Synergistic antitumour effect of recombinant human tumour necrosis factor a with melphalan in isolated limb perfusion in the rat

Manusama, Eric R.; Nooijen, Peet; Stavast, Jeroen; Durante, N. M. C.; Marquet, R. L.; Eggermont, Alexander M.M.

doi:10.1002/bjs.1800830438

Cited by 84 publications

(75 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Perfusions with 40 mg melphalan and 50 mg TNF resulted also in major tumour shrinkage. A significant difference was observed as compared to sham perfusions, TNF perfusions alone and melphalan perfusions alone (P50.05) ( Figure 2B response rate of 70% (data not shown), conform our experience as published in various extensive series of ILP with melphalan and TNF (Manusama et al, 1996;de Wilt et al, 1999).…”

Section: In Vivo Tumour Response To Actinomycin D and Tnf After Ilpsupporting

confidence: 83%

Isolated limb perfusion with actinomycin D and TNF-alpha results in improved tumour response in soft-tissue sarcoma-bearing rats but is accompanied by severe local toxicity

et al. 2002

Self Cite

View full text Add to dashboard Cite

Previously we demonstrated that addition of Tumour Necrosis Factor-a to melphalan or doxorubicin in a so-called isolated limb perfusion results in synergistic antitumour responses of sarcomas in both animal models and patients. Yet, 20 to 30% of the treated tumours do not respond. Therefore agents that synergise with tumour necrosis factor alpha must be investigated. Actinomycin D is used in combination with melphalan in isolated limb perfusion in the treatment of patients with melanoma in-transit metastases and is well known to augment tumour cell sensitivity towards tumour necrosis factor alpha in vitro. Both agents are very toxic, which limits their systemic use. Their applicability may therefore be tested in the isolated limb perfusion setting, by which the tumours can be exposed to high concentrations in the absence of systemic exposure. To study the beneficial effect of the combination in vivo, BN-175 soft tissue sarcoma-bearing rats were perfused with various concentrations of actinomycin D and tumour necrosis factor alpha. When used alone the drugs had only little effect on the tumour. Only when actinomycin D and tumour necrosis factor alpha were combined a tumour response was achieved. However, these responses were accompanied by severe, dose limiting, local toxicity such as destruction of the muscle tissue and massive oedema. Our results show that isolated limb perfusion with actinomycin D in combination with tumour necrosis factor alpha leads to a synergistic anti-tumour response but also to idiosyncratic locoregional toxicity to the normal tissues. Actinomycin D, in combination with tumour necrosis factor alpha, should not be explored in the clinical setting because of this. The standard approach in the clinic remains isolated limb perfusion with tumour necrosis factor alpha in combination with melphalan.

show abstract

Section: In Vivo Tumour Response To Actinomycin D and Tnf After Ilpsupporting

confidence: 83%

Isolated limb perfusion with actinomycin D and TNF-alpha results in improved tumour response in soft-tissue sarcoma-bearing rats but is accompanied by severe local toxicity

et al. 2002

Self Cite

View full text Add to dashboard Cite

show abstract

“…Therefore, a tumour model with a highly aggressive non-immunogenic soft tissue sarcoma in BN rats was developed in our laboratory to address these questions (Manusama et al, 1996). Response after ILP with melphalan and TNF in this model correspond well to what is observed in sarcoma patients in terms of synergy between TNF and melphalan, response rate, and histopathological observations (Manusama et al, 1996;Nooijen et al, 1996a). This rat model could therefore serve as a credible model to study mechanisms and determine ways to optimize ILP efficacy for the clinical setting.…”

mentioning

confidence: 72%

Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats

et al. 1999

Self Cite

View full text Add to dashboard Cite

MelphalanMelphalan (Alkeran, 50 mg per vial, Wellcome, Beckenham, UK) was diluted in 10 ml solvent. Further dilutions were made in 0.9% sodium chloride to give a concentration of 1 µg µl -1 . A volume of 40 µl (= 40 µg) was added to the perfusion circuit.Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats Summary An isolated limb perfusion (ILP) model using soft tissue sarcoma-bearing rats was used to study prerequisites for an effective ILP, such as oxygenation of the perfusate, temperature of the limb, duration of the perfusion and concentration of tumour necrosis factor (TNF). Combination of 50 µg TNF and 40 µg melphalan demonstrated synergistic activity leading to a partial and complete response rate of 71%. In comparison to oxygenated ILP, hypoxia was shown to enhance anti-tumour activity of melphalan alone and TNF alone but not of their combined use. Shorter perfusion times decreased anti-tumour responses. At a temperature of 24-26°C, anti-tumour effects were lost, whereas temperatures of 38-39°C or 42-43°C resulted in higher response rates. However, at 42-43°C, local toxicity impaired limb function dramatically. Synergy between TNF and melphalan was lost at a dose of TNF below 10 µg in 5 ml perfusate. We conclude that the combination of TNF and melphalan has strong synergistic anti-tumour effects in our model, just as in the clinical setting. Hypoxia enhanced activity of melphalan and TNF alone but not the efficacy of their combined use. For an optimal ILP, minimal perfusion time of 30 min and minimal temperature of 38°C was mandatory. Moreover, the dose of TNF could be lowered to 10 µg per 5 ml perfusate, which might allow the use of TNF in less leakage-free or less inert perfusion settings.

show abstract

“…Several laboratories have recently reported, however, promising data utilizing TNF in limb perfusion studies which limit systemic exposure. 22,[26][27][28][29][30][31][32][33] Consequently, coupling TNF expression to a replicationselective Ad should limit its expression to the infected tumor, reducing systemic toxicity and increasing its therapeutic effectiveness alone or in combination therapies.…”

Section: Figure 1 Diagram Of Ad5 E3 Region Depicting Transgene Insertmentioning

confidence: 99%

Gene delivery from the E3 region of replicating human adenovirus: evaluation of the E3B region

Hawkins

Hermiston²

2001

Gene Ther

View full text Add to dashboard Cite

Synergistic antitumour effect of recombinant human tumour necrosis factor a with melphalan in isolated limb perfusion in the rat

Cited by 84 publications

References 22 publications

Isolated limb perfusion with actinomycin D and TNF-alpha results in improved tumour response in soft-tissue sarcoma-bearing rats but is accompanied by severe local toxicity

Isolated limb perfusion with actinomycin D and TNF-alpha results in improved tumour response in soft-tissue sarcoma-bearing rats but is accompanied by severe local toxicity

Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats

Gene delivery from the E3 region of replicating human adenovirus: evaluation of the E3B region

Contact Info

Product

Resources

About