title: The effect of angiotensin II on tumor blood flow and the delivery of microparticulate cytotoxic drugs.
abstract: Colorectal hepatic metastases have a notoriously poor response to conventional systemic chemotherapy. We have synthesised cytotoxic drug (doxorubicin and mitomycin C) containing spheres 40 microns in diameter, using human albumin and ethyl cellulose as matrices. Introduction of these cytotoxic microspheres into the hepatic artery should embolise to the tumor and provide a controlled release depot for the anticancer agent. The vasoconstrictor, angiotensin II (AII) has been shown to increase tumor blood flow relative to normal tissue when administered via the hepatic artery, therefore we have investigated the effect of AII on targeting of cytotoxic microspheres to hepatic metastases. Patients with hepatic metastatic colorectal carcinoma had hepatic arterial catheters inserted at laparotomy and connected to subcutaneous injection ports. Peroperatively, 99mTc-labelled albumin microspheres were administered via the arterial catheter. Fifteen minutes later, AII was infused (10 micrograms per minuter for 4 min) via the catheter and 131I-labelled albumin microspheres were administered as a bolus at the midpoint of the AII infusion. Multiple biopsies were taken of normal liver and tumor metastasis and the tissue radioactivity counted for 99mTc and 131I. Further studies were performed postoperatively in which 99mTc-labelled microspheres were administered via the hepatic artery catheter and their distribution was followed using tomographic SPECT scanning. Combined results of this study suggested that AII can increase tumor SPECT scanning. Combined results of this study suggested that AII can increase tumor blood flow rates relative to normal hepatic tissue by approximately 3-fold.
authors.affiliation: Dept. of Medical Oncology, University of Glasglow, Scotland.
authors.forename: D J
authors.initials: DJ
authors.lastname: Kerr
authors.forename: J A
authors.initials: JA
authors.lastname: Goldberg
authors.forename: J R
authors.initials: JR
authors.lastname: Anderson
authors.forename: N
authors.initials: N
authors.lastname: Wilmott
authors.forename: A T
authors.initials: AT
authors.lastname: Whatelely
authors.forename: C S
authors.initials: CS
authors.lastname: McArdle
authors.forename: J
authors.initials: J
authors.lastname: Mckillop
mesh_terms: D000804:Angiotensin II / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000627:therapeutic use; D004337:Drug Carriers; D006801:Humans; D007261:Infusions, Intra-Arterial / Q000379:methods*; D007457:Iodine Radioisotopes; D008113:Liver Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000556:secondary*; D008863:Microspheres; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage* / Q000627:therapeutic use; D009382:Neoplasms, Unknown Primary / Q000188:drug therapy*; D011877:Radionuclide Imaging; D012004:Rectal Neoplasms / Q000188:drug therapy*; D012039:Regional Blood Flow / Q000187:drug effects*; D013667:Technetium
chemical_list: D004337:Drug Carriers; D007457:Iodine Radioisotopes; D000804:Angiotensin II; D016685:Mitomycin; D013667:Technetium; D004317:Doxorubicin