Biology Reference
In-Depth Information
animal models, can we observe the long-term genotoxic-
ity of
in vivo
chemoselection for transformed viral inte-
gration cells.
125
With the safety record and abundant positive results
of MGMT
in vivo
selection in preclinical studies, myelo-
protection with MGMT has been approved for clinic
trials. Overall, clinical trials with MGMT
in vivo
selection
showed no adverse effect on the treatment or any
possible insertional mutation. Two of the early clinical
trials showed little stem cell selection.
125,126
Combina-
tion of BG and BCNU treatment seems to have an impact
on MGMT expression. Thus in clinical trials with a BG-
resistant mutant form of MGMT designed to assess
in
vivo
selection more frequent drug selection may be
required. Our center, in collaboration with Lentigen,
who patented the use of P140KMGMT for lentiviral
gene transfer into human cells from CWRU and Penn
State, have developed a clinical trial testing the ability
to transduce CD34 cells and observe hematopoietic
stem cell selection in patients undergoing combined
radiation and temozolomide treatment for glioblastoma
multiforme.
In summary, this review addresses the role of MGMT
as a DNA repair protein involved in drug resistance and
tumorigenesis but does not address ongoing efforts to
understand its fundamental role in transcription, DNA
damage signaling and cell cycle checkpoint regulation.
The initial perspective that MGMT had a simple func-
tion in DNA repair belies its conserved function
throughout evolution, and hints that MGMT may be
a far more important protein than currently realized.
8. Candiloro IL, Dobrovic A. Detection of MGMT promoter
methylation in normal individuals is strongly associated with
the T allele of
the rs16906252 MGMT.
Cancer Prev Res
7.
9. Silber JR, Blank A, Bobola MS, et al. O
6
-methylguanine-
DNA methyltransferase-deficient phenotype in human
gliomas: Frequency and time to tumor progression after
alkylating
2009;
:862
2
e
agent-based
chemotherapy.
Clin
Cancer
Res
14.
10. Dumenco LL, Allay E, Norton K, et al. The prevention of thymic
lymphomas in transgenic mice by human O
6
-alkylguanine-DNA
alkyltransferase.
Science
1993;
1999;
5
:807
e
22.
11. Gerson SL, Zaidi NH, Dumenco LL, et al. Alkyltransferase
transgenic mice: Probes of chemical carcinogenesis.
Mutat Res
1994;
:219
259
e
55.
12. Gerson SL, Phillips W, Kastan M, et al. Human CD34
:541
307
e
hemato-
poietic progenitors have low, cytokine-unresponsive O
6
-alkyl-
guanine-DNA alkyltransferase
þ
to O
6
-
and are
sensitive
55.
13. Limp-Foster M, Kelley MR. DNA repair and gene therapy:
Implications
benzylguanine plus BCNU.
Blood
1996;
88
:1649
e
for
translational uses.
Environ Mol Mutagen
81.
14. Zaidi NH, Liu L, Gerson SL. Quantitative immunohistochemical
estimates of O
6
-alkylguanine-DNA alkyltransferase expression in
normal
2000;
:71
35
e
and malignant human colon.
Clin Cancer Res
84.
15. Redmond SM, Joncourt F, Buser K, et al. Assessment of P-
glycoprotein, glutathione-based detoxifying enzymes and O
6
-
alkylguanine-DNA alkyltransferase as potential indicators of
constitutive drug resistance in human colorectal tumors.
Cancer
Res
1991;
1996;
:577
2
e
7.
16. Moriwaki S, Nishigori C, Takebe H, et al. O
6
-alkylguanine-DNA
alkyltransferase activity in human malignant melanoma.
J Der-
matol Sci
1992;
:2092
51
e
10.
17. Lee SM, Rafferty JA, Elder RH, et al. Immunohistological exam-
ination of the inter- and intracellular distribution of O
6
-alkyl-
guanine DNA-alkyltransferase in human liver and melanoma.
