Continuous angiotensin II infusion increases tumour: normal blood flow ratio in colo-rectal liver metastases

Abstract

Summary Insufficient blood flow within colo-rectal hepatic metastases is a factor which may limit drug delivery to, and thus the response of, these tumours to regional chemotherapy. Loco-regional flow may be manipulated pharmacologically to enhance the tumour blood flow relative to that of the normal liver. However, as yet, only transient effects have been studied. Patients receiving regional chemotherapy for unresectable hepatic disease were given a 45 min regional infusion of the vasoconstrictor Angiotensin II. Intrahepatic blood flow distribution was assessed serially by Positron Emission Tomography (PET) imaging together with the trapping tracer copper(II) pyruvaldehyde bis(N-4-methylthiosemicarbazone) (Cu-PTSM) labelled using copper-62. Eleven lesions in nine patients were studied, with no adverse effects. Prior to Angiotensin II administration tumour blood flow was generally found to be greater than that of liver (10/11 lesions; 8/9 patients; median TNR 1.3, iqr 0.9-2.5). A significant increase in relative flow to tumour was seen in response to 10 min Angiotensin II infusion in most cases (7/11 lesions; 7/9 patients; median TNR 2.1, iqr 1.4-4.1; P = 0.008), which appeared to be sustained throughout the 45 min infusion period (median TNR 1.85, iqr 1.3-3.8; P = 0.03). These effects were accompanied by transient elevation of mean arterial pressure, but no change in pulse rate. These observations suggest that prolonged regional vasoconstrictor administration could prove useful in the management of unresectable colo-rectal hepatic metastases, and that further development of vascular manipulation to enhance tumour targeting and drug delivery is warranted. by abdominal CT scan and chest X-ray, who had undergone hepatic arterial cannulation and insertion of an Infusaid model 400 pump (Norwood, Massachussets, USA) for regional floxuridine infusion chemotherapy (0.2 mg per kg body weight per 24 h over 14 days) (Allen-Mersh et al, 1994). At the time of study patients had received between 1 and 7 cycles of treatment. Exclusion criteria were: age > 70 years; Karnofsky score < 80; jaundice, or a history of hypertension, myocardial or cerebrovascular disease. Blood pressure was measured prior to the study, and patients were excluded if the systolic blood pressure was > 160 mmHg or the diastolic pressure was > 85 mmHg on two successive recordings 30 min apart. Ten patients were included in the study.Approval for the study was granted by the Royal Marsden NHS Trust Ethics Committee, and the Committee for Clinical Research. Written informed consent was obtained from all patients. Tracer preparation and PET imagingRadionuclide preparation was carried out using an in-house 62 Zn/ 62 Cu generator (Zweit et al, 1992), and full details of the preparation of 62 Cu-PTSM from H 2 -PTSM ligand have been described elsewhere (Flower et al, 2001). Radiochemical purity of tracer was assessed by instant thin layer chromatography prior to administration and was у 91% in all cases.PET imaging was carried out using a multi-wire proportio...

Perfusion CT Assessment of Tissue Hemodynamics Following Hepatic Arterial Infusion of Increasing Doses of Angiotensin II in a Rabbit Liver Tumor Model

“…Angiotensin II produced heterogeneous patchy contrast enhancement in the normal liver parenchyma that obscured the margins of the distal vessels. These results are similar to the fi ndings reported by Burke et al ( 6 ) where heterogeneous distribution of a tissue-trapping BF tracer was seen on PET images after angiotensin II was infused into the hepatic arteries of patients with colorectal liver metastases. The observed spatial heterogeneity is consistent with the vasoconstrictor exerting its effects primarily on smaller distal arterial branches, as has been shown in the kidney (27)(28)(29).…”

“…This shunts blood from the normal liver parenchyma to the tumor, resulting in increased tumor exposure to transarterially administered therapeutic agents because hepatic tumors derive approximately 90% of their blood supply from the hepatic artery, unlike normal liver tissue, which receives 70%-80% of its blood supply from the portal vein (22)(23)(24). Angiotensin II is a potent vasoconstrictor that has been shown to enhance the liver tumor-normal liver tissue BF ratio ( 3,4,6 ) and reduce the common hepatic arterial BF ( 5 ) after its hepatic arterial administration in patients with primary and metastatic liver tumors. However, the doses of angiotensin II EXPERIMENTAL STUDIES: CT Assessment of Liver Tissue after Infusion of Angiotensin II Wright et al…”

The effect of intra-arterial angiotensin II on the hepatic tumor to non-tumor blood flow ratio for radioembolization: a systematic review

“…A common feature among liver tumors is that the vasculature of liver tumors is immature, lacking normal neurovascular innervation and a well-developed smooth muscle coating [19,20,21]. This allows for manipulation of the fraction of blood flowing to tumorous liver tissue (T/N blood flow ratio) by infusion of a vasoconstrictive agent.…”

“…As opposed to the vasculature of the healthy liver tissue, tumor vessels will not respond to infusion of vasoconstrictive drugs, leading to an increase in preferential blood flow to the tumorous liver tissue. Various vasoconstrictors, including epinephrine, noradrenaline and angiotensin-II have shown the potential to increase the hepatic T/N blood flow ratio, in both preclinical and clinical studies [19,22,23,24,25]. Angiotensin II (AT-II) is an octapeptide hormone that acts as a vasoactive agonist and induces arterial vasoconstriction [26], with the most pronounced effect in the splanchnic vasculature.…”

Loss of function of vascular smooth muscle cells by nitric oxide‐dependent and ‐independent interactions with tumorigenic cells

“…3 In some tumors, the feeder vessels contain little vascular smooth muscle cells (VSMCs) and apparently no innervation. 4 Possibly correlated to these structural findings, hemodynamic studies show that the blood supply of primary tumors or metastases is remarkably resistant to the infusion of various pharmacological vasoconstrictor agents relatively to surrounding normal tissues, [5][6][7][8][9] suggesting that the tumor resistance vessels were in a state of maximal vasodilation or anergy. Other tumor blood vessels, however, exhibit differentiation, with recruitment of ␣-actin positive periendothelial cells (e.g., VSMCs ϩ pericytes) around tumor vessels.…”