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Departments of Cell Physiology [K. A., A. O., H. Y., S. O., H. N., S. Y.] and Pathology [M. N., M. I.], Atomic Disease Institute, Nagasaki University School of Medicine, and Department of Environmental Physiology, Institute of Tropical Medicine, Nagasaki University [T. M.], 1-12-4 Sakamoto, Nagasaki 852, Japan
A newly established metastatic rat pituitary tumor (mGH3) possesses a malignant phenotype that is invasive and hypervascular compared with the original GH3 tumors. mGH3 cells exhibit anchorage independence and expression of elevated levels of parathyroid hormone-related peptide (PTHrP) in vitro. To clarify the role of PTHrP in the development of the malignant phenotype, tumor cells were treated with phosphorothioate antisense PTHrP oligonucleotide. Treatment with antisense PTHrP resulted in a scattering phenomenon in the colony formation assay but did not inhibit cell growth in vitro. Inoculation of mGH3 cells in the cerebral ventricle resulted in a rapid growth of tumor cells within 3 weeks and dissemination throughout the entire ventricular system. Although treatment with sense or mismatched PTHrP oligonucleotide did not influence the subsequent tumor growth, the in vivo coinjection and injection of antisense PTHrP 1 week after tumor cell implantation into the right lateral ventricle markedly reduced tumor size and suppressed metastasis formation. The survival rate of mGH3 tumor-injected rats was prolonged by antisense PTHrP therapy. Our results demonstrated the biological involvement of PTHrP in malignant phenotype in rat pituitary tumors, suggesting that antisense PTHrP may provide a novel antimetastatic therapy for malignant somatotroph tumors.
1 This work was supported in part by research grants from the Nagasaki Medical Association Fund and Grants-in-Aid for General Scientific Research from the Japanese Ministry of Education, Science, and Culture (06807051, 06670729, and 06671463). The rats used for this study were maintained by Dr. H. Satoh and N. Kubo, with the approval of animal experimenters, in the laboratory of the Animal Center for Biomedical Research, Nagasaki University School of Medicine.
2 To whom requests for reprints should be addressed. Phone: 81-958-49-7116; Fax: 81-958-49-7117.
Received 8/ 4/95. Accepted 10/26/95.
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