Tumor Necrosis Factor-α Levels Decrease with Anticytokine Therapy in Patients with Myelodysplastic Syndromes

Abstract

Tumor necrosis factor-alpha (TNF-alpha) levels were measured in the serum (sTNF-alpha) or bone marrow (BM) biopsies of 43 patients with myelodysplastic syndromes (MDS) who subsequently received therapy with a combination of pentoxifylline and ciprofloxacin (PC) with or without dexamethasone (PCD). All 43 patients received only PC therapy for 12 weeks, after which 18 of 36 nonresponders received PCD. A total of 18 of 43 patients showed a hematologic or cytogenetic response or both. BM TNF-alpha levels were semiquantitatively assessed using immunohistochemistry on a scale of 0-8+ and in the serum using enzyme linked immunoassay. The median TNF-alpha for the entire group was 3.0 in BM and 6.9 pg/ml in the serum, and 14 patients had no detectable levels. Responders had higher BM levels (median 3.5 vs. 2.0) than nonresponders, although this was not statistically significant. During PC therapy, a decline in BM TNF-alpha level was seen in the entire group, which was significant at 2 weeks (p = 0.02), 8 weeks (p = 0.001), and 12 weeks (p = 0.0001). Both responders (p = 0.01) and nonresponders (p = 0.03) had a decline at 8 weeks, but at 12 weeks, only the responders continued to show a significant decline (p = 0.03). We conclude that MDS patients with high BM TNF-alpa levels have a better chance of responding to PCD therapy and that the therapy is quite successful in reducing the TNF-alpha levels in a sustained fashion. Future studies need to be directed at identifying agents that would be more potent suppressors of the proapoptotic cytokines in these patients.

Dysregulation of IL-32 in myelodysplastic syndrome and chronic myelomonocytic leukemia modulates apoptosis and impairs NK function

“…The role of TNF␣ in the pathophysiology of MDS has been characterized (4,29), whereas the role of IL-32 is unknown. KG1a cells, used as a model (no stable MDS cell lines are available), were nearly completely resistant to TNF␣-induced apoptosis (25).…”

Anti-TNF therapies in rheumatoid arthritis, Crohn's disease, sepsis, and myelodysplastic syndromes

“…Unfortunately, in both clinical trials, it was impossible to precisely define the mechanism of improvement in the hematopoietic indices since multiple agents were employed in each study and none of the drugs were specifically targeting any particular cytokine. Despite this limitation, we were able to show that the mechanism of action is cytokine related since responders showed the most sustained reductions in TNF-␣ levels (Reza et al, 1998). Obviously, the real test of the efficacy of anti-TNF therapy in ameliorating the cytopenias of MDS patients can only come when this cytokine is directly suppressed by using antibodies or soluble receptors described for RA and Crohn's disease earlier.…”

Efficacy of N-acetylcysteine and all-trans retinoic acid in restoring in vitro effective hemopoiesis in myelodysplastic syndromes

“…There was no evidence that NAC or ATRA add any leukemogenic effect on MDS BM cells, as the number of clusters remained the same after stimulation with either substance, whereas the number of colonies always increased. It has recently been reported that combined therapy with ciprofloxacin, pentoxifylline and dexamethasone is efficacious in reducing TNF-a levels and improving hemopoiesis in MDS patients [9]. Moreover, List et al [32] have demonstrated that the aminothiol amyfostine is capable of improving the in vitro clonogenic activity of MDS hemopoietic precursors.…”

“…It is well documented that MDS patients have increased serum Tumor Necrosis Factor-a (TNF-a) levels [7][8][9][10][11], which may be responsible for pro-apoptotic oxidative damage by inducing the generation of free radicals [12][13][14][15][16]. In line with this hypothesis, Peddie et al [17] have demonstrated the presence of oxidative damage and a reduction in intracellular glutathione (GSH) in MDS CD34+ cells, and a number of in vitro studies have shown the ability of the antioxidant thiol N-acetylcysteine (NAC) to reduce the apoptosis induced by free radicals in neuronal and leukemic cell lines by increasing the supply of intracellular GSH [18][19][20].…”