Linda Nici, Barbara Monfils and Paul Calabresi

Department of Medicine, Rhode Island Hospital and Brown University, Providence, Rhode Island

Abstract

Purpose: Malignant mesothelioma (MM) is a cancer with uniformly poor responses to current therapeutic regimens. This study evaluates whether taurolidine, a novel antineoplastic agent, is effective against human MM cell lines and a murine model of human MM.

Experimental Design: Cell growth inhibition and viability assays were performed on REN, LRK, and H28 cell lines after 24–72-h exposure to 0–200 µM taurolidine. Cell cycle analysis with annexin-V binding, terminal deoxynucleotidyl transferase-mediated nick end labeling assay, electron microscopy, and response to the general caspase inhibitor z-VAD-fmk were performed on MM cell lines after 24–72-h exposure to 50–150 µM taurolidine. Athymic mice were given i.p. injections of 20 x 106 REN cells, followed by i.p. taurolidine (17.5 or 20 mg), 3 days/week for up to 3 weeks. Tumors were assessed at day 30. All statistical tests were two-sided.

Results: A 72-h exposure of MM cells to taurolidine showed IC50 of 28–42.7 µM and 50% viability at 49.8–135 µM. Annexin V assay for apoptosis revealed significant increases in annexin binding after 24–72-h exposure to 50–150 µM taurolidine (P < 0.05), which was significantly inhibited by z-VAD (P < 0.05). MM cells exposed to 50–150 µM taurolidine for 24–72 h showed terminal deoxynucleotidyl transferase-mediated nick end labeling staining consistent with apoptosis, as well as structural evidence of apoptosis via electron microscopy. In vivo, there were significant tumor reductions (62 to >99% reduction) for all dosage regimens compared with untreated controls (P < 0.001). In addition, all control animals exhibited ascites and diaphragmatic tumors while treated animals did not.

Conclusions: Taurolidine has significant antineoplastic activity against MM in vitro and in vivo, in part, due to tumor cell apoptosis. These findings warrant further study for potential clinical usefulness.