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Research Articles: Therapeutics, Targets, and Development

Synergistic tumoricidal effect of combined hMUC1 vaccination and hNIS radioiodine gene therapy

Departments of ¹ Nuclear Medicine, ² Pathology, and ³ Tumor Biology and ⁴ Laboratory of Molecular Imaging and Therapy of Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

Requests for reprints: June-Key Chung, Department of Nuclear Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Korea. Phone: 822-2072-3376; Fax: 822-745-7690. E-mail: jkchung{at}plaza.snu.ac.kr; or Chul-Woo Kim, Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Korea. Fax: 82-2-3673-0662. E-mail: cwkim{at}plaza.snu.ac.kr

Abstract

We examined the merits of combinatorial hMUC1 vaccination and hNIS radioiodine gene therapy and evaluated its tumoricidal effects in an animal tumor model. CMNF (CT26 expressing hMUC1, hNIS, and firefly luciferase) cells were transplanted into 28 mice, and 4 and 11 days after tumor challenge, tumor-bearing mice were immunized i.m. with pcDNA3.1 or pcDNA-hMUC1 vaccine and subsequently administered PBS or ¹³¹I i.p. [four groups (7 mice per group): pcDNA3.1 + PBS, phMUC1 + PBS, pcDNA3.1 + ¹³¹I, and phMUC1 + ¹³¹I groups]. Thirty-two days after tumor challenge, we rechallenged mice in the pcDNA3.1 + ¹³¹I and phMUC1 + ¹³¹I groups with CMNF cells. Tumor progression and tumor-free mice (%) were monitored by bioluminescence. We investigated hMUC1-associated immune response generated by combination therapy. Marked tumor growth inhibition was observed in the phMUC1 + ¹³¹I group by bioluminescence at 32 days after tumor challenge. Mice in phMUC1 + ¹³¹I group showed complete hMUC1-expressing tumor suppression after tumor rechallenge, whereas mice in the pcDNA3.1 + ¹³¹I group did not. The tumor-free mice (%) were much higher in the phMUC1 + ¹³¹I group than in the other three groups. Levels of hMUC1-associated CD8⁺IFN-⁺ T cells were higher in the phMUC1 + ¹³¹I group than in the other three groups. hMUC1-loaded CD11⁺ cells in the phMUC1 + ¹³¹I group were found to be most effective at generating hMUC1-associated CD8⁺IFN-⁺ T cells. The activities of hMUC1-associated cytotoxic T cells in the phMUC1 + ¹³¹I group were higher than in the other three groups. Our data suggest that phMUC1 + ¹³¹I combination therapy synergistically generates marked tumoricidal effects against established hMUC1-expressing cancers. [Mol Cancer Ther 2008;7(7):2252–60]

Grant support: Cancer Research Center, Korean Science & Engineering Foundation through the Tumor Immunity Medical Research Center at Seoul National University College of Medicine; BK21 Project for Medicine, Dentistry, and Pharmacy 2007 (Y.H. Jeon and Y. Choi).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Y.H. Jeon and Y. Choi contributed equally to this study.

⁵ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 3/27/08; revised 4/28/08; accepted 5/ 3/08.