MGMT: Its role in cancer aetiology and cancer therapeutics

Nature Reviews Cancer

Volumn 4, Issue 4, 2004, Pages 296-307

  Gerson, Stanton L ^a  

^a UNIVERSITY HOSPITALS OF CLEVELAND   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6 O ALKYLGUANINE DNA ALKYLTRANSFERASE; 6 O BENZYLGUANINE; ALKYLATING AGENT; CARMUSTINE; DACARBAZINE; DRUG METABOLITE; FOTOMUSTINE; GUANINE; LOMUSTINE; NIMUSTINE; O 6 (4 BROMOETHENYL)GUANINE; O 6 BENZYL 2' DEOXYGUANOSINE; O 6 BENZYL 8 OXOGUANINE; POLYDEOXYRIBONUCLEOTIDE SYNTHASE; PROCARBAZINE; STREPTOZOCIN; TEMOZOLOMIDE; UNCLASSIFIED DRUG;

ALKYLATION; CANCER CHEMOTHERAPY; CANCER GENETICS; CANCER PATIENT; CANCER PREVENTION; CANCER RISK; CARCINOGENESIS; CELL FUNCTION; CELL PROTECTION; CLINICAL TRIAL; DNA REPAIR; DRUG MECHANISM; DRUG TARGETING; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME STRUCTURE; GENE; GENE FUNCTION; GENE MUTATION; GENE OVEREXPRESSION; GENE THERAPY; GENE TRANSFER; GENETIC ANALYSIS; GENETIC CODE; GENETIC CONSERVATION; GENETIC REGULATION; GENETIC STABILITY; GENOME; HEMATOPOIETIC STEM CELL; HUMAN; INHIBITION KINETICS; MALIGNANT NEOPLASTIC DISEASE; MALIGNANT TRANSFORMATION; METHYLATED DNA PROTEIN CYSTEINE METHYLTRANSFERASE GENE; METHYLATION; MOLECULAR EVOLUTION; MUTAGENESIS; NONHUMAN; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; STEM CELL; STRUCTURE ANALYSIS; TISSUE;

EID: 1942469956     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc1319     Document Type: Review

References (133)

1. Wood, R., Biggerstaff, M. & Shivji, M. K. Detection and measurement of nucleotide excision repair synthesis by mammalian cell extracts in vitro. Comp. Methods Enzymol. 7, 163-175 (1995).
2. Wilson, S. H. Mammalian base excision repair and DNA polymerase β. Mutat. Res. 407, 203-215 (1998).
3. Karran, P. & Bignami, M. DNA damage tolerance, mismatch repair and genome instability. Bioessays 16, 833-839 (1994).
4. Frei, J. et al. Alkylation of deoxyribonucleic acid in vivo in various organs of C57BL mice by the carcinogens N-methyl-N-nitrosourea, N-ethyl-N-nitrosourea, and ethyl methanesulphonate in relation to induction of thymic lymphoma. Biochem. J. 174, 1031-1044 (1978).
5. 6alkylguanine-DNA alkyltransferase activity determinations in rat mammary carcinogenesis by procarbazine and N-methyl-N-nitrosourea. Carcinogenesis 11, 411-417 (1990).
6. 6-alkylguanine-DNA alkyltransferase. Science 259, 219-222 (1993).
7. 6-methylguanine-DNA methyltransferase during diethylnitrosamine-induced carcinogenesis and liver regeneration in Sprague-Dawley male rats. J. Cancer Res. Clin. Oncol. 125, 493-499 (1999).
8. Peterson, L. A. et al. Interactions between methylating and pyridyloxobutylating agents in A/J mouse lungs: implications for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis. Cancer Res. 61, 5757-5763 (2001).
9. Zaidi, N. H. et al. Transgenic expression of human MGMT protects against azoxymethane-induced aberrant crypt foci and G to A mutations in the K-ras oncogene of mouse colon. Carcinogenesis 16, 451-456 (1995).
10. Posnick, L. M. & Samson, L. D. Influence of S-adenosylmethionine pool size on spontaneous mutation, dam methylation, and cell growth of Escherichia coli. J. Bacteriol. 181, 6756-6762 (1999).
