Role of the Glutathione Metabolic Pathway in Lung Cancer Treatment and Prognosis

Inherent and acquired drug resistance is a cause of chemotherapy failure, and pharmacogenomic studies have begun to define gene variations responsible for varied drug metabolism, which influences drug efficacy. Platinum-based compounds are the most commonly used chemotherapeutic agents in the treatment of advanced stage lung cancer patients, and the glutathione metabolic pathway is directly involved in the detoxification or inactivation of platinum drugs. Consequently, genotypes corresponding to higher drug inactivation enzyme activity may predict poor treatment outcome. Available evidence is consistent with this hypothesis, although a definitive role for glutathione system genes in lung cancer prognosis needs to be elucidated. We present evidence supporting a role of the glutathione system in acquired and inherited drug resistance and/or adverse effects through the impact of either drug detoxification or drug inactivation, thus adversely effecting lung cancer treatment outcome. The potential application of glutathione system polymorphic genetic markers in identifying patients who may respond favorably, selecting effective antitumor drugs, and balancing drug efficacy and toxicity are discussed.
Ping Yang, Jon O. Ebbert, Zhifu Sun, Richard M. Weinshilboum

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Genetic determinants of lung cancer short-term survival: the role of glutathione-related genes

Survival of lung cancer patients has been dismal. Glutathione enzymes are directly involved in the metabolism of platinum compounds, a group of important chemotherapeutic drugs in cancer treatment. We tested the hypothesis that genes encoding Glutathione enzymes may predict lung cancer short-term survival. Methods: We studied DNA polymorphisms of 250 primary lung cancer patients at four Glutathione-related loci: GSTP1, GSTM1, GSTT1 and γ-GCS that encode Glutathione-S-transferase-π,Glutathione-S-transferase-μ, Glutathione-S-transferase-θ, and γ-glutamylcysteine synthetase, respectively. Pearson's χ2-square tests, Kaplan–Meier survival curves, log rank tests, and Cox regression models were applied in the analysis.

Results: There were 150 (60%) men and 100 (40%) women in this study. Seventeen percent of the patients had never smoked cigarettes, and 61% had stopped smoking at least 6 months prior to their lung cancer diagnosis. Among never smokers, those with null (N) or low (L) genotype experienced a better 1-year-survival rate than those with a positive (P) or high (H) genotype. Patients with P or H at two loci (PP or PH) were compared with patients with N or L at one or both loci (other). Among never smokers, 1-year-survival rates were 60–78% for patients with PP or PH genotypes compared with 89–100% for other types. The survival advantage was greater among advanced-stage patients who were NL or NN than low-stage patients. Similar results were not observed among smokers.

Conclusions: Glutathione-related genes may determine lung cancer survival. Our results, if confirmed, would suggest new directions to enhance cancer treatment, and provide easily measurable markers for clinicians to plan patient-specific therapy.

Ping Yangab, Akira Yokomizoc, Henry D Tazelaarc, Randolph S Markse, Timothy G Lesnicka, Daniel L Millerd, Jeff A Sloana, Eric S Edellf, Rebecca L Meyera, James Jettef, Wanguo Liuc