The Effects of Taurolidine, a Novel Antineoplastic Agent, on Human Malignant Mesothelioma
Monday, November 15th, 2004.
Clinical Cancer Research Vol. 10, 7655-7661, November 15, 2004 [Link]
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.
Glossary
- cell
- the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.
- cancer
- malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.
- tumor
- an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).
- mesothelioma
- a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.
- apoptosis
- a type of cell death in which the cell basically commits suicide; scientists believe some types of cancer may originate from an interruption of this programmed cell death, allowing cells to grow out of control.
- ascites
- (uh-sigh-tees) excess fluid accumulation in the abdominal (peritoneal) cavity.