11. 6-alkylguanine-DNA alkyltransferase. IARC Sci. Publ. 84, 41-43 (1987).
12. 6-alkylguanine-DNA alkyltransferase complexed with BCNU-treated, synthetic oligonuoleotide. Nucleic Acids Res. 17, 6581-6590 (1989).
13. Day, R. S. I., Ziolkowski, C. H. J., Scudiero, D. A., Meyer, S. A. & Mattern, M. R. Human tumor cell strains defective in the repair of alkylation damage. Carcinogenesis 1, 21-32 (1980).
14. 6-ethylguanine in rat brain DNA: correlation with nervous-system-specific Carcinogenesis by ethylnitrosourea. Proc. Natl Acad. Sci. 71, 639-643 (1974).
15. Balling, R. ENU mutagenesis: analyzing gene function in mice. Annu. Rev. Genomics Hum. Genet. 2, 463-492 (2001).
16. 6-methylguanine repair and replication in vivo. Biochemistry 40, 14968-14975 (2001).
17. 6 methylguanine mediated carcinogenic mutations to threshold levels after N-methyl-N-nitrosourea. Oncogene 18, 3783-3787 (1999).
18. 6-methylguanine-DNA methyltransferase-deficient cells in comparison with proficient cells. Cancer Res. 51, 6219-6223 (1991).
19. 6-alkylguanine-DNA alkyltransferase and nucleotide excision repair activities in human cells. Cancer Res, 52, 2008-2011 (1992).
20. 6-alkylguanine-DNA alkyltransferase. Cancer Res. 53, 997-1003 (1993).
21. 6-methylguanine and methylphosphotriester methyltransferase gene using a functional DNA repair assay. Nucleic Acids Res. 13, 1939-1952 (1985).
22. 6-alkylguanine. Proc. Natl Acad. Sci. USA 87, 686-690 (1990). Isolation and sequence of the human MGMT gene.
23. 6-methylguanine-DNA methyltransferase. Carcinogenesis 13, 289-296 (1992).
24. 6-methylguanine-DNA methyltransferase from E. coli. EMBO J. 13, 1495-1501 (1994).
25. 6-AG-DNA alkyltransferase protein, revealing the active-site pocket and the mechanisms of action.
26. 6-methylguanine-DNA methyltransferase is a proteolytic target for the E6 human papillomavirus oncoprotein. Oncogene 21, 5940-5945 (2002).
27. 6-alkylguanine by alkyltransferases. Mutat Res. 462, 83-100 (2000).
28. 6-methylguanine-DNA methyltransferase enhancer binding protein in DNA repair-deficient human cells. Proc. Natl Acad. Sci. USA 94, 4348-4353 (1997).
29. 6-methylguanine -DNA methyltransferase are both required for its nuclear localization: the possible implications. EMBO J. 15, 4050-4060 (1996).
30. 6-alkylguanine-DNA alkyltransferase in human brain tumor cells. Cancer Res. 60, 282-287 (2000).
31. 6-methylguanine-DNA adducts protects transgenic mice from N-methylnitrosourea-induced thymic lymphomas. Cancer Res. 54, 4648-4652 (1994).
32. 6-methylguanine-DNA methyltransferase protects against nitrosamine-induced hepatocarcinogenesis. Proc. Natl Acad. Sci. USA 90, 6468-6472 (1993).
33. 6-methylguanine-DNA methyltransferase (MGMT) in transgenic mice protects against tumor initiation in two-stage skin carcinogenesis. Cancer Res. 56, 3244-3249 (1996).
34. Liu, L., Qin, X. & Gerson, S. L. Reduced lung tumorigenesis in human methylguanine DNA-methyltransferase transgenic mice achieved by expression of transgene within the target cell. Carcinogenesis 20, 279-284 (1999).
35. 6-methylguanine-DNA methyltransferase. Proc. Natl Acad. Sci. USA 98, 12566-12571 (2001).
36. Qin, X. et al. Transgenic expression of human MGMT blocks the hypersensitivity of PMS2-deficient mice to low dose MNU thymic lymphomagenesis. Carcinogenesis 20, 1667-1673 (1999).
37. 6-alkylguanine DNA-alkyltransferase. Oncogene 15, 2127-2132 (1997).
