Combination of carboplatin and intermittent normobaric hyperoxia synergistically suppresses benzo[a]pyrene-induced lung cancer.

BACKGROUND/AIMS: We explored the effects of intermittent normobaric hyperoxia alone or combined with chemotherapy on the growth, general morphology, oxidative stress, and apoptosis of benzo[a]pyrene (B[a]P)-induced lung tumors in mice. METHODS: Female A/J mice were given a single dose of B[a]P and randomized into four groups: control, carboplatin (50 mg/kg intraperitoneally), hyperoxia (95% fraction of inspired oxygen), and carboplatin and hyperoxia. Normobaric hyperoxia (95%) was applied for 3 hours each day from weeks 21 to 28. Tumor load was determined as the average total tumor numbers and volumes. Several markers of oxidative stress and apoptosis were evaluated. RESULTS: Intermittent normobaric hyperoxia combined with chemotherapy reduced the tumor number by 59% and the load by 72% compared with the control B[a]P group. Intermittent normobaric hyperoxia, either alone or combined with chemotherapy, decreased the levels of superoxide dismutase and glutathione and increased the levels of catalase and 8-hydroxydeoxyguanosine. The Bax/Bcl-2 mRNA ratio, caspase 3 level, and number of transferase-mediated dUTP nick end-labeling positive cells increased following treatment with hyperoxia with or without chemotherapy. CONCLUSIONS: Intermittent normobaric hyperoxia was found to be tumoricidal and thus may serve as an adjuvant therapy for lung cancer. Oxidative stress and its effects on DNA are increased following exposure to hyperoxia and even more with chemotherapy, and this may lead to apoptosis of lung tumors.

Curcumin sensitizes human lung cancer cells to apoptosis and metastasis synergistically combined with carboplatin.

Although carboplatin is one of the standard chemotherapeutic agents for non-small cell lung cancer (NSCLC), it has limited therapeutic efficacy due to activation of a survival signaling pathway and the induction of multidrug resistance. Curcumin, a natural compound isolated from the plant Curcuma longa, is known to sensitize tumors to different chemotherapeutic agents. The aim of this study is to evaluate whether curcumin can chemosensitize lung cancer cells to carboplatin and to analyze the signaling pathway underlying this synergism. We investigated the synergistic effect of both agents on cell proliferation, apoptosis, invasion, migration, and expression of related signaling proteins using the human NSCLC cell line, A549. A549 cell was treated with different concentrations of curcumin and carboplatin alone and in combination. Combined treatment with curcumin and carboplatin inhibited tumor cell growth, migration, and invasion compared with either drug alone. Matrix metalloproteinase (MMP)-2 and MMP-9 were more efficiently downregulated by co-treatment than by each treatment alone. mRNA and protein expression of caspase-3 and caspase-9 and proapoptotic genes was increased in cells treated with a combination of curcumin and carboplatin, whereas expression of the antiapoptotic Bcl-2 gene was suppressed. Co-treatment of both agents substantially suppressed NF-κB activation and increased expression of p53. Phosphorylation of Akt, a protein upstream of NF-κB, was reduced, resulting in inhibition of the degradation of inhibitor of κB(IκBα), whereas the activity of extracellular signal-regulated kinase (ERK1/2) was enhanced. Our study demonstrated that the synergistic antitumor activity of curcumin combined with carboplatin is mediated by multiple mechanisms involving suppression of NF-κB via inhibition of the Akt/IKKα pathway and enhanced ERK1/2 activity. Based on this mechanism, curcumin has potential as a chemosensitizer for carboplatin in the treatment of patients with NSCLC.

Diagnostic yield of flexible bronchoscopy without fluoroscopic guidance in evaluating peripheral lung lesions.

BACKGROUND AND OBJECTIVES: Flexible bronchoscopy (FB) is frequently performed in patients with peripheral lung lesions. The aim of this study was to evaluate the diagnostic yield, factors affecting diagnostic yield, complications, and safety of FB without fluoroscopic guidance in patients with peripheral lung lesions. METHODS: We retrospectively reviewed the medical records of all patients who underwent FB without fluoroscopic guidance for the diagnosis of peripheral lung lesions between 1999 and 2004. RESULTS: Ninety-three patients were enrolled. Among these, 38 lesions were malignant, 46 were benign, and 9 were indeterminate. The overall diagnostic rate was 65%, and the diagnostic sensitivities for malignant and benign lesions were 68% and 74%, respectively. The diagnostic yield was significantly higher for lesions >2 cm (70%) than for lesions ≤2 cm (11%; P <0.001). The diagnostic yield of transbronchial lung biopsy (46%) was higher than that of bronchial washing (29%; P=0.025) or brushing (29%; P=0.022). The yield of transbronchial lung biopsy for malignant disease (70%) was higher than that of benign disease (35%; P=0.003). Pneumothoraces and significant bleeding developed in 4.3% and 2.2% of patients, respectively. CONCLUSIONS: This study showed that FB sampling without fluoroscopic guidance was safe with a high rate of accuracy for the diagnosis of lung lesions not visible through a bronchoscope. When we performed a computed tomography scan and determined the exact location of the lesion before FB, the diagnostic yield of FB without fluoroscopic guidance was comparable with that reported earlier using fluoroscopy.