ANTISENSE INHIBITION OF PARATHYROID HORMONE-RELATED PEPTIDE GENE-EXPRESSION REDUCES MALIGNANT PITUITARY-TUMOR PROGRESSION AND METASTASES INTHE RAT

A newly established metastatic rat pituitary tumor (mGH3) possesses a malignant phenotype that is invasive and hypervascular compared with t he 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 th e malignant phenotype, tumor cells were treated with phosphorothioate antisense PTHrP oligonucleotide. Treatment with antisense PTHrP result ed in a scattering phenomenon in the colony formation assay but did no t inhibit cell growth in vitro. Inoculation of mGH3 cells in the cereb ral 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 influ ence the subsequent tumor growth, the in vivo coinjection and injectio n of antisense PTHrP 1 week after tumor cell implantation into the rig ht lateral ventricle markedly reduced tumor size and suppressed metast asis formation. The survival rate of mGH3 tumor-injected rats was prol onged by antisense PTHrP therapy. Our results demonstrated the biologi cal involvement of PTHrP in malignant phenotype in rat pituitary tumor s, suggesting that antisense PTHrP may provide a novel antimetastatic therapy for malignant somatotroph tumors.