Isolated limb perfusion with TNFα and melphalan in a rat osteosarcoma model: a new anti-tumour approach

Manusama, Eric R.; Stavast, Jeroen; Durante, Nicola M.C.; Marquet, R. L.; Eggermont, Alexander M.M.

doi:10.1016/s0748-7983(96)90671-x

Cited by 50 publications

(24 citation statements)

References 20 publications

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“…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

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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

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“…Isolated perfusion with tumour necrosis factor-α in combination with ischaemia (Manusama et al, 1994) or with melphalan (Manusama et al, 1996a(Manusama et al, , 1996b has been reported to result in complete tumour regression in preclinical tumour models. Isolated limb perfusion in patients with in-transit melanoma with TNF-α in combination with melphalan and γ-interferon resulted in high complete remission rates (LiŽnard et al, 1992(LiŽnard et al, , 1994.…”

Section: Discussionmentioning

confidence: 99%

In vivo isolated kidney perfusion with tumour necrosis factor α (TNF-α) in tumour-bearing rats

et al. 1999

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Summary Isolated perfusion of the extremities with high-dose tumour necrosis factor α (TNF-α) plus melphalan leads to dramatic tumour response in patients with irresectable soft tissue sarcoma or multiple melanoma in transit metastases. We developed in vivo isolated organ perfusion models to determine whether similar tumour responses in solid organ tumours can be obtained with this regimen. Here, we describe the technique of isolated kidney perfusion. We studied the feasibility of a perfusion with TNF-α and assessed its anti-tumour effects in tumour models differing in tumour vasculature. The maximal tolerated dose (MTD) proved to be only 1 µg TNF-α. Higher doses appeared to induce renal failure and a secondary cytokine release with fatal respiratory and septic shock-like symptoms. In vitro, the combination of TNF-α and melphalan did not result in a synergistic growth-inhibiting effect on CC 531 colon adenocarcinoma cells, whereas an additive effect was observed on osteosarcoma ROS-1 cells. In vivo isolated kidney perfusion, with TNF-α alone or in combination with melphalan, did not result in a significant anti-tumour response in either tumour model in a subrenal capsule assay. We conclude that, because of the susceptibility of the kidney to perfusion with TNF-α, the minimal threshold concentration of TNF-α to exert its anti-tumour effects was not reached. The applicability of TNF-α in isolated kidney perfusion for human tumours seems, therefore, questionable.Keywords: tumour necrosis factor α; isolated kidney perfusion; rats 433British Journal of Cancer (1999) 79(3/4), 433-439 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received Tumour necrosis factor αRecombinant human TNF-α (rhTNF-α) was kindly provided by Boehringer Ingelheim, Ingelheim, Rhein, Germany. rhTNF-α had a specific activity of 5.8 × 10 7 U mg Ð1 as determined in the murine LÐM cell assay (Kramer and Carver, 1986). Endotoxin levels were less than 1.25 endotoxin U mg Ð1 protein. TNF-α was delivered in 0.5-ml vials in a concentration of 2.4 mg ml Ð1 . MelphalanMelphalan (Alkeran, 50 mg per vial, Wellcome, Beckenham, UK) was diluted in 10 ml of diluent solvent. Further dilutions were made in 0.9% sodium chloride to give a volume of 0.5 ml in the perfusion circuit. Unilateral nephrectomyIt is probable that when two kidneys are perfused in vivo, kidney function as measured by blood urea nitrogen (BUN), creatinine and electrolytes remains stable after isolation and perfusion of one kidney. To analyse to what extent renal function is compromised by unilateral nephrectomy, five rats underwent a unilateral nephrectomy and at regular intervals BUN, creatinine and electrolytes were recorded. The right kidney was chosen for anatomic reasons. The left kidney shows compensatory hypertrophy: the size of the kidney is larger, there is a gain in cell volume and diameter of the glomerulus as well as a larger volume of the tubule (Fine, 1986).Operative procedures were carried out under clean conditions. Anaesthesia was induced with ether (diethylether p....

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“…6,7,9 In our laboratory, Manusama et al 7 modified the technique of ILP in rats, originally described by Benckhuijsen et al 10 In this model, by using the BN-175 soft tissue sarcoma, it was shown that only when TNF was combined with melphalan or doxorubicin could a tumor response be reached. In comparison to the clinical setting, our rat model demonstrated partial or complete regression of the tumor in approximately 75% of rats receiving an ILP with melphalan plus TNF.…”

Section: Ilp Modelmentioning

confidence: 99%

Improved antitumor response to isolated limb perfusion with tumor necrosis factor after upregulation of endothelial monocyte-activating polypeptide II in soft tissue sarcoma

Lans

Hagen

Horssen

et al. 2002

Annals of Surgical Oncology

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Background: Experiments with tumor necrosis factor ␣ (TNF) in rodents have shown that a high dose can lead to hemorrhagic necrosis in tumors. Endothelial monocyte-activating polypeptide II (EMAP-II) is a novel tumor-derived cytokine, and its expression increases the TNF-1 receptor on tumor endothelium, enhances the induction of tissue factor on tumor endothelial cells, and has an antiangiogenic effect. It has recently been shown that in vivo sensitivity of tumor vasculature to TNF is determined by tumor production of EMAP-II. Methods:We measured the level of EMAP-II in a TNF-resistant soft tissue sarcoma. We subsequently stabile-transfected this cell line with a retroviral construct containing the EMAP gene.In an extremity perfusion model in tumor-bearing rats, we measured response rates to TNF therapy.Results: Functional EMAP-II production was increased after this transfection. Immunostaining of paraffin-embedded tumor tissue sections in rats showed an overexpression of human EMAP-II. Results of the TNF perfusions in rats suggest that this tumor is more sensitive to TNF therapy.Conclusions: EMAP-II is produced in various levels. One can increase the sensitivity of tumor for TNF therapy in vivo by upregulating the EMAP-II production. This result leaves an opportunity for enhanced TNF response of tumors in future settings.

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Isolated limb perfusion with TNFα and melphalan in a rat osteosarcoma model: a new anti-tumour approach

Cited by 50 publications

References 20 publications

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

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

In vivo isolated kidney perfusion with tumour necrosis factor α (TNF-α) in tumour-bearing rats

Improved antitumor response to isolated limb perfusion with tumor necrosis factor after upregulation of endothelial monocyte-activating polypeptide II in soft tissue sarcoma

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