Rationale for using TNFα and chemotherapy in regional therapy of melanoma

✍ Scribed by F. Lejeune; D. Liénard; A. Eggermont; H. Schraffordt Koops; F. Rosenkaimer; J. Gérain; J. Klaase; B. Kroon; J. Vanderveken; P. Schmitz

• Publisher: John Wiley and Sons
• Year: 1994
• Tongue: English
• Weight: 950 KB
• Volume: 56
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.240560110

✦ Synopsis

Recombinant tumor necrosis factor-alpha (rTNFa) has potent antitumor activity in experimental studies on human tumor xenografts. However, in humans, the administration of rTNFa is hampered by severe systemic side-effects. The maximum tolerated dose ranges from 350 to 500 mg/m2, which is at least 1 O-fold less than the efficient dose in animals. Isolation perfusion of the limbs (ILP) allows the delivery of high dose rTNFa in a closed system with acceptable side-effects. A protocol with a triple-drug regimen was based on the reported synergism of rTNFa with chemotherapy, with interferon-y, and with hyperthermia. In melanoma-in-transit metastases (stage IllA or AB) we obtained a 91 % complete response, compared with 52% after ILP with melphalan alone. Release of nanograms levels of TNFa in the systemic circulation was evident but control of this leakage and appropriate intensive care resulted in acceptable toxicity. Angiographic, immunohistological, and immunological studies suggest that the efficacy of this protocol is due to a dual targeting: rTNFa activates and electively lyses the tumor endothelial cells while melphalan is mainly cytotoxic to the tumor cells. ILP with rTNFa appears to be a useful model for studying the biochemotherapy of cancer in man.