Effects of increasing doses of a bolus injection and an intravenous long-term therapy of taurolidine on subcutaneous (metastatic) tumor growth in rats.
BACKGROUND
Experimental studies have shown that taurolidine suppresses intraperitoneal tumor growth following local application in rats. In opposite, a single intravenous therapy affected neither intraperitoneal nor subcutaneous growth of malignancies. Thus, an intravenous long-term therapy with taurolidine was investigated in rats after administration of a subcutaneous tumor load. VEGF and TNFalpha production and their effects on tumor growth have not been elucidated so far.


METHODS
VEGF and TNFalpha levels of rat colon adenocarcinoma cells (DHD/K12/TRb) were analyzed in the supernatant undergoing treatment of increasing taurolidine doses in vitro. Besides the cell experiments rats were treated intravenously. At the beginning of the operation, 10 000 colon adenocarcinoma cells were applied subcutaneously at the back of the rats. Then the animals (n = 80, BD IX rats) were randomized into eight groups and underwent a standardized midline laparotomy for 30 min. At the end of the operation the animals were given either a bolus (1 ml Ringer's solution) or a long-term intravenous therapy (7 days, eight-hourly 1 ml 1%, 2%, or 3% taurolidine) were performed. For long-term therapy, a jugularis vein port catheter system was placed and left for 1 week. The influence on subcutaneous tumor growth, animal growth, general side effects and leukocyte/granulocyte levels were analyzed. Total tumor weights were determined 4 weeks after cell application.


RESULTS
The VEGF and TNFalpha levels decreased rapidly after taurolidine therapy with low doses in vitro. The subcutaneous tumor growth showed a downtrend of tumor weight (P = 0.075) with a statistical significance in solid tumor counts (P = 0.04) at the back of the animals. A slight and temporary depression in animal growth was observed only in long-term therapy groups. Independent of the therapeutic agents and the application forms, the operation itself caused a slight leukopenia shortly after the operation compensated by a moderate leukocytosis in the following course. Fast injections of taurolidine led to a reduction of breathing rate.


CONCLUSIONS
Only the intravenous long-term therapy of 3% taurolidine led to a slight downregulation in subcutaneous tumor growth. The changes of leukocyte counts were not affected by taurolidine. Fast injections have to be avoided. The findings prompted us to start new experiments to determine the influence of increasing doses of taurolidine on progressive tumor growth in rats.
Braumann
Chris
C
Department of General, Visceral, Vascular and Thoracic Surgery, Medical Faculty Charité, Humboldt University, Schumannstrasse 20/21, Berlin, Germany. chris.braumann@charite.de
Schoenbeck
Marco
M
Menenakos
Charalambos
C
Kilian
Maik
M
Jacobi
Christoph A
CA
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D007275:Injections, Intravenous; D007958:Leukocyte Count; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D051381:Rats; D013654:Taurine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013829:Thiadiazines / Q000008:administration & dosage* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000970:Antineoplastic Agents; D013829:Thiadiazines; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D013654:Taurine; C012566:taurolidine