The contribution of extracellular components to the measurement of pHMRS of a variety of rat tumours (nitrosomethyl urea induced mammary tumours, GH3 prolactinomas, Hepatoma 9618a, UA hepatomas and Walker sarcomas) has been assessed. Acid extractable P(i) was between 2.6 and 12.5 mumol/G wet wt depending on tumour type, and of this 53 +/- 4.8% (mean +/- SEM) was MRS-visible. The P(i) content of tumour exudate was 2-3 mM, of interstitial fluid (sampled from a micropore chamber incorporated within a tumour) 1.7 mM, and of blood plasma 1.95 mM. The mean extracellular volumes of the tumours, measured by distribution of 3H2O and [14C]inulin, were 49-55% depending on tumour type and were at least twice that found in normal liver. Calculations suggested that for most tumours with an extracellular volume not exceeding 55%, at least 65% of the P(i)(MRS) signal was derived from intracellular P(i), and thus that pH(MRS) is a measure of pHi. For each tumour type, pHMRS was measured both in 'pulse-acquire' mode at 1.9 T which may include signals from surrounding tissue, and in localized mode at 4.7 T where the signal came uniquely from tumour tissue. The steady state pHMRS was either neutral or on the alkaline side of neutrality (pH range 7.04-7.37). Raised lactate content and decreased buffering capacity (compared to normal tissues) accompanied these neutral to alkaline pH values.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary The effects of different doses of angiotensin 11 (0.02 to 0.5 jlg kg-' min-' on mean arterial blood pressure, tissue blood flow and tissue vascular resistance were investigated in BD9 rats. Blood flow was measured using the uptake of 12511 or 4C-labelled iodoantipyrine ('25I-IAP and '4C-IAP). Spatial heterogeneity of blood flow within tumours, before and after angiotensin II infusion, was also measured using '4C-IAP and an autoradiographic procedure. Mean arterial blood pressure rose steeply with angiotensin II dose. Blood flow to skeletal muscle, skin overlying the tumour, contralateral skin, small intestine and kidney tended to decline in a dose-dependent manner. Blood flow to the tumour was also reduced (to 80% of control values) but there was no dose response. Blood flow to the heart was slightly increased and blood flow to the brain was unaffected by angiotensin II. Vascular resistance, in all tissues, was increased by angiotensin II infusion. The increase in tumour tissue was similar to that found in skeletal muscle and small intestine and is likely to be caused by a direct vasoconstricting effect of the drug rather than autoregulation of tumour blood flow in the face of an increase in perfusion pressure. The reduction in overall blood flow at the highest perfusion pressure was due to a preferential effect of angiotensin II at the tumour periphery. These results show that some tumours, at least, can respond directly to the effects of vasoactive agents.

This review discusses the relationship between tumour oxygenation status, tumour cell death and the 31P MRS parameters associated with cellular energy metabolism (phosphocreatine, nucleoside triphosphates and Pi). The presence of cells dying by apoptosis, and during mitosis would be unlikely to affect the 31P spectrum directly since they represent only a small fraction of tumour cells and remain energized until phagocytosed. Histologically necrotic cells also probably contribute nothing to the 31P spectrum. Instead, the spectrum appears to reflect the degree of hypoxia of the remaining viable cells, and the metabolic alterations required to sustain ATP synthesis as the oxygen supply diminishes. The biochemical theory developed to account for the 31P spectra of acutely hypoxic tissues does not apply to chronically hypoxic tumours. The concentrations of free ADP and Pi have major roles in the control of oxidative phosphorylation and glycolysis, as in normal tissues, but the precise relationships are still obscure. Cell-killing following therapy may indirectly affect 31P MRS parameters via changes in oxygen concentration brought about by an improvement in tumour blood flow and alterations in oxygen consumption rates and diffusion distances.

Summary The effects of different doses of hydralazine and prostacyclin on the 31P magnetic resonance spectra of the LBDS, fibrosarcoma were investigated and related to their effects on mean arterial blood pressure (MABP) and heart rate. The effect of reducing MABP by bleeding the animals, via the tail artery, was also investigated. Tumour spectral changes following high dose drug treatment (an (Hahn, 1974;Overgaard & Bichel, 1977;Overgaard & Nielsen, 1980). Hydralazine has also been shown to potentiate the cytotoxicity in solid rodent tumours in vivo of the bioreductive drugs RSU-1069(Chaplin & Acker, 1987 and SR4233 (Brown, 1987). These drugs are cytotoxic to hypoxic cells and their potentiation by hydralazine is presumably brought about by induced hypoxia secondary to a decrease in tumour blood flow.Selective reduction of tumour blood flow also has potential in more conventional chemotherapy. Stratford et al. (1987) showed that a carefully timed administration of hydralazine could increase the cytotoxic action of melphalan in transplanted rodent tumours whilst normal tissue toxicity remained unaffected. This could be explained by a hydralazine-induced selective reduction in tumour blood flow leading to entrapment of melphalan in the tumour tissue.Hydralazine is used clinically to control hypertension. Its plasma half-life in man is less than 60 min (Shepherd et al., 1980), but its half-life in vascular smooth muscle may be as high as 30 h (Gross, 1977) which is a possible disadvantage for application in tumour therapy. Horsman et al. (1989) have shown that, in mice, the mean arterial blood pressure, which falls on administration of hydralazine, has not returned to normal 8 h after injection. Tumour blood flow was not measured directly but there was also some indication that it too had not returned to pre-drug levels by 8 h. Any longterm reduction in the tumour blood supply would be a disadvantage for radiotherapy. Therefore, in the present study, the effect of hydralazine on cardiovascular parameters and tumour energy metabolism was compared with that of prostacyclin, an endogenous vasodilator formed from arachidonic acid (Moncada et al., 1976). This compound is rapidly hydrolysed in whole blood and plasma with a half-life of around 6 min (Orchard & Robinson, 1981). In man, the onset and offset of the cardiovascular actions of prostacyclin are rapid, less than 5 min, which means that its effects can be easily reversed (O'Grady et al., 1980;Lewis & Dollery, 1983