Abstract
Effects of recombinant tumour necrosis factor (TNF) on functional and structural vascular volumes in solid murine Meth A tumours were investigated by injection of Hoechst 33342 and staining for the vascular basement membrane component laminin, respectively. Systemic injection of 3 x 10(4) U TNF caused an initial increase in functional volume in the tumour, but a strong decrease from 1 to 48 h after treatment. Early effects of intralesional treatment were more moderate. Systemic injection of 10(4) U TNF or 0.3 or 3 micrograms lipid A caused a fall in functional volume at 4 h, but a recovery was seen at 24 h. This recovery did not occur after treatment with a combination of 10(4) U TNF and 0.3 micrograms lipid A. Structural vascular volume was not markedly reduced until 24 h after treatment with the high doses of the separate agents and the combination. All effects appeared generally more prominent in the tumour centre than in the borders. Data suggest that TNF induces initially an active hyperaemia that rapidly converts to passive hyperaemia. A prolonged disturbance of tumour blood supply is probably necessary for therapeutic activity. Breakdown of laminin in the vascular basement membrane may be a cause of loss of vascular integrity.
Highlights
The ability of endotoxins to induce necrosis of established solid tumours has been the subject of many studies (Gratia & Linz, 1931; Shear & Perrault, 1943; Nowotny, 1985)
Determination of optimum conditions for vascular staining of Functional vessels could be visualised at a high resolution in tumour sections of mice injected with 0.8 mg Hoechst 33342 (H33342) 20 s before sacrifice (Figure 2a)
Reduction of the injected dose of H33342 down to 0.1 mg led to a dose-dependent decrease in fluorescence intensity of the functional vessels, but did not affect estimation of FV in the tumour
Summary
The ability of endotoxins to induce necrosis of established solid tumours has been the subject of many studies (Gratia & Linz, 1931; Shear & Perrault, 1943; Nowotny, 1985). Observations, that TNF can induce extensive necrosis of tumours that lack sensitivity to TNF in vitro (Creasey et al, 1986; Asher et al, 1987; Bloksma & Hofhuis, 1987) suggest that, at least in these instances, the tumour cells are killed by an indirect mechanism. Ample data have indicated that the tumour vasculature is a primary target of the action of TNF and endotoxin (Gratia & Linz, 1931; Shear & Perrault, 1943; Kawai et al, 1987). Hyperaemia, congestion, thrombus formation and vascular damage have been observed in tumours within 4 h of treatment with either of both agents (Kuper et al, 1982; Kawai et al, 1987; Van de Wiel et al, 1989). In SAl tumours functional evidence of an early disturbance of tumour blood flow upon TNF treatment has been obtained by using 51Cr-labelled erythrocytes (Havell et al, 1988)
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