Pharmacologic intervention with angiotensin II and kininase inhibitor enhanced efficacy of radioimmunotherapy in human colon cancer xenografts.
Induced hypertension and kininase inhibition can enhance tumor targeting of radiolabeled monoclonal antibody (MAb) by altering tumor circulation. This study investigated the effect of this manipulation on the antitumor efficacy of radioimmunotherapy (RIT).


METHODS
Mice bearing human colon cancer xenografts were administered 2.0 microg/kg/min of angiotensin II (AT-II) for 1 h and 30 microg of a kininase inhibitor, enalapril maleate, before the administration of 3.7 MBq (131)I-A7, an IgG1 against 45-kDa glycoprotein on colorectal cancer, and tumor growth was observed thereafter. The mechanism of the manipulation effect was investigated by estimation of the tissue absorbed dose and radioluminography of tumors.


RESULTS
The pharmacologic manipulation with AT-II and enalapril improved the tumor quadrupling time (Tq) of 3.7 MBq RIT from 24.3 +/- 2.75 d to 33.1 +/- 2.83 d (P < 0.05). Addition of this manipulation made 3.7 MBq RIT as effective as 9.25 MBq RIT alone (Tq, 37.2 +/- 2.97 d). Dose estimation showed that the manipulation increased the tumor absorbed dose 1.55-fold without affecting the doses to normal tissues. Uniform intratumoral distribution in the manipulated tumors was shown by radioluminography.


CONCLUSIONS
Larger and more uniform tumor radiation produced by this pharmacologic manipulation can benefit RIT with (131)I-MAb.
Department of Nuclear Medicine, Kanazawa University School of Medicine, Japan.
S
S
Kinuya
K
K
Yokoyama
A
A
Kawashima
T
T
Hiramatsu
S
S
Konishi
N
N
Shuke
N
N
Watanabe
T
T
Takayama
T
T
Michigishi
N
N
Tonami
D000804:Angiotensin II / Q000008:administration & dosage*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D003110:Colonic Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000532:radiotherapy*; D004656:Enalapril / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy; D011877:Radionuclide Imaging; D011879:Radiotherapy Dosage; D014662:Vasoconstrictor Agents / Q000008:administration & dosage*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000911:Antibodies, Monoclonal; D007457:Iodine Radioisotopes; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D004656:Enalapril