The role of pemetrexed in advanced non small-cell lung cancer: Special focus on pharmacology and mechanism of action

Current Drug Targets

Volumn 11, Issue 1, 2010, Pages 37-47

  Joerger, M ^a   Omlin, A ^a   Cerny, T ^a   Fruh M ^a  

^a CANTONAL HOSPITAL ST GALLEN   (Switzerland)

Author keywords

Brain metastases; Lung cancer; Pemetrexed; Pharmacokinetics; Thymidylate synthase

Indexed keywords

BEVACIZUMAB; CARBOPLATIN; CETUXIMAB; CISPLATIN; CYANOCOBALAMIN; DIHYDROFOLATE REDUCTASE; DOCETAXEL; ERLOTINIB; FOLIC ACID; GEMCITABINE; METHOTREXATE; NAVELBINE; OROTATE PHOSPHORIBOSYLTRANSFERASE; OXALIPLATIN; PACLITAXEL; PEMETREXED; PHOSPHORIBOSYLGLYCINAMIDE FORMYLTRANSFERASE; THYMIDYLATE SYNTHASE; ANTINEOPLASTIC AGENT; DRUG DERIVATIVE; GLUTAMIC ACID DERIVATIVE; GUANINE;

ADVANCED CANCER; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; BLOOD BRAIN BARRIER; BLOOD TOXICITY; BRAIN METASTASIS; CANCER RADIOTHERAPY; CLINICAL TRIAL; DIARRHEA; DOSE KIDNEY FUNCTION RELATION; DRUG EFFICACY; DRUG HALF LIFE; DRUG PENETRATION; DRUG SAFETY; FATIGUE; HUMAN; LETHARGY; LUNG NON SMALL CELL CANCER; MAXIMUM TOLERATED DOSE; MUCOSA INFLAMMATION; MULTIPLE CYCLE TREATMENT; NAUSEA; NEUTROPENIA; NONHUMAN; OVERALL SURVIVAL; PROGNOSIS; RASH; REVIEW; VOMITING; LUNG TUMOR;

ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CARCINOMA, NON-SMALL-CELL LUNG; CLINICAL TRIALS AS TOPIC; GLUTAMATES; GUANINE; HUMANS; LUNG NEOPLASMS;

EID: 77949435506     PISSN: 13894501     EISSN: None     Source Type: Journal    
DOI: 10.2174/138945010790030974     Document Type: Review

References (94)

