Oxidative stress and inflammation contribute to lung toxicity after a common breast cancer chemotherapy regimen

Abstract

. Oxidative stress and inflammation contribute to lung toxicity after a common breast cancer chemotherapy regimen. Am J Physiol Lung Cell Mol Physiol 283: L336-L345, 2002. First published March 29, 2002 10.1152/ ajplung.00012.2002-Delayed pulmonary toxicity syndrome after high-dose chemotherapy (HDC) and autologous hematopoietic support occurs in up to 64% of women with advanced-stage breast cancer. Using a similar, but nonmyeloablative, HDC treatment regimen in mice, we found both immediate and persistent lung injury, coincident with marked decreases in lung tissue glutathione reductase activity and accompanied by increases in lung oxidized glutathione, bronchoalveolar lavage (BAL) lipid peroxidation, and BAL total cell counts. Most interestingly, at 6 wk, BAL total cell counts had increased fourfold, with lymphocyte cell counts increasing Ͼ11-fold. A single supplemental dose of glutathione prevented early lung injury at 48 h but showed no lung-protective effects at 6 wk, whereas single doses of other thiol-sparing agents (Ethyol and glutathione monoethyl ester) showed no benefit. These data suggest that this HDC regimen results in acute and persistent lung toxicity, induced in part by oxidative stress, that culminates with an acute lung cellular inflammatory response. Continuous glutathione supplementation and/or attenuation of the delayed pulmonary inflammatory response may prove beneficial in preventing lung toxicity after the use of these chemotherapeutic agents. delayed pulmonary toxicity syndrome; high-dose chemotherapy; lung injury; glutathione BREAST CANCER is the most common type of cancer among women in the United States and is also well known for its high frequency of recurrence. A high-dose chemotherapy (HDC) regimen utilizing cyclophosphamide, cisplatin, and carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)] followed by autologous hematopoietic stem cell support has been developed to overcome the recurrence of cancer in these patients (31). Unfortunately, associated with this regimen is a high incidence (39-64%) of pulmonary drug toxicity (40,44). Patients who develop pulmonary drug toxicity frequently manifest symptoms of dyspnea, dry cough, fever, and hypoxemia, which, if left untreated, can be associated with significant mortality and morbidity (31). We have coined the term delayed pulmonary toxicity syndrome (DPTS) to differentiate this late-onset lung toxicity associated with this specific HDC regimen (44). It should be worth emphasizing that DPTS was described in patients undergoing autologous transplant, as contrasted to allogeneic transplant, in which additional factors, such as graft-vs.-host disease and complications due to the immunotherapy regimen, may come into play (16). Whether the pathogenesis of DPTS is part of the spectrum of idiopathic pneumonia syndrome (10) or is a separate entity remains to be determined.All three drugs used for the HDC regimen are known to be cytotoxic to the lung at high doses; however, the mechanism by which these drugs cause lung damage either indi...

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“…14 Some of the toxic effects of chemotherapy drugs are caused by the increased production of infl ammatory mediators. 15,16 Consistent with previous studies, we demonstrated that AraC caused infl ammatory cell Fig. 1A-D. The effect of sodium zinc dihydrolipoylhistidinate against cytosine arabinoside-induced alopecia.…”

“…Chemotherapy also increases oxidative stress, 16 which is associated with infl ammation. 20 High levels of ROS activate the oxidant-sensitive nuclear transcription factor NF-κB, thereby upregulating infl ammatory cytokine expression.…”

Safety and Efficacy of Weekly Oral Oltipraz in Chronic Smokers

“…Glutathione peroxidase activity in BAL fluid was determined by using the Bioxytech GPx-340 kit (Oxis International) according to the manufacturer's instructions with minor modifications. Plasma glutathione peroxidase activity was measured as described previously (26). GST activity in BAL fluid and plasma was measured using a Bioxytech GST-340 kit (Oxis International) according to the manufacturer's instructions.…”

Results of a phase I/II trial adding carmustine (300 mg/m2) to melphalan (200 mg/m2) in multiple myeloma patients undergoing autologous stem cell transplantation

“…Carmustine can cause pulmonary toxicity, usually in the form of interstitial pneumonitis, possibly due to the inhibition of glutathione reductase in alveolar macrophages; melphalan can have pulmonary toxicity as well. [15][16][17] The dose-escalation schema and trial design were linked with serial assessments of pulmonary function. 18,19 We report minimal pulmonary toxicity at the highest planned dose level (melphalan 200 mg/m 2 ) with a 49% rate of complete and near complete responses (CR).…”