Characterisation of tumour blood flow using a 'tissue-isolated' preparation

Tozer, Gillian M.; Shaffi, KM; Prise, Vivien E.; Cunningham, Vincent J.

doi:10.1038/bjc.1994.445

Cited by 23 publications

(20 citation statements)

References 23 publications

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“…The mathematical model used was adapted from Kety (1960) and is described elsewhere in detail (Tozer et al, 1994). Perfusion pressure for all tissues was assumed to change in direct proportion to MABP, and changes in tissue vascular resistance (TVR) following treatment, for the tumour and normal tissues, were calculated from the changes in MABP divided by the changes in blood flow rate.…”

Section: Analysis Of Blood Flow Resultsmentioning

confidence: 99%

The endothelin B (ETB) receptor agonist IRL 1620 is highly vasoconstrictive in two syngeneic rat tumour lines: potential for selective tumour blood flow modification

et al. 2005

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The vascular effects of the endothelin B (ET B ) receptor agonist IRL 1620 were investigated in the rat P22 carcinosarcoma and a range of normal tissues in BDIX rats. Tissue blood flow rate was calculated from measurements of tissue uptake of radiolabelled iodoantipyrine. A comparison of vascular effects in the P22 tumour and the HSN sarcoma growing in CBH/CBi rats was made using laser Doppler flowmetry, showing similar effects of IRL 1620, with red cell flux rapidly decreasing by 50 -60% and then returning to control levels within approximately 30 min. This corresponded to similar levels but different spatial organisation of ET B binding sites in the two tumours, as measured by autoradiography. The decrease in tumour blood flow and an increase in vascular resistance suggest that the vascular component of ET B receptors in the P22 tumour is localised on contractile elements rather than on endothelial cells. ET A receptors were also identified. Vasoconstriction occurred uniformly throughout the P22 tumour mass, consistent with a measured homogeneous distribution of ET B receptors. IRL 1620 caused vasoconstriction in normal skeletal muscle, kidney and small intestine of the BDIX rat as well as in tumour, but did not affect blood flow in other tissues. These effects could be useful for limiting toxicity of certain chemotherapeutic agents. Fully functional ET B receptors are clearly expressed on tumour vasculature and IRL 1620 shows promise for short-term modification of tumour blood flow. Expression levels of ET B receptors on the tumour vasculature could be useful for predicting which tumours are likely to respond to IRL 1620.

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Section: Analysis Of Blood Flow Resultsmentioning

confidence: 99%

The endothelin B (ETB) receptor agonist IRL 1620 is highly vasoconstrictive in two syngeneic rat tumour lines: potential for selective tumour blood flow modification

et al. 2005

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“…Tissue-isolated tumours, whose vascular supply was derived solely from the superior epigastric vascular pedicle, were grown in the right inguinal fat pad of 10 to 11-week-old male BD9 rats. The method used was essentially as described previously (Tozer et al, 1994), except that no attempt was made to physically enclose the growing tumour to prevent vessel ingrowth from surrounding normal tissue. Instead, the surgically prepared fat containing a small (approximately 1 mm3) piece of donor tumour was loosely sutured in position in the inguinal cleft in order to prevent twisting of the vascular pedicle but allow movement of the growing tumour within the cleft.…”

Section: Materials and Methods Tumoursmentioning

confidence: 99%

“…Instead, the surgically prepared fat containing a small (approximately 1 mm3) piece of donor tumour was loosely sutured in position in the inguinal cleft in order to prevent twisting of the vascular pedicle but allow movement of the growing tumour within the cleft. This technique results in a lower incidence of inflammation than that resulting from enclosure of the growing tumour in silicon [as used previously (Tozer et al, 1994)], while retaining a capacity for preventing vessel ingrowth from surrounding normal tissue. Tumours were used for experimentation when their vascular supply was seen to derive solely from the 1956 epigastric vascular pedicle (approximately 50% of preparations).…”

Section: Materials and Methods Tumoursmentioning

confidence: 99%

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Reduced capacity of tumour blood vessels to produce endothelium-derived relaxing factor: significance for blood flow modification

