Quantitative relationship between guanine O(6)-alkyl lesions produced by Onrigin™ and tumor resistance by O(6)-alkylguanine-DNA alkyltransferase.

Biochemical Pharmacology
Kimiko IshiguroA C Sartorelli

Abstract

O(6)-Alkylguanine-DNA alkyltransferase (AGT) mediates tumor resistance to alkylating agents that generate guanine O(6)-chloroethyl (Onrigin™ and carmustine) and O(6)-methyl (temozolomide) lesions; however, the relative efficiency of AGT protection against these lesions and the degree of resistance to these agents that a given number of AGT molecules produces are unclear. Measured from differential cytotoxicity in AGT-ablated and AGT-intact HL-60 cells containing 17,000 AGT molecules/cell, AGT produced 12- and 24-fold resistance to chloroethylating (90CE) and methylating (KS90) analogs of Onrigin™, respectively. For 50% growth inhibition, KS90 and 90CE generated 5,600 O(6)-methylguanines/cell and ∼300 O(6)-chloroethylguanines/cell, respectively. AGT repaired O(6)-methylguanines until the AGT pool was exhausted, while its repair of O(6)-chloroethylguanines was incomplete due to progression of the lesions to AGT-irreparable interstrand DNA cross-links. Thus, the smaller number of O(6)-chloroethylguanine lesions needed for cytotoxicity accounted for the marked degree of resistance (12-fold) to 90CE produced by AGT. Transfection of human or murine AGT into AGT deficient transplantable tumor cells (i.e., EMT6, M109 and U251) generate...Continue Reading

References

Mar 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·T P BrentP M Potter
Nov 1, 1987·Journal of Medicinal Chemistry·K ShyamA C Sartorelli
Jun 1, 1995·Mutation Research·J K Wiencke, J Wiemels
Feb 2, 1996·Journal of Medicinal Chemistry·K ShyamA C Sartorelli
Apr 18, 2000·Mutation Research·A E Pegg
Mar 14, 2002·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Geoffrey P Margison, Mauro F Santibáñez-Koref
May 1, 2002·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Stanton L Gerson
Nov 9, 2005·Molecular Cancer Therapeutics·Kimiko IshiguroAlan C Sartorelli
May 2, 2006·Molecular Cancer Therapeutics·Kimiko IshiguroAlan C Sartorelli
Dec 6, 2006·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Francis GilesSusan O'Brien
Mar 3, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ling YanLili Liu
Feb 19, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sridharan GururanganLarry E Kun
Jan 20, 2009·Current Medicinal Chemistry·Lucio Tentori, Grazia Graziani
Feb 19, 2010·Expert Opinion on Pharmacotherapy·Norbert Vey, Frank Giles

❮ Previous
Next ❯

Citations

Dec 15, 2011·The Journal of Biological Chemistry·Giuseppe PeruginoMaria Ciaramella
Jun 1, 2014·Journal of Molecular Modeling·Rezika LarabiMeziane Brahimi
May 5, 2012·Chemical Biology & Drug Design·Philip G PenkethAlan C Sartorelli
Nov 25, 2011·International Journal of Radiation Biology·Sara RockwellAlan C Sartorelli
Aug 22, 2016·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Guohui SunRugang Zhong
Mar 7, 2017·Future Medicinal Chemistry·Guohui SunRugang Zhong
Dec 6, 2017·International Journal of Molecular Sciences·Riccardo MiggianoMaria Ciaramella
Jun 28, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Guohui SunRugang Zhong
Dec 19, 2019·International Journal of Molecular Sciences·Weinan XiaoRugang Zhong
Jan 10, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Philip G PenkethKrishnamurthy Shyam

❮ Previous
Next ❯

Related Concepts

Related Feeds

AML: Role of LSD1 by CRISPR (Keystone)

Find the latest rersearrch on the ability of CRISPR-Cas9 mutagenesis to profile the interactions between lysine-specific histone demethylase 1 (LSD1) and chemical inhibitors in the context of acute myeloid leukemia (AML) here.

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease with approximately 20,000 cases per year in the United States. AML also accounts for 15-20% of all childhood acute leukemias, while it is responsible for more than half of the leukemic deaths in these patients. Here is the latest research on this disease.