1. [No authors listed] Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995; 311(7010): 899-909.
2. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355(24): 2542-50.
3. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009; 27(8): 1227-34.
4. Smit EF, van Meerbeeck JP, Lianes P, Debruyne C, Legrand C, Schramel F, et al. Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group-EORTC 08975. J Clin Oncol 2003; 21(21): 3909-17.
5. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346(2): 92-98.
6. Le CT, Scagliotti G, Natale R, Danson S, Rosell R, Stahel R, et al. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer 2005; 47(1): 69-80.
7. Alberola V, Camps C, Provencio M, Isla D, Rosell R, Vadell C, et al. Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial. J Clin Oncol 2003; 21(17): 3207-13.
8. Scagliotti GV, Parikh P, von PJ, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008; 26(21): 3543-51.
9. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De MF, von PJ, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004; 22(9): 1589-97.
10. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003; 21(14): 2636-44.
11. Scagliotti GV. Pemetrexed: a new cytotoxic agent in the development for first-line non-small-cell lung cancer. Lung Cancer 2005; 50(Suppl 1): S18-S19.
12. Goldman ID, Zhao R. Molecular, biochemical, and cellular pharmacology of pemetrexed. Semin Oncol 2002; 29(6 Suppl 18): 3-17.
13. Calvert AH. Biochemical pharmacology of pemetrexed. Oncology (Williston Park) 2004; 18(13 Suppl 8): 13-17.
14. Adjei AA. Pemetrexed (Alimta): a novel multitargeted antifolate agent. Expert Rev Anticancer Ther 2003; 3(2): 145-56.
15. Cohen MH, Johnson JR, Wang YC, Sridhara R, Pazdur R. FDA drug approval summary: pemetrexed for injection (Alimta) for the treatment of non-small cell lung cancer. Oncologist 2005; 10(6): 363-8.
16. Hazarika M, White RM, Johnson JR, Pazdur R. FDA drug approval summaries: pemetrexed (Alimta). Oncologist 2004; 9(5): 482-8.
17. Shih C, Habeck LL, Mendelsohn LG, Chen VJ, Schultz RM. Multiple folate enzyme inhibition: mechanism of a novel pyrrolopyrimidine-based antifolate LY231514 (MTA). Adv Enzyme Regul 1998; 38: 135-52.
18. Rhee MS, Ryan TJ, Galivan J. Glutamyl hydrolase and the multitargeted antifolate LY231514. Cancer Chemother Pharmacol 1999; 44(5): 427-32.
19. Teicher BA, Chen V, Shih C, Menon K, Forler PA, Phares VG, et al. Treatment regimens including the multitargeted antifolate LY231514 in human tumor xenografts. Clin Cancer Res 2000; 6(3): 1016-23.
20. Britten CD, Izbicka E, Hilsenbeck S, Lawrence R, Davidson K, Cerna C, et al. Activity of the multitargeted antifolate LY231514 in the human tumor cloning assay. Cancer Chemother Pharmacol 1999; 44(2): 105-10.
21. Tonkinson JL, Marder P, Andis SL, Schultz RM, Gossett LS, Shih C, et al. Cell cycle effects of antifolate antimetabolites: implications for cytotoxicity and cytostasis. Cancer Chemother Pharmacol 1997; 39(6): 521-31.
22. Giovannetti E, Mey V, Nannizzi S, Pasqualetti G, Marini L, Del TM, et al. Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells. Mol Pharmacol 2005; 68(1): 110-18.
23. Teicher BA, Alvarez E, Liu P, Lu K, Menon K, Dempsey J, et al. MTA (LY231514) in combination treatment regimens using human tumor xenografts and the EMT-6 murine mammary carcinoma. Semin Oncol 1999; 26(2 Suppl 6): 55-62.
24. Shih C, Chen VJ, Gossett LS, Gates SB, MacKellar WC, Habeck LL, et al. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res 1997; 57(6): 1116-23.
25. Rinaldi DA, Kuhn JG, Burris HA, Dorr FA, Rodriguez G, Eckhardt SG, et al. A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation. Cancer Chemother Pharmacol 1999; 44(5): 372-80.
