Antitumor activity of a novel glyco-nitric oxide conjugate in ovarian carcinoma

BACKGROUND. Several studies have shown that nitric oxide (NO)-releasing age nts can kill tumor cells. Unfortunately, currently available NO delivery mo lecules do not target tumor cells preferentially. To exploit the overexpres sion of glucose transport proteins and the high level of glucose transport characteristics of tumor cells, glucose was conjugated to S-nitroso-N-acety l-penicillamine (2-gluSNAP) and evaluated for cytotoxicity in human ovarian carcinoma cells. METHODS The cytotoxicity of 2-gluSNAP and SNAP was assessed by clonogenic c ell survival assays performed in A2780S (cisplatin sensitive) and A2780cP ( cisplatin-resistant) ovarian carcinoma cells in vitro. Immunoblotting and i mmunohistochemistry were used to assess the expression of Glut-1 hexose tra nsport protein in the cell lines as well as in paraffin blocks from 28 surg ical specimens of epithelial ovarian carcinoma. Apoptosis was assessed by a n end-labeling assay. RESULTS. The ovarian carcinoma cell lines consistently were more sensitive to 2-gluSNAP than SNAP alone. The median effective doses (MEDs) for 2-gluSN AP and SNAP in the A2780s cell line were 0.0042 mu M and 20.4 mu M, respect ively. Therefore, 2-GluSNAP was nearly 5000-fold more potent than the NO-do nating moiety (SNAP) alone. In the A2780cP cells, the MED for 2-gluSNAP (0. 38 mu M) was 250-fold lower than that for SNAP alone (100 mu M) Immunoblott ing and immunohistochemistry studies showed overexpression of Glut-1 in the cell lines and in 23 of 28 epithelial ovarian carcinoma specimens. CONCLUSIONS. The novel glyco-NO conjugate 2-gluSNAP exhibits a much greater cytotoxicity than the parent NO donor without the hexose moiety. These age nts have the potential to target tumor cells preferentially, that overexpre ss Glut-1. This transporter is expressed highly in epithelial ovarian carci noma. (C) 2000 American Cancer Society.