oxytocin and Glioblastoma

Oxytocin receptors (OTR) have been described in a number of tumours of different origin, and represent a new target for specific radiolabelled oxytocin (OT) analogues in cancer diagnosis and therapy. By linking the DOTA chelating agent to position 8 of the deamino derivative of Lys(8)-vasotocin (dLVT), we obtained a new compound (DOTA-dLVT) with the following characteristics: (1) it forms a monomeric and stable compound that binds to OTR with an affinity comparable to that of the endogenous OT ligand; (2) it is characterised by a very good selectivity profile for the human OTR, with a low affinity binding to the closely related V1a, V1b and V2 vasopressin receptor subtypes; (3) it induces rapid and persistent receptor internalisation and (4) when radiolabelled, [(111)In]-DOTA-dLVT is efficiently and selectively taken up by OTR-positive tumours grown in mice. These features makes radiolabelled DOTA-dLVT a very good candidate for the radiotargeting of OTR-expressing tumours.

Topics: Animals; Breast Neoplasms; Carcinoma; Chelating Agents; COS Cells; Glioblastoma; Heterocyclic Compounds, 1-Ring; Humans; Indium Radioisotopes; Isotope Labeling; Mice; Neoplasms; Oxytocin; Protein Binding; Radioactive Tracers; Radioligand Assay; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Oxytocin; Sensitivity and Specificity; Stomach Neoplasms; Tissue Distribution; Transfection; Tumor Cells, Cultured; Vasotocin

To determine whether oxytocin (OT) could be added to the list of growth factors acting on neoplastic cells of nervous origin, we investigated the presence of oxytocin receptors (OTR) in human primary neuroblastomas and glioblastomas and related cell lines. OTR were demonstrated both at mRNA level (using a RT-PCR procedure) and at protein level (using immunocytochemical and immunofluorescence procedures). In order to clarify whether OT exerts any biological effect on these tumors through OTR, we also studied cell proliferation in 3 human neuroblastoma cell lines (SK-N-SH, SH-SY5Y, IMR-32) and one human anaplastic astrocytoma cell line (MOG-G-UVW) treated with OT 1 nM to 100 nM for 48 and 96 hr. At these doses, a dose-dependent inhibitory effect on cell proliferation was demonstrated. This inhibition was accompanied by a significant increase in the intracellular concentration of cAMP, which we have reported to be the intracellular mediator of the OT anti-proliferative effect in breast-carcinoma cell lines. Our data indicate that specific OTR are present in human neuroblastomas and glioblastomas. Through these receptors, OT could inhibit cell proliferation and modulate tumor growth.

Topics: Brain Neoplasms; Cell Division; Cell Line; Cyclic AMP; Fluorescent Antibody Technique; Glioblastoma; Humans; Immunohistochemistry; Neuroblastoma; Oxytocin; Polymerase Chain Reaction; Receptors, Oxytocin; RNA, Messenger; Transcription, Genetic; Tumor Cells, Cultured