Angiotensin II as a potential method of targeting cytotoxic-loaded microspheres in patients with colorectal liver metastases

Abstract

Summary Regional chemotherapy is commonly used to treat patients with colorectal liver metastases. However, improvement in survival has still not been demonstrated. Cytotoxic loaded albumin microspheres for arterial administration have been described as a means of improving the therapeutic index, but their distribution depends upon the prevailing pattern of arterial blood-flow at the time of injection. In this study, the ability of the vasoactive drug angiotensin II to target arterially injected microspheres to colorectal liver metastases is assessed in nine patients using scintigraphic planar and tomographic imaging.The median tumour: normal ratio in nine patients with colorectal liver metastases was 3.4:1 before the administration of angiotensin II. The corresponding ratio after administration of angiotensin II was 7.3:1. The median improvement factor was 1.8 (P <0.05).The data suggest that worthwhile tumour targeting can be achieved with angiotensin II in patients with colorectal liver metastases.Post-mortem studies have shown that up to 70% of patients dying after a potentially curative resection for colorectal cancer, die with liver metastases. The prognosis of patients with colorectal liver metastases is generally poor, survival being in the range of 3 to 9 months (Woods, 1984;Nielsen et al., 1971).Surgical resection of colorectal hepatic metastases may be effective in patients with limited disease (Bradpiece et al., 1987), but may not be feasible in the majority of patients where multiple tumours are present. Although some recent studies of combined systemic 5 fluorouracil and folinic acid or interferon show promising results (O'Connell, 1989;Kerr, 1989;Wadler et al., 1989), conventional systemic chemotherapy has been associated with poor response rates. Attention has therefore turned to regional chemotherapy.It is known that established colorectal liver metastases receive their blood supply from the hepatic artery and the administration of anti-cancer drugs via an indwelling hepatic arterial catheter is now widely practised (Ridge et al., 1987). Unfortunately, although the tumour response rates may increase when chemotherapeutic agents are administered intraarterially rather than systemically (Berger, 1981) a significant increase in survival among treated patients has not been demonstrated by randomised controlled trial (Malik & Wrigley, 1988).Novel chemotherapeutic drug delivery systems including cytotoxic loaded or radioactive microspheres for administration by the arterial route, have been developed. We have previously described cytotoxic loaded albumin microspheres (diameter 20-40IAm) which are trapped in the liver when injected into the hepatic artery (McArdle et al., 1988;Willmott et al., 1985), the drug being released as the microsphere degrades. However intra-arterial injection of such particles results in their unselective distribution throughout the liver, microsphere concentration within different regions of the organ being dependent upon the prevailing distribution of arterial blood-flow. How...

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

“…Infusion of Angiotensin II via the hepatic artery therefore would be expected to constrict normal liver vessels, so reducing liver blood flow, but leave tumour vessels, and therefore flow, relatively unaffected. This has previously been demonstrated with a short Angiotensin II infusion using both microspheres (Goldberg et al, 1991) and Laser Doppler Flowmetry (LDF) (Hemingway et al, 1992) to assess blood flow. However, previous animal studies using LDF (Dworkin et al, 1997), and clinical studies using planar imaging (Sasaki et al, 1985) have demonstrated only transient Angiotensin II-induced enhancement of tumour:normal blood flow ratio, which was not sustained throughout a prolonged Angiotensin II infusion via the hepatic artery.…”

“…Angiotensin II is a powerful vasoconstrictor which has been shown to alter the distribution of blood flow in favour of intrahepatic tumour perfusion during short (3-4 min) intra-arterial infusions of the compound (Sasaki et al, 1985). Enhanced tumour targeting of radiolabelled microspheres as a consequence of modified hepatic blood flow distribution has also been demonstrated following 100s of intra-arterial infusions (Goldberg et al, 1991). Whether or not prolonged intra-arterial infusion of Angiotensin II can lead to sustained enhancement of tumour : normal blood flow ratio in humans is presently not known, and is an important factor in determining the practical value of this method of vascular manipulation for use with regional chemotherapy.…”

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

“…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…”

A blood–tumor barrier limits gene transfer to experimental liver cancer: the effect of vasoactive compounds

“…It has been shown that the tumor/normal liver distribution ratio of a marker may be doubled when AII is co-administered with DSM. 45 Nitric oxide is a pluripotent regulatory molecule which is involved in the regulation of microvasculature. 29 Physiological levels of nitric oxide maintain the vascular integrity, but high levels induce vasodilatation and microvascular leakage.…”