Assessment of tumor necrosis factor alpha blockade as an intervention to improve tolerability of dose-intensive chemotherapy in cancer patients.

PURPOSE: Maintaining dose-intensity with chemotherapeutic agents is hindered by a number of adverse effects including asthenia/fatigue. Tumor necrosis factor (TNF) is one of the cytokines responsible for the fatigue and cachexia associated with malignancies. We used etanercept (TNF-decoy receptor) to maintain dose-intensity of weekly docetaxel. PATIENTS AND METHODS: Initially, 12 patients with advanced malignancies were randomly assigned to either docetaxel 43 mg/m2 weekly alone (cohort A) or the same docetaxel dose plus etanercept 25 mg subcutaneously twice weekly (cohort B). Subsequently, higher doses of docetaxel in combination with etanercept were evaluated. Pharmacokinetics (PKs), nuclear factor-kappa B (NF-kappaB) activation, and intracellular cytokines levels were measured. Patients completed weekly questionnaires quantifying asthenia/fatigue. RESULTS: Twenty-nine of 36 intended docetaxel doses during the first cycle were delivered in cohort A, and 35 of 36 doses were delivered in cohort B (P = .055). Three cohort B patients received additional cycles in the absence of disease progression or severe toxicity, whereas no patients from cohort A received additional cycles. Escalation to docetaxel 52 mg/m2 weekly with etanercept resulted in neutropenia, not fatigue, as the limiting adverse effect, and the addition of filgrastim permitted the maintenance of dose-intensity in additional patients. Patients randomly selected to receive etanercept/docetaxel self-reported less fatigue (P < .001), and docetaxel PKs show no relevant influence of etanercept. NF-kappaB activation and increased expression of TNF-alpha were associated with increments in docetaxel dose. Antitumor activity was noticed exclusively in patients receiving etanercept. CONCLUSION: The addition of etanercept is safe and had no impact on docetaxel concentrations. The significant improvement in tolerability and the trend toward preservation of dose-intensity suggests further exploration of TNF blockade as an adjunct to cancer therapies.

In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells.

Cellular homeostasis requires a balance between cell production, cell survival, and cell death. Production of natural killer (NK) cells from bone marrow precursor cells requires interleukin 15 (IL-15); however, very little is known about the factors controlling survival of mature NK cells in vivo. Because mice deficient in IL-15 (IL-15(-/-) mice) fail to develop NK cells, it is not known whether mature NK cells can survive in an environment lacking IL-15. We hypothesized that IL-15 might indeed be required for survival of mature NK cells in vivo. Freshly isolated NK cells labeled with 5-(and-6)-carboxyfluorescein diacetate, succinimidyl ester (CFSE) were adoptively transferred into IL-15(-/-) mice and littermate control (IL-15(+/-)) mice. Within 36 hours after transfer, NK cells were detected in both IL-15(-/-) and IL-15(+/-) mice; however, significantly more (P <.003) CFSE-positive (CFSE(+)) NK cells were found in control mice than in IL-15(-/-) mice. By 5 days, similar numbers of CFSE(+) NK cells were still easily detected in IL-15(+/-) mice, whereas no CFSE(+) NK cells survived in IL-15(-/-) mice. Furthermore, mice with severe combined immunodeficiency treated with the Fab fragment of a blocking antibody recognizing a signaling subunit of the IL-15 receptor, IL-2/15Rbeta, had a significant ( approximately 90%) loss of NK cells compared with control mice. Finally, NK cells from Bcl-2 transgenic mice that were adoptively transferred into IL-15(-/-) mice did survive. These results show conclusively that IL-15 is required for mature NK cell survival in vivo and suggest that IL-15 mediates its effect on NK cell survival by means of Bcl-2.

Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels.

BACKGROUND: Chronic hypoxic pulmonary hypertension (CH-PHT) is associated with suppressed expression and function of voltage-gated K(+) channels (Kv) in pulmonary artery (PA) smooth muscle cells (SMCs) and a shift in cellular redox balance toward a reduced state. We hypothesized that dichloroacetate (DCA), a metabolic modulator that can shift redox balance toward an oxidized state and increase Kv current in myocardial cells, would reverse CH-PHT. METHODS AND RESULTS: We studied 4 groups of rats: normoxic, normoxic+DCA (DCA 70 mg. kg(-1). d(-1) PO), chronically hypoxic (CH), and CH+DCA. CH and CH+DCA rats were kept in a hypoxic chamber (10% FiO(2)) for 2 to 3 weeks. DCA was given either at day 1 to prevent or at day 10 to reverse CH-PHT. We used micromanometer-tipped catheters and measured hemodynamics in closed-chest rats on days 14 to 18. CH+DCA rats had significantly reduced pulmonary vascular resistance, right ventricular hypertrophy, and PA remodeling compared with the CH rats. CH inhibited I(K), eliminated the acute hypoxia-sensitive I(K), and decreased Kv2.1 channel expression. In the short term, low-dose DCA (1 micromol/L) increased I(K) in CH-PASMCs. In a mammalian expression system, DCA activated Kv2.1 by a tyrosine kinase-dependent mechanism. When given long-term, DCA partially restored I(K) and Kv2.1 expression in PASMCs without altering right ventricular pyruvate dehydrogenase activity, suggesting that the beneficial effects of DCA occur by nonmetabolic mechanisms. CONCLUSIONS: DCA both prevents and reverses CH-PHT by a mechanism involving restoration of expression and function of Kv channels. DCA has previously been used in humans and may potentially be a therapeutic agent for pulmonary hypertension.