-depleted mammalian cells. These data suggest that the failure to observe large gains in misonidazole sensitizing efficiency in thiol-depleted tumors in vivo may be due, in part, to the presence of biological reducing agents such as alpha-tocopherol.

We have studied the intracellular uptake of a number of neutral, acidic, and basic radiosensitizers. For neutral sensitizers, we observed a correlation between the measured intracellular concentration and sensitization, but for bases, a large change in average intracellular concentration results in only a small change in sensitization. In addition, by modifying the intralysosomal pH, we have altered the measured average intracellular concentration of the weak base pimonidazole by a factor of two, although this had no detectable effect upon sensitization. Using spin filtration of solutions of sensitizers with naked calf thymus DNA or chromatin we have assessed the affinity of DNA for sensitizers with different prototropic and lipophilic properties. We have also shown that this anomalous behavior of the basic sensitizers could be partly explained on the basis of intracellular localization adjacent to the DNA due to ionic interactions. Thus, intracellular localization needs to be considered when interpreting average intracellular uptake data.