26. Rinaldi DA, Burris HA, Dorr FA, Woodworth JR, Kuhn JG, Eckardt JR, et al. Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation. J Clin Oncol 1995; 13(11): 2842-50.
27. McDonald AC, Vasey PA, Adams L, Walling J, Woodworth JR, Abrahams T, et al. A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate. Clin Cancer Res 1998; 4(3): 605-10.
28. Brandes JC, Grossman SA, Ahmad H. Alteration of pemetrexed excretion in the presence of acute renal failure and effusions: presentation of a case and review of the literature. Cancer Invest 2006; 24(3): 283-7.
29. Ouellet D, Periclou AP, Johnson RD, Woodworth JR, Lalonde RL. Population pharmacokinetics of pemetrexed disodium (ALIMTA) in patients with cancer. Cancer Chemother Pharmacol 2000; 46(3): 227-34.
30. Latz JE, Chaudhary A, Ghosh A, Johnson RD. Population pharmacokinetic analysis of ten phase II clinical trials of pemetrexed in cancer patients. Cancer Chemother Pharmacol 2006; 57(4): 401-11.
31. Mita AC, Sweeney CJ, Baker SD, Goetz A, Hammond LA, Patnaik A, et al. Phase I and pharmacokinetic study of pemetrexed administered every 3 weeks to advanced cancer patients with normal and impaired renal function. J Clin Oncol 2006; 24(4): 552-62.
32. Sweeney CJ, Takimoto CH, Latz JE, Baker SD, Murry DJ, Krull JH, et al. Two drug interaction studies evaluating the pharmacokinetics and toxicity of pemetrexed when coadministered with aspirin or Ibuprofen in patients with advanced cancer. Clin Cancer Res 2006; 12(2): 536-42.
33. Joerger M, Huitema AD, van den Bongard HJ, Baas P, Schornagel JH, Schellens JH, et al. Determinants of the elimination of methotrexate and 7-hydroxy-methotrexate following high-dose infusional therapy to cancer patients. Br J Clin Pharmacol 2006; 62(1): 71-80.
34. Dickgreber NJ, Fink TH, Latz JE, Hossain AM, Musib LC, Thomas M. Phase I and pharmacokinetic study of pemetrexed plus cisplatin in chemonaive patients with locally advanced or metastatic malignant pleural mesothelioma or non-small cell lung cancer. Clin Cancer Res 2009; 15(1): 382-9.
35. Dy GK, Suri A, Reid JM, Sloan JA, Pitot HC, Alberts SR, et al. A phase IB study of the pharmacokinetics of gemcitabine and pemetrexed, when administered in rapid sequence to patients with advanced solid tumors. Cancer Chemother Pharmacol 2005; 55(6): 522-30.
36. Hughes A, Calvert P, Azzabi A, Plummer R, Johnson R, Rusthoven J, et al. Phase I clinical and pharmacokinetic study of pemetrexed and carboplatin in patients with malignant pleural mesothelioma. J Clin Oncol 2002; 20(16): 3533-44.
37. Li KM, Rivory LP, Clarke SJ. Pemetrexed pharmacokinetics and pharmacodynamics in a phase I/II study of doublet chemotherapy with vinorelbine: implications for further optimisation of pemetrexed schedules. Br J Cancer 2007; 97(8): 1071-76.
38. Adamo V, Franchina T, Adamo B, Scandurra G, Scimone A. Brain metastases in patients with non-small cell lung cancer: focus on the role of chemotherapy. Ann Oncol 2006; 17(Suppl 2): ii73-5.
39. Sorensen JB, Hansen HH, Hansen M, Dombernowsky P. Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J Clin Oncol 1988; 6(9): 1474-80.
40. Komaki R, Cox JD, Stark R. Frequency of brain metastasis in adenocarcinoma and large cell carcinoma of the lung: correlation with survival. Int J Radiat Oncol Biol Phys 1983; 9(10): 1467-70.
41. Postmus PE, Smit EF. Chemotherapy for brain metastases of lung cancer: a review. Ann Oncol 1999; 10(7): 753-9.
42. Dziadziuszko R, Ardizzoni A, Postmus PE, Smit EF, Price A, Debruyne C, et al. Temozolomide in patients with advanced nonsmall cell lung cancer with and without brain metastases. a phase II study of the EORTC Lung Cancer Group (08965). Eur J Cancer 2003; 39(9): 1271-6.
