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High Doses of Taurolidine Inhibit Advanced Intraperitoneal Tumor Growth in Rats

https://doi.org/10.1016/j.jss.2005.03.012Get rights and content

Background

The antitumor agent taurolidine (TRD) affects tumor growth in animals. Thus far, no animal studies have been published concerning the systemic or local toxicity and the effectiveness of long-term intraperitoneal (i.p.) and intravenous (i.v.) administration on advanced tumor growths.

Materials and methods

In a first experiment (A) the systemic toxicity of the liver and kidneys was examined only after i.v. treatment in 40 rats (BD IX). For local toxicity the superior vena cava (SVC) was histologically analyzed.

In a second study (B) 20,000 colon adenocarcinoma cells (DHD/K12/TRb) were initially applied i.p. after laparotomy in 80 rats (BD IX). After 28 days a port catheter system was placed in the SVC and left for 1 week. The animals were randomized into eight groups (n = 10) and received a 7-day treatment (eight hourly, 1 ml): 1, 2, 3% TRD or Ringer’s solution (control group) either i.p. or i.v. Total i.p. tumor weight was measured 4 weeks after the end of the therapy. Side effects on differential blood counts and animal weight changes were examined.

Results

No organ lesions were detected in liver, kidneys, and SVC in experiment A. The i.v. administration of 2% TRD (P = 0.034) and 3% TRD (P = 0.05) as well the i.p. application of 2% TRD (P = 0.05) decreased the development of advanced i.p. tumor lesions. No changes of differential blood count nor relevant animal weight changes resulted. Three port catheter-related infections were examined.

Conclusions

TRD does not impair the liver tissue, kidneys, SVC, and leucopoiesis. The intravenous therapy of 2% TRD is safe and anti-tumorigenic in advanced local tumor growth in rats.

Introduction

Different anti-tumorigenic substances have been examined and analyzed over the last few years in animal experiments. The side effects of the chemotherapeutic agents used can be a major problem in antineoplastic therapy. Taurolidine (TRD), a synthetic product derived from the aminosulfone acid taurine, consists of two aromatic rings, which are connected with a CH2-group [1]. The substance was found to suppress the growth of various abdominal tumor cell lines [2], malignant glioma [3], and human squamous cell carcinoma in vitro and in vivo [4].

It has been shown that the tumor necrosis factor α (TNFα) production and the vascular endothelial growth factor level (VEGF) could also be reduced in colonic tumor cells (DHD/K12/TRb) [5]. Although the underlying antitumor mechanisms have not been explained exactly, TRD significantly inhibited intraperitoneal tumor growth in early stages of the disease in rats [6, 7, 8, 9], reduced pancreatic cancer progression in hamsters [10, 11], and effectively inhibited subcutaneous xenograft tumor growth in mice [12]. Other studies confirmed that cytotoxic effects were not observed in physiological cells after single administration such as human fibroblasts [2].

Local therapy of TRD has been shown to reduce intraperitoneal tumor growth without side effects in animals [2, 6]. Other animal studies performed by our working group investigated the effects of a single intravenous injection of TRD (0.5%) on tumor growth in laparoscopy or laparotomy [8, 9]. It seems that only a direct contact of the substance with the tumor cells can inhibit tumor growth when low doses are used. Although TRD was found to induce apoptosis [6], the used intravenous low-dose TRD injections did not inhibit neither intraperitoneal nor subcutaneous tumor growth. In the current study our aim was to investigate the role of TRD on established tumor loads.

Reflecting these remarkable anti-tumorigenic and specific effects, we hypothesized that TRD could be used as an interesting long-term therapy agent in advanced tumor stages or even metastases. In a first study (experiment A) the antitumor potential of increasing intravenously and intraperitoneally administered doses were evaluated. The possible toxic effects on the liver, the kidneys, and the superior vena cava (SVC) were histologically examined, scored, and presented. A second study (experiment B) analyzed the effects on intraperitoneal tumor growth in progressive tumor stages after a long-term intravenous and intraperitoneal therapy in rats. To investigate side effects, body weight changes and peripheral blood were taken to analyze the differential blood counts.

Section snippets

Experiment A

This study was investigated to evaluate the organ toxicity of increasing taurolidine doses. The therapy agents were prepared as recommended by the manufacturer as described in experiment B.

Experiment A

No animal died during this toxicity study.

Experiment B

No animal died during the different long-term therapy strategies.

Discussion

Taurolidine was found to exert antibiotic and anti-tumorigenic effects on different prokaryotic and eukaryotic cells [1]. It suppresses tumor growth in many cell lines [2, 4, 10, 12, 15] and reduces the TNFα production in mesangial rat cell cultures [16] and by malignant colonic tumor cells with an IC50 value of 0.5 mm. Additionally, the major pro-angiogenetic factor VEGF production was also reduced within a 6-h contact (IC50 1.5 mm) [5]. Many data showed a selective influence on various tumor

Acknowledgments

We thank Professor Dr. J. M. Mueller, the Director of the Department of Surgery, and Professor Dr. W. Dubiel, the Chief of the Division of Molecular Biology, for continuous support.[18, 19]

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