38. 6-alkylguanine DNA-alkyltransferase. (AGT) prevents MNU induced lymphomas in heterozygous p53 deficient mice. Oncogene 20, 5258-5263 (2001).
39. Shiraishi, A., Sakumi, K. & Sekiguchi, M. Increased susceptibility to chemotherapeutic alkylating agents of mice deficient in DNA repair methyltransferase. Carcinogenesis 21, 1879-1883 (2000). This group first reported the phenotype of Mgmt loss in vivo, with increased mutagenesis, carcinogenesis and sensitivity to chemotherapy.
40. Glassner, B. et al. DNA repair methyltransferase (MGMT) knockout mice are sensitive to the lethal effects of chemotherapeutic alkylating agents. Mutagenesis 14, 339-347 (1999).
41. Kawate, H. et al. Separation of killing and tumorigenic effects of an alkylating agent in mice defective in two of the DNA repair genes. Proc. Natl Acad. Sci. USA 95, 5116-5120 (1998).
42. 6-alkylguanine-DNA alkyltransferase activity based on cellular DNA content in human, rat and mouse tissues. Carcinogenesis 7, 745-749 (1986).
43. 6-alkylguanine-DNA alkyltransferase activity in normal and tumour tissue from human colon and rectum. Int. J. Cancer 85, 68-72 (2000).
44. 6-methylguanine-DNA methyltransferase. Cancer Chemother Pharmacol. 37, 547-555 (1996).
45. 6methylguanine-DNA methyltransferase in histologically normal brain adjacent to primary human brain tumors. Proc. Natl Acad. Sci. USA 93, 6941-6946 (1996).
46. 6-alkylguanine during DNA synthesis in murine bone marrow hematopoietic precursors. Cancer Res. 47, 89-95 (1987).
47. 6-methylguanine-DNA methyltransferase in human normal and tumor tissue from brain, lung and ovary. Cancer Res. 51, 4131-4134 (1991).
48. 6-methylguanine. Biochem. Pharmacol. 43, 1101-1107 (1992).
49. 6-alkylguanine-DNA alkyltransferase. A target for the modulation of drug resistance. Hematol. Oncol. Clin. North Am. 9, 431-450 (1995).
50. 6-alkylguanine-DNA alkyltransferase and sensitivity to procarbazine in human brain-tumor xenografts. J. Neurosurg, 70, 573-577 (1989).
51. 6alkylguanine-DNA alkyltransferase activity correlates with the therapeutic response of human rhabdomyosarcoma xenografts to 1-(2-chloroethyl)-3-(trans-4-methyl-cyclohexyl)-1-nitrosourea. Proc. Natl. Acad. Sci. USA 82, 2985-2989 (1985).
52. Liu, L., Markowitz, S. & Gerson, S. L. Mismatch repair mutations override alkyltransferase in conferring resistance to temozolomide but not to 1,3-bis(2-chloroethyl) nitrosourea. Cancer Res. 56, 5375-5379 (1996).
53. Aquilina, G. et al. N-(2-chloroethyl)-N′-cyclohexyl-N-nitrosourea sensitivity in mismatch repair-defective human cells. Mutat Res. 381, 227-241 (1997).
54. Aquilina, G. et al. N-(2-chloroethyl)-N′-cyclohexyl-N-nitrosourea sensitivity in mismatch repair-defective human cells. Cancer Res. 58, 135-141 (1998).
55. Grombacher, T., Mitra, S. & Kaina, B. Induction of the alkyltransferase (MGMT) gene by DNA damaging agents and the glucocorticoid dexamethasone and comparison with the response of base excision repair genes. Carcinogenesis 17, 2329-2336 (1996).
56. 6-methylguanine-DNA methyltransferase gene by glucocorticoid hormone. Oncogene 18, 525-532 (1999).
57. 6-alkylguanine-DNA alkyltransferase mRNA expression in rat liver during regeneration, inflammation and preneoplasia. J. Cancer Res. Clin. Oncol. 127, 591-602 (2001).
58. 6-methylguanine DNA methyltransferase (MGMT) CpG island is associated with heterochromatinization of the MGMT transcription start site and silencing of the gene. Mol. Cell. Biol. 17, 5612-5619 (1997).
