Co-immunotherapy with interleukin-2 and taurolidine for progressive metastatic melanoma

O’Brien, G. C.; Ra, Chisei; Bouchier‐Hayes, David; Redmond, H. P.

doi:10.1007/bf03168992

Cited by 23 publications

(16 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the use of IL-2 is restricted by its dose-dependent toxicity, which is mainly VLS. Some studies have been done to diminish IL-2 toxicity and maintain its effectiveness, such as coimmunotherapy with IL-2 and other factors, like taurokidine, temozolomide, GM-CSF, and IFN-␣ (7,8). Nonetheless, at present, there is no specific therapy against VLS.…”

Section: Ascular Leak Syndrome (Vls)mentioning

confidence: 99%

Blockade of Hyaluronan Inhibits IL-2-Induced Vascular Leak Syndrome and Maintains Effectiveness of IL-2 Treatment for Metastatic Melanoma

Guan

Nagarkatti

2007

The Journal of Immunology

View full text Add to dashboard Cite

Vascular leak syndrome (VLS) is a life-threatening toxicity induced during IL-2 treatment of cancer patients. The mechanism of IL-2-induced VLS is still poorly understood. At present, there is no specific therapy for VLS. Previous studies from our laboratory demonstrated that hyaluronan (HA), a large glycosaminoglycan, abundant in the extracellular matrix and on the cell surface, caused a marked increase of IL-2-induced VLS in the lungs and liver of C57BL/6 mice. Conversely, blockade or knockout of its major receptor, CD44, resulted in a marked decrease of VLS, thereby suggesting a role for HA in VLS. In this study, we report a novel means to prevent IL-2-induced VLS by blocking endogenous HA with HA-specific binding peptide, Pep-1, a newly isolated peptide which specifically binds to soluble, cell-associated, and immobilized forms of HA. Our results demonstrated that blocking HA with Pep-1 dramatically inhibited IL-2-induced VLS in both normal mice as well as in mice bearing melanoma. Moreover, Pep-1 treatment maintained the effectiveness of IL-2 and prevented the metastasis of melanoma. IL-2-induced emigration of lymphocytes across the endothelium and cytotoxicity against tumor by lymphokine-activated killer cells were not affected by Pep-1. Instead, use of Pep-1 maintained endothelial integrity and reduced their apoptosis during IL-2-induced VLS. These data suggested that HA plays a critical role in regulating endothelial cell damage and induction of IL-2-mediated VLS. Also, blockade of HA using Pep-1 could constitute a novel therapeutic modality to prevent IL-2-mediated toxicity, thereby facilitating the effectiveness of high-dose IL-2 in the treatment of metastatic melanomas.

show abstract

Section: Ascular Leak Syndrome (Vls)mentioning

confidence: 99%

Blockade of Hyaluronan Inhibits IL-2-Induced Vascular Leak Syndrome and Maintains Effectiveness of IL-2 Treatment for Metastatic Melanoma

Guan

Nagarkatti

2007

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Experimental studies have shown minimal toxicity or hematological adverse effects so far. The treatment of TRD has been shown to reduce tumor growth in various animal experiments [1,13,14] . Previous experimental data of our own demonstrated that intraperitoneal application of TRD in rats after establishment of an experimental tumor model did not result in any relevant side effects [7,15] .…”

Section: Discussionmentioning

confidence: 99%

Leukopoiesis Is Not Affected after Intravenous Treatment with the Novel Antineoplastic Agent Taurolidine

