Original articleGenetic determinants of lung cancer short-term survival: the role of glutathione-related genes
Introduction
Over the past half century, survival after a lung cancer diagnosis has improved little, particularly for patients with advanced disease [1], [2]. Currently, lung cancer treatment modalities are determined by tumor histology, disease stage, and influenced by a patient's performance status [1], [3]. If treated at all, patients with inoperable or advanced stage disease receive a variety of chemotherapeutic agents. Anti-cancer drugs typically have a very narrow therapeutic index, meaning a close margin between clinical effective dose and toxicity limit dose. For any given treatment regimen, tumor response rate and patients’ survival time are unpredictable, even after adjusting for disease stage, histology, and performance status. There are no host-specific measures on which to base an optimal choice of the type, dose, delivery schedule or combination of these drugs. Therefore, individualized dose optimization algorithms of chemotherapy agents are desperately needed to maximize treatment efficacy and minimize unwanted toxicity.
Glutathione (GSH) synthesis and GSH-dependent enzymes (GSH system) are directly involved in detoxification or inactivation of several groups of major anti-cancer drugs [4], [5], [6], [7], [8], [9]. Platinum-based compounds and alkylating agents are important drugs in lung cancer chemotherapy, and both are mainly inactivated through the GSH system. The key elements of this system, as shown in Fig. 1, are the amount of GSH itself and the enzymes that catalyze the conjugation of substrates to GSH. The important enzymes are γ-glutamylcystein synthetase (γ-GCS), glutathione-S-transferase-Pi (GSTπ), glutathione-S-transferase mu (GSTμ) and glutathione-S-transferase theta (GSTθ) [4], [8]. Two lines of evidence, from multiple cancer sites, indicate the important role of these enzymes in anticancer treatment sensitivity and responses [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]. First, elevated GSH and/or GSH-dependent enzyme levels correlate with inferior treatment response [14], [15], [16], [17], [18], [19]. Secondly, inhibition or reduction of GSH and/or GSH-system increases treatment response rates [12], [20], [21], [22], [35]. Genetic polymorphisms with functional significance have been well characterized for GSH-related enzymes [36], [37], [38], [39], [40], [41], [42], [43], [44]. Testing for the presence of the genes which encode for these enzymes has the potential to offer clinicians a powerful tool in determining which patients are likely to respond to which drugs. In this study, we have tested the hypothesis that in patients with lung cancer, genotypes corresponding to low activity levels of critical enzymes in the GSH system are associated with improved short-term survival.
Section snippets
Study participants and data collection
The study group included 250 patients with pathologically confirmed primary lung cancer who were diagnosed and/or treated at the Mayo Clinic (Rochester, MN) between 1997 and 1999 and were followed-up for 1 year. All of these cases have been enrolled with informed consent approved by Mayo Clinic Institutional Review Board. This study was designed to conduct genetic and molecular epidemiology research on lung cancer etiology and prognosis [45].
During the interview at enrollment, we obtained the
Results
Selected characteristics of the 250 patients at diagnosis are provided in Table 1. The gender ratio was 3:2 for male to female. Sixteen and one-half percent of the patients had never smoked cigarettes. Among tobacco users, 73% had quit smoking for at least 6 months before their lung cancer diagnosis. Information on pack-years of cigarette smoking was available for 206 (82.4%) patients, and over 84% of them had a history of 20 pack-years or greater, to a maximum of 200 pack-years. More than
Discussion
Our results provide preliminary evidence that genotypes corresponding to lower GSH metabolic system functions may be associated with improved lung cancer survival, particularly among never-smoking patients. In clinical practice, body surface area has been the uniform standard for computing the dose of anticancer drugs, yet wide variability in plasma active drug concentration and toxicity can be found among patients with the same body surface area. A more rational dose optimization algorithm
Acknowledgements
We owe gratitude to Dr M.S. Allen, Dr N.M. Lindor, Dr J.L. Myers, Dr D.E. Midthun, Dr J. Meyer, Dr S.N. Thibodeau, Dr C. Deschamps, Dr A.M. Patel, Dr V.F. Trastek, Dr A. Adjei, Dr A. Jatoi, and Dr E. Perez for their support in various aspects of this work. We thank M. Goodman and S. Ernst for secretarial support to this manuscript. This work has been supported in part by research grants CA77118, CA80127, and CA25224 from the National Institutes of Health, and the United States Public Health
References (65)
Revisions in the international system for staging lung cancer
Chest
(1997)- et al.
