Taurolidine: preclinical evaluation of a novel, highly selective, agent for bone marrow purging.
Taurolidine has been shown to have remarkable cytotoxic activity against selected human tumor cells at concentrations that spare normal cells. In this study we have extended this observation and assessed the ability of Taurolidine to purge tumor cells from chimeric mixtures of bone marrow (BM) and neoplastic cells. Normal murine BM and human leukemic (HL-60) or ovarian (PA-1) tumor cell lines were used as models. Exposure of tumor cells to 2.5 mM Taurolidine for 1 h resulted in the complete elimination of viable cells. In contrast, exposure of BM to 5 mMTaurolidine for 1 h reduced CFU-GM, BFU-E and CFU-GEEM colony formation by only 23.0%, 19.6% and 25.2%, respectively. Inhibition of long-term BM culture (LTBMC) growth following a 1 h exposure to 5 mM Taurolidine also was approximately 20% compared to untreated LTBMC. Finally, chimeric cultures were generated from BM and HL-60GR or PA-1GR cells (tumor cells transfected with the geneticin resistance gene). Exposure of these chimeric cultures to 5 mM Taurolidine for 1 h totally eliminated viable cancer cells while minimally reducing viable BM cells. This finding was confirmed by subsequent positive selection for surviving tumor cells with geneticin. These findings reveal that Taurolidine holds promise for use in BM purging.
Ribizzi
I
I
Department of Medicine, Division of Clinical Pharmacology, Brown University and RI Hospital, Providence, RI, USA.
Darnowski
J W
JW
Goulette
F A
FA
Akhtar
M S
MS
Chatterjee
D
D
Calabresi
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016465:Bone Marrow Purging / Q000379:methods*; D016026:Bone Marrow Transplantation; D002678:Chimera; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005839:Gentamicins / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D013654:Taurine / Q000031:analogs & derivatives / Q000494:pharmacology*; D013829:Thiadiazines / Q000494:pharmacology*; D014182:Transplantation, Autologous; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D005839:Gentamicins; D013829:Thiadiazines; D013654:Taurine; C012566:taurolidine; C010680:antibiotic G 418