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Pharmacologic Intervention with Angiotensin II and Kininase Inhibitor Enhanced Efficacy of Radioimmunotherapy in Human Colon Cancer Xenografts

Departments of Nuclear Medicine and Pathology (I), Kanazawa University School of Medicine, Kanazawa
Department of Radiology, Asahikawa Medical College, Asahikawa
Department of Radiology, Toyama Medical and Pharmaceutical University, Toyama
Department of Radiological Technology, Kanazawa University School of Health Science, Kanazawa, Japan

Correspondence: For correspondence or reprints contact: Seigo Kinuya, MD, Department of Nuclear Medicine, Kanazawa University School of Medicine, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan.

ABSTRACT

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 µg/kg/min of angiotensin II (AT-II) for 1 h and 30 µg of a kininase inhibitor, enalapril maleate, before the administration of 3.7 MBq ¹³¹I-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. Conclusion: Larger and more uniform tumor radiation produced by this pharmacologic manipulation can benefit RIT with ¹³¹I-MAb.

Key Words: radioimmunotherapy • tumor circulation • induced hypertension • kininase inhibitor

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