43. Boogerd W, van der Sande JJ, van ZN. Teniposide sometimes effective in brain metastases from non-small cell lung cancer. J Neurooncol 1999; 41(3): 285-9.
44. Minotti V, Crino L, Meacci ML, Corgna E, Darwish S, Palladino MA, et al. Chemotherapy with cisplatin and teniposide for cerebral metastases in non-small cell lung cancer. Lung Cancer 1998; 20(2): 93-8.
45. Malacarne P, Santini A, Maestri A. Response of brain metastases from lung cancer to systemic chemotherapy with carboplatin and etoposide. Oncology 1996; 53(3): 210-3.
46. Donelli MG, Zucchetti M, D'Incalci M. Do anticancer agents reach the tumor target in the human brain? Cancer Chemother Pharmacol 1992; 30(4): 251-60.
47. Neijstrom ES, Capizzi RL, Rudnick SA, Kirsch M, Delaney D, Kahn L, et al. High-dose methotrexate in small cell lung cancer. Lack of efficacy in preventing CNS relapse. Cancer 1983; 51(6): 1056-61.
48. Schinkel AH, Wagenaar E, Mol CA, van DL. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 1996; 97(11): 2517-24.
49. Postmus PE, Holthuis JJ, Haaxma-Reiche H, Mulder NH, Vencken LM, van Oort WJ, et al. Penetration of VP 16-213 into cerebrospinal fluid after high-dose intravenous administration. J Clin Oncol 1984; 2(3): 215-20.
50. Gerstner ER, Fine RL. Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol 2007; 25(16): 2306-12.
51. Stapleton SL, Reid JM, Thompson PA, Ames MM, McGovern RM, McGuffey L, et al. Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates. Cancer Chemother Pharmacol 2007; 59(4): 461-6.
52. Dai H, Chen Y, Elmquist WF. Distribution of the novel antifolate pemetrexed to the brain. J Pharmacol Exp Ther 2005; 315(1): 222-9.
53. Omlin A, D'Addario G, Gillessen S, Cerny T, von HA, Fruh M. Activity of pemetrexed against brain metastases in a patient with adenocarcinoma of the lung. Lung Cancer 2009 [Epub ahead of print].
54. Westerhof GR, Schornagel JH, Kathmann I, Jackman AL, Rosowsky A, Forsch RA, et al. Carrier- and receptor-mediated transport of folate antagonists targeting folate-dependent enzymes: correlates of molecular-structure and biological activity. Mol Pharmacol 1995; 48(3): 459-71.
55. Jackman AL, Taylor GA, Gibson W, Kimbell R, Brown M, Calvert AH, et al. ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study. Cancer Res 1991; 51(20): 5579-86.
56. Rustum YM, Harstrick A, Cao S, Vanhoefer U, Yin MB, Wilke H, et al. Thymidylate synthase inhibitors in cancer therapy: direct and indirect inhibitors. J Clin Oncol 1997; 15(1): 389-400.
57. Spears CP, Gustavsson BG, Berne M, Frosing R, Bernstein L, Hayes AA. Mechanisms of innate resistance to thymidylate synthase inhibition after 5-fluorouracil. Cancer Res 1988; 48(20): 5894-5900.
58. Pizzorno G, Moroson BA, Cashmore AR, Russello O, Mayer JR, Galivan J, et al. Multifactorial resistance to 5,10-dideazatetrahydrofolic acid in cell lines derived from human lymphoblastic leukemia CCRF-CEM. Cancer Res 1995; 55(3): 566-73.
59. Rees C, Beale P, Trigo JM, Mitchell F, Jackman A, Smith R, et al. Phase I trial of ZD9331, a nonpolyglutamatable thymidylate synthase inhibitor, given as a 5-day continuous infusion to patients with refractory solid malignancies. Clin Cancer Res 2003; 9(6): 2049-55.
60. de Jonge MJ, Punt CJ, Sparreboom A, Planting AS, Peters ME, van De SJ, et al. Phase I and pharmacologic study of oral ZD9331, a novel nonpolyglutamated thymidylate synthase inhibitor, in adult patients with solid tumors. J Clin Oncol 2002; 20(7): 1923-31.
61. Worzalla JF, Shih C, Schultz RM. Role of folic acid in modulating the toxicity and efficacy of the multitargeted antifolate, LY231514. Anticancer Res 1998; 18(5A): 3235-9.