Tozer

Prise²,

Bell³

et al. 1996

Br J Cancer

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Summary The effect of nitric oxide-dependent vasodilators on vascular resistance of tumours and normal tissue was determined with the aim of modifying tumour blood flow for therapeutic benefit. Isolated preparations of the rat P22 tumour and normal rat hindlimb were perfused ex vivo. The effects on tissue vascular resistance of administration of sodium nitroprusside (SNP) and the diazeniumdiolate (or NONO-ate) vasodilators Constitutive and inducible isoforms of nitric oxide synthase (cNOS and iNOS respectively) have been detected in both experimental and human tumours (Buttery et al., 1993; Chhatwal et al., 1994;Cobbs et al., 1995;Thomsen et al., 1994Thomsen et al., , 1995. Competitive inhibition of NOS, using analogues of L-arginine at high doses, has been shown to decrease blood flow and energy status of experimental tumours and enhance the activity of bioreductive drugs (Andrade et al., 1992;Tozer et al., 1995;Wood et al., 1993, Correspondence: GM Tozer Received 2 April 1996; revised 11 July 1996; accepted 16 July 1996 1994). However, the capacity for EDRF production in tumours is unknown. Any difference from normal would provide a potential means of selectively modifying tumour blood flow for therapeutic benefit.The aims of this study were (1) to determine the sensitivity of tumour vs normal tissue blood vessels to the vasodilatory effect of NO; and (2) to determine the capacity of tumour vs normal tissue endothelial cells for production of EDRF. To this end, isolated preparations of the rat P22 tumour and normal rat hindlimb were perfused ex vivo. The effects on vascular resistance of administration of the NO donors SNP and NOC-7 (endothelium-independent vasodilators) were compared with the effects of administration of ACh (an endothelium-dependent vasodilator) in tumour and normal tissue. Some of the results for tumour alone have appeared in preliminary form as part of conference proceedings . Materials and methods TumoursEarly generations of the P22 transplanted rat carcinosarcoma were used for these experiments. Tissue-isolated tumours, whose vascular supply was derived solely from the superior epigastric vascular pedicle, were grown in the right inguinal fat pad of 10 to 11-week-old male BD9 rats. The method used was essentially as described previously (Tozer et al., 1994), except that no attempt was made to physically enclose the growing tumour to prevent vessel ingrowth from surrounding normal tissue. Instead, the surgically prepared fat containing a small (approximately 1 mm3) piece of donor tumour was loosely sutured in position in the inguinal cleft in order to prevent twisting of the vascular pedicle but allow movement of the growing tumour within the cleft. This technique results in a lower incidence of inflammation than that resulting from enclosure of the growing tumour in silicon [as used previously (Tozer et al., 1994)], while retaining a capacity for preventing vessel ingrowth from surrounding normal tissue. Tumours were used for experimentation when their vascular supply was seen to der...

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“…Its origin and subcutaneous maintenance in BD9 rats have been described previously . Growth of the P22 tumour as a Itissueisolated' preparation in which the tumour microcirculation is derived from a single artery and vein has also been described previously (Tozer et al, 1994b) and is based on the method first described by Gullino and Grantham (1961) and Grantham et al (1973). This type of model has subsequently been used for characterising various aspects of the tumour microcirculation (Vaupel et al, 1985;Jain, 1989a.b.…”

Section: Tumoursmentioning

confidence: 99%

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

Tozer

Shaffi²

1995

Br J Cancer

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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...

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Characterisation of tumour blood flow using a 'tissue-isolated' preparation

Cited by 23 publications

References 23 publications

The endothelin B (ETB) receptor agonist IRL 1620 is highly vasoconstrictive in two syngeneic rat tumour lines: potential for selective tumour blood flow modification

The endothelin B (ETB) receptor agonist IRL 1620 is highly vasoconstrictive in two syngeneic rat tumour lines: potential for selective tumour blood flow modification

Reduced capacity of tumour blood vessels to produce endothelium-derived relaxing factor: significance for blood flow modification

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

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