59. 6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res. 59, 793-797 (1999). First report of MGMT promoter methylation leading to loss of MGMT expression in human tumors in vivo.
60. Kang, G. H. et al. Epstein-Barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma. Am. J. Pathol. 160, 787-794 (2002).
61. 6-methylguanine DNA methyltransferase gene is associated with the loss of nucleosome-like positioning. Mol. Cell. Biol. 17, 5813-5822 (1997).
62. 6-methylguanine-DNA methyltransferase in sputum. Cancer Res. 62, 2248-2252 (2002).
63. 6-methylguanine-DNA methyltransferase gene by transcriptional coactivators cAMP response element-binding protein-binding protein and p300. J. Biol. Chem. 275, 34197-34204 (2000).
64. 6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res. 60, 2368-2371 (2000).
65. 6-methylguanine-DNA methyltransferase gene is associated significantly with K-ras mutation, lymph node invasion, tumor staging, and disease free survival in patients with gastric carcinoma. Cancer 92, 2760-2768 (2001).
66. Nakamura, M. et al. Promoter methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C→A:T mutations of the TP53 tumor suppressor gene. Carcinogenesis 22, 1715-1719 (2001).
67. 6-Methylguanine-DNA methyltransferase promoter hypermethylation shifts the p53 mutational spectrum in non-small cell lung cancer. Cancer Res. 61, 8113-8117 (2001).
68. 6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B1-DNA adducts and p53 mutation in hepatocellular carcinoma. Int. J. Cancer 103, 440-444 (2003).
69. 6-methylguanine-DNA methyltransferase in human lung adenocarcinoma relates to high-grade histology and worse prognosis among smokers. Jpn. J. Cancer Res. 93, 184-189 (2002).
70. 6-methylguanine-DNA methyltransferase combined with mismatch-repair proteins hMLH1 and hMSH2 is related to poor prognosis in human biliary tract carcinoma. Ann. Surg. Oncol. 9, 371-379 (2002).
71. Esteller, M. et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N. Engl. J. Med. 343, 1350-1354 (2000). Indication that loss of MGMT expression through promoter methylation improved disease prognosis after chemotherapy.
72. 6-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma. J. Natl Cancer Inst. 94, 26-32 (2002).
73. Dolan, M. E. & Schilsky, R. L. Silence is golden: gene hypermethylation and survival in large-cell lymphoma. J. Natl Cancer Inst. 94, 6-7 (2002).
74. 6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a Southwest Oncology Group study. J Clin. Oncol. 16, 3310-3315 (1998).
75. 6-methylguanine-DNA methyltransferase to monofunctional alkylating-agent resistance in human brain tumor-derived cell lines. Mol. Carcinog. 13, 70-80 (1995).
76. 6-benzylguanine plus chloroethylnitrosoureas in human breast cancer. Cancer Chemother. Pharmacol. 44, 319-326 (1999).
77. 6-alkylguanine alkyltransferase-directed DNA repair in metastatic colon cancers. J. Clin. Oncol. 13, 2301-2308 (1995).
78. 6-BG, a potent inhibitor of alkyltransferase.
79. 6-benzylguanine using a transgenic model. Cancer Res. 56, 1880-1885 (1996).
80. Daniels, D. S. et al. Active and alkylated human AGT structures: a novel zinc site, inhibitor and extrahelical base binding. EMBO J. 19, 1719-1730 (2000).
81. 6-alkylguanine-DNA alkyltransferase. Prog. Nucleic Acid Res. Mol. Biol. 51, 167-223 (1995).
82. 6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in a human colon cancer xenograft completely resistant to BCNU alone. Biochem. Pharmacol. 45, 483-491 (1993).
83. 6-benzylguanine in vitro and in vivo. J. Pharmacol. Exp. Ther. 291, 1269-1275 (1999).
84. 6-BG causing complete inhibition of human tumour alkyltranseferase could be reached without toxicity.
85. 6-benzylguanine followed by carmustine in patients with advanced cancer. Clin. Cancer Res. 6, 3025-3031 (2000).