62. Niyikiza C, Baker SD, Seitz DE, Walling JM, Nelson K, Rusthoven JJ, et al. Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy. Mol Cancer Ther 2002; 1(7): 545-52.
63. Bunn P, Paoletti P, Nyikiza C. Vitamin B12 and folate reduce toxiciy of Alimta (Pemetrexed Disodium LY231514, MTA) a novel antifolate/ antimetabolite. Proc Am Soc Clin Oncol 2001; 20(76a).
64. Cullen MH, Zatloukal P, Sorenson S, Novello S, Fischer JR, Joy AA, et al. A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer. Ann Oncol 2008; 19(5): 939-45.
65. Clarke SJ, Abratt R, Goedhals L, Boyer MJ, Millward MJ, Ackland SP. Phase II trial of pemetrexed disodium (ALIMTA, LY231514) in chemo-therapy-naive patients with advanced non-small-cell lung cancer. Ann Oncol 2002; 13(5): 737-41.
66. Rusthoven JJ, Eisenhauer E, Butts C, Gregg R, Dancey J, Fisher B, et al. Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced non-small-cell lung cancer: A phase II study. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1999; 17(4): 1194.
67. Smit EF, Mattson K, von PJ, Manegold C, Clarke S, Postmus PE. ALIMTA (pemetrexed disodium) as second-line treatment of non-small-cell lung cancer: a phase II study. Ann Oncol 2003; 14(3): 455-60.
68. Belani CP, Brodowicz T, Ciuleanu T, Kim JH, Krzakowski M, Laack E, et al. Maintenance pemetrexed (Pem) plus best supportive care (BSC) versus placebo (Plac) plus BSC: A randomized phase III study in advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2009; 27(18s).
69. Clarke SJ, Boyer MJ, Millward M, Underhill C, Moylan E, Yip D, et al. A phase I/II study of pemetrexed and vinorelbine in patients with non-small cell lung cancer. Lung Cancer 2005; 49(3): 401-12.
70. Manegold C, Gatzemeier U, von PJ, Pirker R, Malayeri R, Blatter J, et al. Front-line treatment of advanced non-small-cell lung cancer with MTA (LY231514, pemetrexed disodium, ALIMTA) and cisplatin: a multicenter phase II trial. Ann Oncol 2000; 11(4): 435-40.
71. Shepherd FA, Dancey J, Arnold A, Neville A, Rusthoven J, Johnson RD, et al. Phase II study of pemetrexed disodium, a multitargeted antifolate, and cisplatin as first-line therapy in patients with advanced nonsmall cell lung carcinoma: a study of the National Cancer Institute of Canada Clinical Trials Group. Cancer 2001; 92(3): 595-600.
72. Zinner RG, Fossella FV, Gladish GW, Glisson BS, Blumenschein GR Jr, Papadimitrakopoulou VA, et al. Phase II study of pemetrexed in combination with carboplatin in the first-line treatment of advanced nonsmall cell lung cancer. Cancer 2005; 104(11): 2449-56.
73. Scagliotti GV, Kortsik C, Dark GG, Price A, Manegold C, Rosell R, et al. Pemetrexed combined with oxaliplatin or carboplatin as first-line treatment in advanced non-small cell lung cancer: a multicenter, randomized, phase II trial. Clin Cancer Res 2005; 11(2 Pt 1): 690-6.
74. Monnerat C, Le CT, Kelly K, Obasaju CK, Brahmer J, Novello S, et al. Phase II study of pemetrexed-gemcitabine combination in patients with advanced-stage non-small cell lung cancer. Clin Cancer Res 2004; 10(16): 5439-46.
75. Kelly K, Crowley J, Bunn PA, Jr., Presant CA, Grevstad PK, Moinpour CM, et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 2001; 19(13): 3210-8.
76. Gronberg BH, Bremnes RM, Flotten O, Amundsen T, Brunsvig PF, Hjelde HH, et al. Phase III Study by the Norwegian Lung Cancer Study Group: Pemetrexed Plus Carboplatin Compared With Gemcitabine Plus Carboplatin As First-Line Chemotherapy in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 2009 [Epub ahead of print].