Braumann¹,

Menenakos²,

Atanassov³

et al. 2008

Eur Surg Res

View full text Add to dashboard Cite

Background/Aim: Chemotherapy can induce serious leukopenia. The aim of our study was to investigate the effects on leukopoiesis when the antineoplastic agent taurolidine (TRD) is administered by a bolus injection or during repetitive treatment (21 cycles) over 7 days in rats. Methods: Rats were intravenously treated with a single injection (A) or by a 7-day treatment (B) with increasing doses of TRD versus control (isotone sodium) in a standardized animal model. Hematological adverse effects on leukopoiesis were analyzed in peripheral blood. Results: (A) Neither the highest TRD concentration (3%) nor 1 or 2% caused a significant difference between the control and TRD groups (p > 0.085) in the perioperative course after bolus administration. (B) The administration of TRD 3% led to a slight change of granulocyte and monocyte counts compared to the control group particularly on postoperative day 7, but this difference was not significant. In both protocols a slight postoperative increase in leukocytes was observed. Conclusion: We report that TRD administered intravenously in an antitumor dose does not affect leukopoiesis in rats. Thus, the agent offers a promising and safe means in cancer treatment. The effects are currently investigated in incurable cancer patients.

show abstract

“…At present, the standard therapy comprises surgical resection with a wide margin of healthy tissue, typically accompanied by radiation treatment in order to reduce the chance of local recurrence (4,5). Unfortunately, distant metastasis occurs in ~50% of all patients, and surgical treatment is thus unavailable (6,7).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the safety and efficacy of TRAIL and taurolidine use on human fibrosarcoma xenografts in vivo

et al. 2016

View full text Add to dashboard Cite

Abstract. Fibrosarcomas are rare malignant soft tissue tumours that exhibit a poor response to current therapeutic regimens. Previously, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and taurolidine were observed to induce apoptosis synergistically in HT1080 human fibrosarcoma cells in vitro. Consequently, the present study aimed to assess the safety and efficacy of TRAIL in combination with taurolidine on the local growth of fibrosarcoma xenografts in vivo. HT1080 fibrosarcoma cells were inoculated subcutaneously into both flanks of 49 athymic nude mice in order to establish tumour xenografts. TRAIL and taurolidine were applied intraperitoneally at various single and cumulative treatment doses. After 12 days, the experiment was terminated and surviving animals were euthanised. Tumour progression was determined during and following treatment. To assess the potential toxic effects of the two compounds, the organs (lung, liver, kidney and heart) of all animals were examined histologically. The results revealed that combined treatment with TRAIL and taurolidine significantly inhibited the growth of HT1080 xenografts, whereas untreated animals had steadily increasing tumours. The most effective combination was TRAIL at 2 µg per application (cumulative dose, 16 µg) and taurolidine at 30/15 mg per application (cumulative dose, 180 mg), reducing the mean size of implanted xenografts to 10.9 mm 2 following treatment (vs. 48.9 mm 2 in the control group; P=0.0100). Despite distinct tumour mass reduction, the rate of mortality was significantly increased in animals treated with TRAIL and taurolidine in a taurolidine dose-dependent manner; however, histological examinations of relevant organs revealed no evidence of systemic toxicity (mean survival time, 7.9 days in the treated groups vs. 12 days in the control group; P<0.0010). In summary, whilst the combination of TRAIL and taurolidine synergistically inhibited the growth of fibrosarcoma xenografts in vivo, it was also accompanied by significantly increased mortality rate. Thus, although taurolidine is assumed to be a compound with an acceptable toxicity profile, and therefore increasingly used in clinical trials, the current findings raise concerns with regard to its safety and therapeutic index, and indicate the requirement for further detailed toxicity tests.

show abstract

Co-immunotherapy with interleukin-2 and taurolidine for progressive metastatic melanoma

Abstract: Co-administration of taurolidine with high-dose rIL-2 in stage IV melanoma patients appears to greatly enhance the tolerability of this regime without diminishing its therapeutic value.

Cited by 23 publications

References 21 publications

Blockade of Hyaluronan Inhibits IL-2-Induced Vascular Leak Syndrome and Maintains Effectiveness of IL-2 Treatment for Metastatic Melanoma

Blockade of Hyaluronan Inhibits IL-2-Induced Vascular Leak Syndrome and Maintains Effectiveness of IL-2 Treatment for Metastatic Melanoma

Leukopoiesis Is Not Affected after Intravenous Treatment with the Novel Antineoplastic Agent Taurolidine

Evaluation of the safety and efficacy of TRAIL and taurolidine use on human fibrosarcoma xenografts in vivo

Contact Info

Product

Resources

About