86. 6-benzylguanine for patients undergoing surgery for malignant glioma. J. Clin. Oncol. 16, 3570-3575 (1998).
87. Dowlati, A. et al. Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation. Clin. Cancer Res. 7, 2971-2976 (2001).
88. 6-benzylguanine in humans: metabolic, pharmacokinetic, and pharmacodynamic findings. J. Clin. Oncol. 16, 1803-1810 (1998).
89. 6-benzylguanine: implications for dacarbazine activation. Clin. Cancer Res. 7, 4239-4244 (2001).
90. 6-benzylguanine for patients with recurrent or progressive malignant glioma. J. Clin. Oncol. 18, 3522-3528 (2000).
91. 6benzylguanine and BCNU in multiple myeloma. Proc. Am. Soc. Clin. Oncol. 22, 602 (2003).
92. 6benzylguanine and topical BCNU in the treatment of T-cell cutaneous lymphoma. Proc. Am. Soc. Clin. Oncol. 22, 571 (2002).
93. 6-benzyguanine in patients with recurrent malignant glioma. Proc. Am. Soc. Clin. Oncol. 21, 314 (2001).
94. 6-benzylguanine in the treatment of patients with recurrent or progressive cerebral anaplastic gliomas. Proc. Am. Soc. Clin. Oncol. 22, 103 (2003).
95. 6-benzylguanine in the treatment of patients with recurrent or progressive cerebral anaplastic gliomas. Proc. Am. Soc. Clin. Oncol. 22, 311 (2003).
96. 6-(4-bromothenyl)guanine on different temozolomide schedules in a human melanoma xenograft model. Int. J. Cancer 100, 615-617 (2002).
97. 6-benzyl-2′-deoxyguanosine and 1,3-bis(2-chloroethyl)1-nitrosourea. Clin. Cancer Res. 5, 3676-3681 (1999).
98. 6-methylguanine-DNA methyltransferase mRNA in brain-tumor model resistant to chloroethyl-nitrosourea. AntiCancer Res. 22, 2029-2036 (2002).
99. Mariani, L. et al. Ribozyme and free alkylated base: a dual approach for sensitizing Mex+ cells to the alkylating antineoplastic drug. Cancer Gene Ther 7, 905-909 (2000).
100. 6-alkylguanine-DNA alkyltransferase gene in normal tissue and cancer. Clin Cancer Res. 5, 209-213 (1999).
101. 6-methylguanine-DNA methyltransferase gene in esophageal cancer tissues from Northern China. Int. J. Cancer 71, 719-723 (1997).
102. 6-benzylguanine. Biochem. Pharmacol. 58, 1279-1285 (1999).
103. 6-alkylguanine-DNA alkyltransferase: identification of a missense variation in the active site region. Pharmacogenetics 9, 81-87 (1999).
104. 6-alkylguanine DNA alkyltransferase gene in lung cancer risk. Cancer Epidemiol. Biomarkers Prev. 9, 339-342 (2000).
105. 6-methylguanine-DNA methyltransferase SNPs: a frequency comparison of patients with familial melanoma and healthy individuals in Sweden. Hum. Mutat. 20, 408-409 (2002).
106. 6-methylguanine-DNA methyltransferase (MGMT) and N-methylpurine-DNA glycosylase (MPG) in lung cancer patients from Poland. Hum. Mutat. 14, 269-270 (1999).
107. 6-methylguanine-DNA methyltransferase. Biochemistry 36, 5769-5776 (1997).
108. 6-BG-resistant.
109. Encell, L. P., Coates, M. M. & Loeb, L. A. Engineering human DNA alkyltransferases for gene therapy using random sequence mutagenesis. Cancer Res. 58, 1013-1020 (1998).
110. 6-benzylguanine-resistant DNA alkyltransferases in human hematopoietic cells. Proc. Natl Acad. Sci. USA 98, 4950-4954 (2001).
111. 6-benzylguanine-resistant alkyltransferase mutations in mismatch-deficient colon cancer. Cancer Res. 62, 3070-3076 (2002).
112. Reese, J. S. et al. MGMT expression in murine bone marrow is a major determinant of animal survival after alkylating agent exposure. J. Hematother. Stem Cell Res. 10, 115-123 (2001).
