Cytotoxicity of human prostate cancer cell lines in vitro and induction of apoptosis using 213Bi-Herceptin α-conjugate

Li, Yong; Cozzi, Paul J; Qu, Chang F; Zhang, David Y; Abbas Rizvi, Syed M; Raja, Chand; Allen, Barry J

doi:10.1016/j.canlet.2003.10.035

« Previous Next »Cancer Letters
Volume 205, Issue 2 , Pages 161-171, 18 March 2004

Cytotoxicity of human prostate cancer cell lines in vitro and induction of apoptosis using ²¹³Bi-Herceptin α-conjugate

Yong Li
- Center for Experimental Radiation Oncology, Cancer Care Center, St George Hospital, Gray St, Kogarah 2217, New South Wales, Australia
Paul J Cozzi
- Department of Surgery, St George Hospital, Gray St, Kogarah, UNSW, New South Wales 2217, Australia
- Department of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia
Chang F Qu
- Center for Experimental Radiation Oncology, Cancer Care Center, St George Hospital, Gray St, Kogarah 2217, New South Wales, Australia
- Department of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia
David Y Zhang
- Center for Experimental Radiation Oncology, Cancer Care Center, St George Hospital, Gray St, Kogarah 2217, New South Wales, Australia
Syed M Abbas Rizvi
- Center for Experimental Radiation Oncology, Cancer Care Center, St George Hospital, Gray St, Kogarah 2217, New South Wales, Australia
- Department of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia
Chand Raja
- Center for Experimental Radiation Oncology, Cancer Care Center, St George Hospital, Gray St, Kogarah 2217, New South Wales, Australia
Barry J Allen
- Center for Experimental Radiation Oncology, Cancer Care Center, St George Hospital, Gray St, Kogarah 2217, New South Wales, Australia
- Department of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia
- Corresponding author. Address: Center for Experimental Radiation Oncology, Cancer Care Center, St George Hospital, Gray St, Kogarah 2217, New South Wales, Australia. Tel.: +61-2-9350-3855; fax: +61-2-9350-2456

Received 28 July 2003; received in revised form 11 October 2003; accepted 25 October 2003.

Abstract

HER-2 has been implicated in the oncogenesis of human prostate cancer (CaP) and is the target of a new treatment for metastatic breast cancer using the humanised monoclonal antibody (MAb) trastuzumab (Herceptin). In this study, a novel α-particle emitting [²¹³Bi]Herceptin construct, which targets the HER-2 extracellular domain on CaP cells, was prepared and evaluated in vitro. We used immunocytochemistry, flow cytometry and Western blot analysis to examine the expression of HER-2 in a panel of established human CaP cell lines, used the MTS assay to evaluate the cytotoxicity of ²¹³Bi-Herceptin on these cell lines and the TUNEL assay to document apoptosis. The results indicate that LNCaP-LN3 cells express high levels of HER-2 protein, in contrast, DU 145 cells express low to medium levels, and PC-3 cells express an undetectable level of HER-2 protein. ²¹³Bi-Herceptin was specifically cytotoxic to LNCaP-LN3 cells in a concentration-dependent fashion, cause the cells to undergo apoptosis, whereas DU 145 showed an HER-2 level-dependent response to ²¹³Bi-Herceptin cytotoxicity. In contrast, PC-3 cells were resistant to ²¹³Bi-Herceptin-induced cytotoxicity. The ²¹³Bi-Herceptin induced apoptosis in LNCaP-LN3 cells could be inhibited by incubation with unlabeled Herceptin. Our results suggest that ²¹³Bi-Herceptin α-conjugate might be a promising new agent for the treatment of preangiogenic cancer cell clusters or micro-metastases with high levels of HER-2 expression.

Keywords: Prostate cancer cell lines, Targeted α-therapy, α-Particle emitter ²¹³Bi, HER-2/neu, Herceptin