Therapeutic potential of antisense oligodeoxynucleotides to down-regulate thymidylate synthase in mesothelioma

Molecular Cancer Therapeutics. 2006 Jun;5(6):1423-33. [Link]

Janet Flynn¹, Randal W. Berg^1,2,3, Tracy Wong^1,4, Marijke van Aken⁷, Mark D. Vincent^1,3, Masakazu Fukushima⁸ and James Koropatnick^1,2,3,4,5,6

¹ London Regional Cancer Program and ² Lawson Health Research Institute, London Health Sciences Centre; ³ Departments of Oncology, ⁴ Physiology and Pharmacology, ⁵ Microbiology and Immunology, and ⁶ Pathology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada; ⁷ Faculty of Medicine, Utrecht University, the Netherlands; and ⁸ Hanno Research Centre, Taiho Pharmaceuticals, Hanno-City, Japan

Requests for reprints: James Koropatnick, Victoria Research Laboratories, London Regional Cancer Program, London Health Sciences Centre, 790 Commissioners Road East, London, Ontario, Canada N6A 4L6. Phone: 519-685-8500, ext. 58654; Fax: 519-685-8681. E-mail: jkoropat@uwo.ca

Abstract

Malignant mesothelioma is an aggressive tumor of the serosal surfaces of the lungs, heart, and abdomen. Survival rates are poor and effective treatments are not available. However, recent therapeutic regimens targeting thymidylate synthase (TS) in malignant mesothelioma patients have shown promise. We have reported the use of an antisense oligodeoxynucleotide targeting TS mRNA (antisense TS ODN 83) to inhibit growth of human tumor cells. To test the potential for antisense targeting of TS mRNA in treatment of malignant mesothelioma, we assessed and compared the effects of antisense TS ODN 83 on three human malignant mesothelioma cell lines (211H, H2052, and H28) and human nonmalignant mesothelioma cells (HT29 colorectal adenocarcinoma, HeLa cervical carcinoma, and MCF7 breast tumor cell lines). We report that ODN 83 applied as a single agent effectively reduced TS mRNA and protein in malignant mesothelioma cell lines. Furthermore, it inhibited malignant mesothelioma growth significantly more effectively than it inhibited growth of nonmalignant mesothelioma human tumor cell lines: a difference in susceptibility was not observed in response to treatment with TS protein-targeting drugs. In malignant mesothelioma cells, antisense TS both induced apoptotic cell death and reduced proliferation. In nonmalignant mesothelioma cells, only reduced proliferation was observed. Thus, antisense TS-mediated induction of apoptosis may be the basis for the high malignant mesothelioma sensitivity to antisense targeting of TS. Further preclinical and clinical study of TS antisense oligodeoxynucleotides, alone and in combination with TS-targeting chemotherapy drugs, in mesothelioma is warranted.