Down-regulation of tumor necrosis factor expression by pentoxifylline in cancer patients: a pilot study.

The wasting syndrome (cachexia) characterized by anorexia, malaise, and weight loss is observed in many patients with cancer or chronic infection. The excessive levels of tumor necrosis factor-alpha (TNF)/cachectin reported in 50% of cancer patients exhibiting clinically active disease may therefore mediate, at least in part, the cachexia associated with malignancy. Pentoxifylline, a substituted methylxanthine approved for treatment of intermittent claudication, has been shown in preclinical studies to down-regulate TNF RNA expression as well as TNF activity. We report that pentoxifylline suppressed TNF RNA levels on all three occasions in patients with initially elevated levels of TNF RNA. Pentoxifylline did not suppress TNF RNA to subnormal levels in all five patients with initially normal TNF RNA levels. Four patients reported an increased sense of well-being, improved appetite and ability to perform the activities of daily living. Two of these five patients with normal TNF levels each had a weight gain of more than 5% after 3 weeks of pentoxifylline therapy suggesting that, although TNF may be important in the pathogenesis of cancer cachexia, other anorexia-producing cytokines that are potentially affected by pentoxifylline may also be involved. No severe adverse effects were observed. Taken together these findings suggest that pentoxifylline can down-regulate TNF expression and improve the sense of well-being in cancer patients. A larger study with a randomized, double-blind, placebo-controlled design and more sophisticated estimates of quality of life will be needed to confirm these observations.

Cytokine dysregulation in AIDS: in vivo overexpression of mRNA of tumor necrosis factor-alpha and its correlation with that of the inflammatory cytokine GRO.

The human immunodeficiency virus establishes an intimate interaction with the immune system. The virus can use cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (Il-1), to regulate its own expression by modifying the normal immunoregulatory network. We demonstrate that mRNA of the cytokine TNF-alpha from peripheral blood mononuclear cells is overexpressed in virtually all patients with AIDS who do not have active opportunistic infections compared with uninfected volunteers (p < 0.0001). This overexpression correlates with elevated mRNA levels of the recently discovered GRO (p < 0.05), a cytokine involved in the inflammatory response.

Pentoxifylline (Trental) decreases the replication of the human immunodeficiency virus type 1 in human peripheral blood mononuclear cells and in cultured T cells.

Pentoxifylline (Trental), used routinely for the treatment of intermittent claudication, has been shown previously to decrease the levels of tumor necrosis factors-alpha (TNF-alpha) RNA in cancer patients and to lead to a general improvement of well being. Increased TNF-alpha levels have been observed not only in cancer patients but also in cachectic patients with the acquired immunodeficiency syndrome (AIDS), and TNF-alpha is known to increase the expression of the human immunodeficiency virus type 1 (HIV-1) via activating its long terminal repeat (LTR). Moreover, TNF-alpha decreases the therapeutic efficacy of zidovudine (AZT). Here we show a significant decrease in HIV-1 replication by pentoxifylline in infected human peripheral blood mononuclear cells. The reduction was proportional to the downregulation of expression of a reporter gene, the bacterial gene for chloramphenicol acetyl transferase, linked to the HIV-1 LTR in human monocytoid cells. We conclude that patients with AIDS may benefit from pentoxifylline treatment because of its blockage of TNF-alpha-mediated HIV-1 upregulation, from increased efficacy of AZT, and also from improvement in TNF-alpha-induced cachexia.