77. Smit EF, Burgers SA, Biesma B, Smit HJ, Eppinga P, Dingemans AM, et al. Randomized phase II and pharmacogenetic study of pemetrexed compared with pemetrexed plus carboplatin in pretreated patients with advanced non-small-cell lung cancer. J Clin Oncol 2009; 27(12): 2038-45.
78. Gronberg BH, Bremnes RM, Aasebo U, Brunsvig P, Flotten O, Amundsen T, et al. A prospective phase II study: high-dose pemetrexed as second-line chemotherapy in small-cell lung cancer. Lung Cancer 2009; 63(1): 88-93.
79. Socinski MA, Raju RN, Neubauer M, Smith DA, Richards DA, Savin M, et al. Pemetrexed in relapsed small-cell lung cancer and the impact of shortened vitamin supplementation lead-in time: results of a phase II trial. J Thorac Oncol 2008; 3(11): 1308-16.
80. Jalal S, Ansari R, Govindan R, Bhatia S, Bruetman D, Fisher W, et al. Pemetrexed in second line and beyond small cell lung cancer: a Hoosier Oncology Group phase II study. J Thorac Oncol 2009; 4(1): 93-6.
81. Socinski MA, Smit EF, Lorigan P, Konduri K, Reck M, Szczesna A, et al. Phase III study of pemetrexed plus carboplatin (PC) versus etoposide plus carboplatin (EC) in chemonaive patients with extensive-stage disease small-cell lung cancer (ED-SCLC): Interim results. ASCO Annual Meeting 2008; NSA.
82. Peterson Pea. Is pemetrexed more effective in adenocarcinoma and large cell lung cancer than in squamous cell carcinoma? A retrospective analysis of a phase III trial of pemetrexed versus docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC). WCLC Seoul 2007, #P2-328 2007.
83. Georgoulias V, Papadakis E, Alexopoulos A, Tsiafaki X, Rapti A, Veslemes M, et al. Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet 2001; 357(9267): 1478-84.
84. Nakagawa T, Tanaka F, Otake Y, Yanagihara K, Miyahara R, Matsuoka K, et al. Prognostic value of thymidylate synthase expression in patients with p-stage I adenocarcinoma of the lung. Lung Cancer 2002; 35(2): 165-70.
85. Nakagawa T, Otake Y, Yanagihara K, Miyahara R, Ishikawa S, Fukushima M, et al. Expression of thymidylate synthase is correlated with proliferative activity in non-small cell lung cancer (NSCLC). Lung Cancer 2004; 43(2): 145-9.
86. Kamoshida S, Shiogama K, Shimomura R, Inada K, Sakurai Y, Ochiai M, et al. Immunohistochemical demonstration of fluoropyrimidine-metabolizing enzymes in various types of cancer. Oncol Rep 2005; 14(5): 1223-30.
87. Ishihama H, Chida M, Araki O, Karube Y, Seki N, Tamura M, et al. Comparison of 5-fluorouracil-related gene expression levels between adenocarcinomas and squamous cell carcinomas of the lung. Jpn J Clin Oncol 2009; 39(1): 33-36.
88. Ceppi P, Volante M, Saviozzi S, Rapa I, Novello S, Cambieri A, et al. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer 2006; 107(7): 1589-96.
89. Kawakami K, Watanabe G. Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of thymidylate synthase gene. Cancer Res 2003; 63(18): 6004-7.
90. Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, Ingles SA, Sherrod A, et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenom J 2001; 1(1): 65-70.
91. Iacopetta B, Grieu F, Joseph D, Elsaleh H. A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil. Br J Cancer 2001; 85(6): 827-30.
92. Jakobsen A, Nielsen JN, Gyldenkerne N, Lindeberg J. Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity. J Clin Oncol 2005; 23(7): 1365-9.
93. Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, et al. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA 2001; 98(24): 13790-5.
94. Govindan R, Bogart J, Wang X, Hodgson L, Kratzke R., Vokes EE. Phase II study of pemetrexed, carboplatin and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non small-cell lung cancer. J Clin Oncol 2009; 27(15s): Abstract 7505.