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

Abstract

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.

TNF-αPolymorphisms in Juvenile Idiopathic Arthritis: Which Potential Clinical Implications?

“…This data was not confirmed by other studies that reported a direct cytotoxic effect of TNF- α on tumoral cell [125], an indirect action on tumor vessels [126] and a synergic action with conventional antineoplastic agents [127, 128]. …”

Tumor Necrosis Factor: Renaissance as a Cancer Therapeutic?

“…In rat sarcoma ILP models, doxorubicin augmented rTNF-alpha activity, but less so than the augmentation observed with rTNF-alpha and melphalan [136,137]. Actinomycin D and rTNF-alpha were combined and found to have potent antitumor activity in a rat sarcoma ILP model; however severe toxicity including destruction of the regional muscle tissue and edema was observed [138]. A consistent theme of these studies was the idea that rTNF-alpha increased the exposure of the tumor cells to the chemotherapeutics by altering vascular permeability.…”

Tumor necrosis factor, cancer and anticancer therapy

“…Conversely, in several animal and human models of systemic [62] and/or locoregional cancer treatment the combination of TNF with conventional antineoplastic agents (e.g. melphalan, doxorubicin, paclitaxel, actinomycin-D, cisplatin) strikingly increases the tumor response rates [55][56][57][58][59]63]. The mechanism of this anticancer synergism has been the object of some hypotheses.…”

“…Despite the antitumor effects illustrated above, TNF alone is only marginally active in inducing tumor regression in some in vivo animal models (using both autologous and xenogeneic/human tumors) [55][56][57][58][59] and most importantly in humans, even when high doses are given through locoregional drug-delivery systems [2,60,61]. Conversely, in several animal and human models of systemic [62] and/or locoregional cancer treatment the combination of TNF with conventional antineoplastic agents (e.g.…”