Mammalian glutathione S-transferase: regulation of an enzyme system to achieve chemotherapeutic efficacy
Pharmacol. Ther.
(1995) - et al.
Relationship of glutathione and glutathione-S-transferase to cisplatin sensitivity in human head and neck squamous carcinoma cell lines
Cancer Lett.
(1994) - et al.
Factors influencing the sensitivity of two human bladder carcinoma cell lines to cis-diamminedichloroplatinum(II)
Chem. Biol. Interact.
(1987) - et al.
Sensitization of drug resistant human ovarian cancer cells to cyanomorpholino doxorubicin (MRA-CN) by modulation of glutathione metabolism
Int. J. Radiat. Oncol. Biol. Phys.
(1992) - et al.
Mitomycin C sensitivity in human bladder cancer cells: possible role of glutathione and glutathione transferase in resistance
Arch. Biochem. Biophys.
(1994) - et al.
Expression of glutathione S-transferase-pi in human ovarian cancer as an indicator of resistance to chemotherapy
Gynecol. Oncol.
(1994) - et al.
Role of cellular glutathione and glutathione S-transferase in the expression of alkylating agent cytotoxicity in human breast cancer cells
Biochem. Pharmacol.
(1994) - et al.
Pi-class glutathione S-transferase: regulation and function
Chem. Biol. Interact.
(1998) Clinical studies of reversal of drug resistance based on glutathione
Chem. Biol. Interact.
(1998)
Analysis of l-myc and GSTM1 genotypes in Chinese non-small cell lung carcinoma patients
Lung Cancer
Assays of CYP2C8- and CYP3A4-mediated metabolism of taxol in vivo and in vitro
Methods Enzymol.
Microsatellite instability in human cancer: a prognostic marker for chemotherapy?
Exp. Cell Res.
Cancer of the lung
Importance of glutathione and associated enzymes in drug response
Oncol. Res.
The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance
Crit. Rev. Biochem. Mol. Biol.
Invited commentary: potential contribution of the glutathione S-transferase supergene family to resistance to oxidative stress
Free Radical Res.
Glutathione S-transferase isoenzymes and glutathione peroxidase activity in normal and tumour samples from human lung
Carcinogenesis (London)
Glutathione and related enzyme activity in human lung cancer cell lines
Br. J. Cancer
Glutathione S transferase Pi is a powerful indicator in chemotherapy of human lung squamous-cell carcinoma
Respiration
Immunohistochemical expression of glutathione S-transferase-Pi can predict chemotherapy response in patients with nonsmall cell lung carcinoma
Cancer
Glutathione derivatives enhance Adriamycin cytotoxicity in a human lung adenocarcinoma cell line
Anticancer Res.
Expression of mu class glutathione S-transferase correlates with event-free survival in childhood acute lymphoblastic leukemia
Cancer Res.
Cellular basis for differential sensitivity to cisplatin in human germ cell tumour and colon carcinoma cell lines
Br. J. Cancer
Decreased DNA interstrand cross-linking and cytotoxicity induced in human brain tumor cells by 1,3-bis(2-chloroethyl)-1-nitrosourea after in vitro reaction with glutathione
Cancer Res.
Mechanism of cross-resistance to cisplatin in a mitomycin C-resistant human bladder cancer cell line
Int. J. Cancer
Role of glutathione and dependent enzymes in anthracycline-resistant HL60/AR cells
Cancer Res.
Relationship between melanogenesis, glutathione levels and melphalan toxicity in human melanoma cells
Melanoma Res.
Determinants of drug response in a cisplatin-resistant human lung cancer cell line
Jpn. J. Cancer Res.
Immunohistochemical expression of glutathione S-transferase pi (GST-pi) and chemotherapy response in malignant ovarian tumors
J. Obstet. Gynecol.
Expression of glutathione S-transferase-pi in operative specimens as marker of chemoresistance in patients with ovarian cancer
J. Obstet. Gynecol. (Peking)
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