Br
J Cancer
1992;
:6
4
e
60.
18. Citron M, Schoenhaus M, Graver M, et al. O
6
-methylguanine-
DNA methyltransferase in human normal and malignant lung
tissues.
Cancer Invest
1993;
66
:355
e
References
63.
19. Bobola MS, Berger MS, Ellenbogen RG, et al. O
6
-methylguanine-
DNA methyltransferase in pediatric primary brain tumors:
Relation to patient and tumor characteristics.
Clin Cancer Res
2001;
:258
11
e
1. Gerson SL. Clinical relevance of MGMT in the treatment of
cancer.
J Clin Oncol
2002;
99.
2. Citron M, Schoenhaus M, Graver M, et al. O
6
-methylguanine-
DNA methyltransferase in human normal and malignant lung
tissues.
Cancer Invest
1993;
20
:2388
e
9.
20. Chen ZP, Yarosh D, Garcia Y, et al. Relationship between O
6
-
methylguanine-DNA methyltransferase levels and clinical
response induced by chloroethylnitrosourea therapy in glioma
patients.
Can J Neurol Sci
1999;
7
:613
e
63.
3. Gerson SL, Trey JE, Miller K, et al. Comparison of O
6
-alkylgua-
nine-DNA alkyltransferase activity based on cellular DNA
content
:258
11
e
in human,
rat and mouse tissues.
Carcinogenesis
9.
21. Batts ED, Maisel C, Kane D, et al. O(6)-benzylguanine and BCNU
in multiple myeloma: a phase II trial.
Cancer Chemother Pharmacol
2007;
:104
26
e
9.
4. Souliotis VL, Zongza V, Nikolopoulou V, et al. Measurement of
O
6
-methylguanine-type adducts in DNA and O
6
-alkylguanine-
DNA-alkyltransferase repair activity in normal and neoplastic
human tissues.
Comp Biochem Physiol B
1992;
1986;
:745
7
e
21.
22. Geoffrey P, Margison GP, Santib´ ˜ ez Koref MF, Povey AC.
Mechanisms of carcinogenicity/chemotherapy by O
6
-methyl-
guanine.
Mutagenesis
2002;
:415
60
e
75.
5 Silber JR, Blank A, Bobola MS, et al. O
6
-methylguanine-DNA
methyltransferase-deficient phenotype in human gliomas:
Frequency and time to tumor progression after alkylating agent-
based chemotherapy.
Clin Cancer Res
1999;
:269
101
e
7.
23. Rydberg B, Lindahl T. Nonenzymatic methylation of DNA by the
intracellular methyl group donor S-adenosyl-L-methionine is
a potentially mutagenic reaction.
EMBO J
1982;
17
:483
e
14.
6. Gerson SL, Phillips W, Kastan M, et al. Human CD34
:807
5
e
6.
24. Liu L, Qin X, Gerson SL. Reduced lung tumorigenesis in human
methylguanine DNA-methyltransferase transgenic mice ach-
ieved by expression of transgene within the target cell.
Carcino-
genesis
1999;
(2):211
hemato-
poietic progenitors have low, cytokine-unresponsive O
6
-alkyl-
guanine-DNA alkyltransferase
1
e
þ
to O
6
-
and are
sensitive
55.
7. Kokkinakis DM, Ahmed MM, Delgado R, et al. Role of O
6
-
methylguanine-DNA methyltransferase in the resistance of
pancreatic
benzylguanine plus BCNU.
Blood
1996;
:1649
88
e
84.
25. Pegg AE. Mammalian O
6
-alkylguanine-DNA alkyltransferase:
regulation and importance in response to alkylating carcinogen-
esis and therapeutic agents.
Cancer Res.
1990;
:279
20
e
tumors
to DNA alkylating agents.
Cancer Res
1997;
57
:5360
e
8.
50
:6119
e
29.
