Oxidative stress and inflammation contribute to lung toxicity after a common breast cancer chemotherapy regimen.
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 >11-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.
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Amir M
AM
Abushamaa
Thomas A
TA
Sporn
Rodney J
RJ
Folz
D004999:Amifostine / Q000494:pharmacology; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D001772:Blood Cell Count; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002330:Carmustine / Q000009:adverse effects*; D002452:Cell Count; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D019803:Glutathione Disulfide / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D066298:In Vitro Techniques; D008054:Lipid Peroxides / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D018384:Oxidative Stress; D011014:Pneumonia / Q000139:chemically induced*
D018906:Antineoplastic Agents, Alkylating; D000975:Antioxidants; D008054:Lipid Peroxides; C042431:S-ethyl glutathione; D005980:Glutathione Reductase; D005978:Glutathione; D004999:Amifostine; D002330:Carmustine; D019803:Glutathione Disulfide