The effects of taurolidine, a novel antineoplastic agent, on human malignant mesothelioma.
OBJECTIVE
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.


METHODS
Cell growth inhibition and viability assays were performed on REN, LRK, and H28 cell lines after 24-72-h exposure to 0-200 microm 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 microm taurolidine. Athymic mice were given i.p. injections of 20 x 10(6) 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 microm and 50% viability at 49.8-135 microm. Annexin V assay for apoptosis revealed significant increases in annexin binding after 24-72-h exposure to 50-150 microm taurolidine (P <0.05), which was significantly inhibited by z-VAD (P <0.05). MM cells exposed to 50-150 microm 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.
Nici
Linda
L
Department of Medicine, Rhode Island Hospital and Brown University, Providence, Rhode Island 02908, USA. Linda_Nici@brown.edu
Monfils
Barbara
B
Calabresi
Paul
P
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001835:Body Weight; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008854:Microscopy, Electron; D010718:Phosphatidylserines / Q000737:chemistry; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013829:Thiadiazines / Q000494:pharmacology*; D013997:Time Factors
D000590:Amino Acid Chloromethyl Ketones; D017304:Annexin A5; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010718:Phosphatidylserines; D013829:Thiadiazines; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D013654:Taurine; C012566:taurolidine; D020169:Caspases