TY - JOUR
T1 - Modulation of nitrosourea resistance in human colon cancer by O6-methylguanine
AU - Gerson, Stanton L.
AU - Berger, Nathan A.
AU - Arce, Cheryl
AU - Petzold, Shirley J.
AU - Willson, James K V
N1 - Funding Information:
Acknowledgements-We thank Dr. Thomas Pretlow, CWRU Cancer Research Center Tissue Procurement Service, for his expert processingo f the colon biopsy samplesP, eterM arncoha,F eng-Ying Lu and SusanK essan for expert technical assistance,a nd Lynne Lucas for preparationo f the manuscript.T his work was supported in part by Grants ESCA-00134,C A-45609,P OlCA-51183 and P30CA-43703fr om the National Instituteso f Health and CN-34 from the American Cancer Society.
PY - 1992/3/3
Y1 - 1992/3/3
N2 - Human colon cancer is resistant to a variety of alkylating agents including the nitrosoureas. To specifically evaluate nitrosourea resistance, we studied the role of O6-alkylguanine-DNA alkyltransferase (alkyltransferase) which is known to repair nitrosourea-induced cytotoxic DNA damage. Alkyltransferase activity varied over a similar wide range in 25 colon cancer biopsies and 14 colon cancer cell lines but the activity was not correlated with differentiation status, Dukes' classification or in vitro growth characteristics. 1, 3-Bis-(2-chloroethyl)-1-nitrosourea (BCNU) resistance and alkyltransferase activity were highly correlated (R2 = 0.929, P < 0.001) in 7 different colon cancer cell lines, suggesting that the alkyltransferase is an important component of nitrosourea resistance in colon cancer cells. In the BCNU-resistant, high alkyltransferase VACO 6 cell line, inactivation of the alkyltransferase by O6-methylguanine caused a proportional decrease in the BCNU IC50, consistent with that predicted by the regression line. Enzyme inactivation was also associated with a marked increase in DNA cross-link formation. Because alkyltransferase correlates with BCNU resistance in colon cancer, and resistance can be reversed by inactivating the protein, the alkyltransferase may have an important role in nitrosourea resistance in human colon cancer cells. These data provide the rationale for clinical trials in colon cancer with biochemical modulators of the alkyltransferase to increase the therapeutic response to nitrosoureas.
AB - Human colon cancer is resistant to a variety of alkylating agents including the nitrosoureas. To specifically evaluate nitrosourea resistance, we studied the role of O6-alkylguanine-DNA alkyltransferase (alkyltransferase) which is known to repair nitrosourea-induced cytotoxic DNA damage. Alkyltransferase activity varied over a similar wide range in 25 colon cancer biopsies and 14 colon cancer cell lines but the activity was not correlated with differentiation status, Dukes' classification or in vitro growth characteristics. 1, 3-Bis-(2-chloroethyl)-1-nitrosourea (BCNU) resistance and alkyltransferase activity were highly correlated (R2 = 0.929, P < 0.001) in 7 different colon cancer cell lines, suggesting that the alkyltransferase is an important component of nitrosourea resistance in colon cancer cells. In the BCNU-resistant, high alkyltransferase VACO 6 cell line, inactivation of the alkyltransferase by O6-methylguanine caused a proportional decrease in the BCNU IC50, consistent with that predicted by the regression line. Enzyme inactivation was also associated with a marked increase in DNA cross-link formation. Because alkyltransferase correlates with BCNU resistance in colon cancer, and resistance can be reversed by inactivating the protein, the alkyltransferase may have an important role in nitrosourea resistance in human colon cancer cells. These data provide the rationale for clinical trials in colon cancer with biochemical modulators of the alkyltransferase to increase the therapeutic response to nitrosoureas.
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U2 - 10.1016/0006-2952(92)90618-S
DO - 10.1016/0006-2952(92)90618-S
M3 - Article
C2 - 1554383
AN - SCOPUS:0026582048
SN - 0006-2952
VL - 43
SP - 1101
EP - 1107
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 5
ER -