Abstract
Tumor necrosis factor-α (TNF-α) has been discussed as a potential anticancer agent for many years, however initial enthusiasm about its clinical use as a systemic agent was curbed due to significant toxicities and lack of efficacy. Combination of TNF-α with chemotherapy in the setting of hyperthermic isolated limb perfusion (ILP), has provided new insights into a potential therapeutic role of this agent. The therapeutic benefit from TNF-α in ILP is thought to be not only due to its direct anti-proliferative effect, but also due to its ability to increase penetration of the chemotherapeutic agents into the tumor tissue. New concepts for the use of TNF-α as a facilitator rather than as a direct actor are currently being explored with the goal to exploit the ability of this agent to increase drug delivery and to simultaneously reduce systemic toxicity. This review article provides a comprehensive overview on the published previous experience with systemic TNF-α. Data from 18 phase I and 10 phase II single agent as well as 18 combination therapy studies illustrate previously used treatment and dose schedules, response data as well as the most prominently observed adverse effects. Also discussed, based on recent preclinical data, is a potential future role of systemic TNF-α in combination with liposomal chemotherapy to facilitate increased drug uptake into tumors.
Highlights
Tumor necrosis factor-α (TNF-α) was discovered in 1975 and subsequently cloned in 1984 [1, 2] and has been the focus of considerable interest as an anticancer agent
In vitro and in vivo studies using the TNF-α resistant melanoma cell line B16BL6 demonstrated that IFN-γ sensitizes cancer cells to the effects of TNF-α, inducing necrosis and tumor response, which were previously absent [28]
It appears that a systemic TNF-α dose of 150-200 μg/m2, given as a 30 minute intravenous infusion was identified as MTD in several studies
Summary
TNF-α was discovered in 1975 and subsequently cloned in 1984 [1, 2] and has been the focus of considerable interest as an anticancer agent. In vitro and in vivo studies using the TNF-α resistant melanoma cell line B16BL6 demonstrated that IFN-γ sensitizes cancer cells to the effects of TNF-α, inducing necrosis and tumor response, which were previously absent [28]. Investigation of the interaction of TNF-α and radiation in 14 human tumor cells lines demonstrated synergistic or additive cytotoxicity with the maximum effect when TNF-α was given 4-12 hours before irradiation [34] The mechanism of this synergism is thought to be due to the induction of oxygen free radical species and resulting DNA damage. Study design varied with single dose of rhTNF-α, multiple dosing (daily to every three weeks) and continuous infusion (one to five day duration) being tested Overall, it appears that a systemic TNF-α dose of 150-200 μg/m2, given as a 30 minute intravenous infusion was identified as MTD in several studies. Compared to other phase II studies this regimen was fairly dose-dense which may have increased the significant toxicity observed
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