113. Lazarus, H. M. et al. High-dose carmustine, etoposide, and cisplatin and autologous bone marrow transplantation for relapsed and refractory lymphoma. J. Clin. Oncol. 10, 1682-1689 (1992).
114. 6-methylguanine-DNA methyltransferase-transduced marrow progenitors repopulate nonmyeloablated mice after drug selection. Blood 95, 3078-3084 (2000). Indication that mutant MGMT genes delivered by gene transfer into haematopoietic stem cells can allow selective survival and at least 300-fold enrichment in vivo.
115. Ragg, S. et al. Direct reversal of DNA damage by mutant methyltransferase protein protects mice against dose-intensified chemotherapy and leads to in vivo selection of hematopoietic stem cells. Cancer Res. 60, 5187-5195 (2000).
116. Bowman, J. et al. Myeloablation is not required to select and maintain expression of the drug resistance gene, mutant MGMT, in primary and secondary recipients. Mol. Ther. 8, 42-50 (2003).
117. 6-benzylguanine and 1,3-bis(2chloroethyl) -1-nitrosourea and allows intensive therapy of 1,3-bis(2-chloroethyl)-1-nitrosourea-resistant human colon cancer xenografts. Hum. Gene Ther. 10, 1021-1030 (1999).
118. Abkowitz, J. et al. Evidence that the number of hematopoietic stem cells is conserved in mammals. Blood 100, 2665-2667 (2002).
119. + hematopoietic progenitors at low multiplicity of infection confers significant resistance to BG/BCNU and allows selection in vitro. Mol. Ther. 5, 381-387 (2002).
120. Zielske, S. et al. In vivo selection of MGMT(P140K) lentivirus-transduced human NOD/SCID repopulating cells without pretransplant irradiation conditioning. J. Clin. Invest. 112, 1561-1570 (2003).
121. Tano, K. et al. Site-directed mutation of the Escherichia coli ada gene: effects of substitution of methyl acceptor cysteine-321 by histidine in Ada protein. J. Bacteriol. 171, 1535-1543 (1989).
122. 6-alkylguanine-DNA alkyltransferase. Mutat. Res. 460, 151-163 (2000).
123. Iwakuma, T. et al. Organization and expression of the mouse gene for DNA repair methyltransferase. DNA Cell Biol. 15, 863-872 (1996).
124. 6-benzylguanine (NSC-637037) and BCNU (carmustine, NSC-409962) in male and female Beagle dogs. Proc. Am. Assoc. Cancer Res. 36, 328 (1994).
125. 6-alkylguanine-DNA alkyltransferase DNA repair in mycobacteria: pathogenic and non-pathogenic species differ. Tuberculosis 82, 45-53 (2002).
126. Chinot, O. et al. Safety and efficacy of temozolomide in patients with recurrent anaplastic oligodendrogliomas after standard radiotherapy and chemotherapy. J. Clin. Oncol. 19, 2449-2455 (2001).
127. Macdonald, D., Temozolomide for recurrent high-grade glioma. Semin. Oncol. 28, 3-12 (2001).
128. 6-methylguanine in human leukocyte DNA after intravenous exposure to dacarbazine. Carcinogenesis 12, 285-288 (1991).
129. Spiro, T., Liu, L. & Gerson, S. New cytotoxic agents for the treatment of metastatic malignant melanoma: temozolomide and related alkylating agents in combination with guanine analogues to abrogate drug resistance. Forum (Genova) 10, 274-285 (2000).
130. Lazarus, H. M. et al. Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for relapsed non-Hodgkin's lymphoma: blood and bone marrow progenitor growth studies. A phase II Eastern Cooperative Oncology Group Trial. Blood 78, 830-837 (1991).
131. Ron, J. et al. Long-term follow-up in managing anaplastic astrocytoma by multimodality approach with surgery followed by postoperative radiotherapy and PCV-chemotherapy: phase II trial. Am. J. Clin. Oncol. 25, 296-302 (2002).
132. Westphal, M. et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neurooncol. 5, 79-88 (2003).
133. Sakumi, K. et al. Methylnitrosourea-induced tumorigenesis in MGMT gene knockout mice. Cancer Res. 57, 2415-2418 (1997).