The response of tumour vasculature to angiotensin II revealed by its systemic and local administration to 'tissue-isolated' tumours

Abstract

Sumnman-A tissue-isolated preparation of the P22 rat carcinosarcoma was used to investigate the tumour vascular response to angiotensin II (ATII). In particular. the relative importance of systemic and local tumour factors was assessed by comparing tumour vascular resistance during systemic administration of ATII and during administration directly into the tumour-supplying artery. The effect of hypervolaemia on tumour vascular resistance was determined as well as the effect of ATII on oxygen metabolism. Tumour vascular resistance was increased by ATII in a dose-dependent manner. The response was biphasic with an initial peak in resistance followed by a lower plateau phase. Systemic administration of ATII was more effective in increasing tumour vascular resistance than direct administration. This suggests that systemic administration is not causing any reopening of previously collapsed tumour blood vessels. Further evidence for this is that hypervolaemia caused no reduction in tumour vascular resistance and that there was no difference in oxygen extraction by tumours between groups treated with systemically and directly administered ATII. A heterogeneous distribution of ATII receptors in the P22 tumour is a more likely explanation for the known heterogeneity of blood flow response to ATII.Kewords: P22 tumour; angiotensin II: vascular resistance; blood flow; oxygen metabolism Intravenous infusion of angiotensin II (ATII) has been found to increase tumour blood flow relative to most normal tissues, and this has led to the concept of 'hypertension chemotherapy'. in which ATII is used to improve the relative delivery of chemotherapeutic agents to tumours (Susuki et al., 1981;Takematsu et al.. 1985;Noguchi et al., 1988;Kobayashi et al.. 1990Kobayashi et al.. . 1991Anderson et al., 1991;Kerr et al., 1992; Mutoh et al., 1992). However, in absolute terms, ATII has been found to increase blood flow in some tumours (Tokuda et al.. 1990; Honr et al., 1991;Tanda et al., 1991) while decreasing it in others (Jirtle et al., 1978;Tozer and Shaffi, 1993). A decrease in absolute tumour blood flow could compromise delivery of drug to tumour microregions. Whether tumour blood flow increases or decreases is dependent upon the balance between drug-induced hypertension ansing from systemic vasoconstriction and local vasoconstriction induced within the tumour itself (since blood flow = perfusion pressure . vascular resistance). Presumably, this balance varies with tumour type. although the underlying factors which determine response remain unclear. It is important to identify these factors in order to predict the response of a particular tumour to ATII.We have previously found that ATII causes a significant increase in the vascular resistance of early generation, subcutaneous transplants of the P22 rat carcinosarcoma Tozer et al., 1994a). We also found that the degree of vasoconstriction induced by ATII was dependent on pretreatment blood flow. That is, in whole tumours, vasoconstriction was greatest where blood flow to control tumours...

Kinetic modelling of dissolution dynamic nuclear polarisation 13C magnetic resonance spectroscopy data for analysis of pyruvate delivery and fate in tumours

“…Both parameters were depressed from normal unanaesthetised values, as expected, and tended to reduce with time, although stabilising towards the end of the procedure. MABP was 72 ± 4 mmHg at the start of the experiment (Figure 7B), which was somewhat lower than we have previously measured in the same animal strain, with propofol 26 or Hypnorm/Hypnovel anaesthesia, 28 as opposed to the isoflurane anaesthesia used here. Consistent with a depressed respiration rate, average arterial oxygen partial pressure (pO 2 ), calculated over the whole experimental time‐course, measured 64 ± 3 mmHg, down from the normal range of 80–100 mmHg.…”

Use of the radiation‐inducible WAF1 promoter to drive iNOS gene therapy as a novel anti‐cancer treatment

“…• donors have been used in vitro to achieve radiosensitisation and cytotoxicity [3,6,7] but their application in vivo at the doses required would result in unacceptable systemic effects [8,9], predominantly hypotension, and so these agents are not ideal for clinical use. Indirect activation of inducible nitric oxide synthase (iNOS), the enzyme responsible for generation of NO…”

“…While the role of NO • in tumours is not fully understood, it is clear from the literature that NO • has enormous potential as an anti-cancer agent if it can be targeted reliably to tumours at high concentrations. Spontaneous and bioreductive NO • donors have been used in vitro to achieve radiosensitisation and cytotoxicity [3,6,7] but their application in vivo at the doses required would result in unacceptable systemic effects [8,9], predominantly hypotension, and so these agents are not ideal for clinical use. Indirect activation of inducible nitric oxide synthase (iNOS), the enzyme responsible for generation of NO • at high concentrations, by interferon gamma (IFNγ ) has also been used in vitro [3], but its systemic toxicity is already well documented [10], and clinical application would be problematical.…”

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“…The reduced tumor perfusion results in a hypoxic and acidic milieu, which further promotes immunosuppression ( 46 – 48 ). Vascular endothelial growth factor (VEGF)–induced vascular leakiness ( 48 ) and AngII-mediated vasoconstriction ( 76 , 77 , 80 ) further impair tumor perfusion and aggravate hypoxia. GM-CSF, granulocyte-macrophage colony-stimulating factor.…”

“…The impaired perfusion and hypoxic condition of tumors can be further aggravated by AngII-induced vasoconstriction and increased vascular resistance ( Fig. 2 ) ( 76 , 77 ). Our laboratory has shown that AngII transiently enhanced tumor blood flow and interstitial fluid pressure by increasing the mean arterial blood pressure in different tumor types ( 78 , 79 ).…”