scholarly journals Cross-Linking of the DNA Repair ProteinO6-Alkylguanine DNA Alkyltransferase to DNA in the Presence of Antitumor Nitrogen Mustards

2008 ◽  
Vol 21 (4) ◽  
pp. 787-795 ◽  
Author(s):  
Rachel Loeber ◽  
Erin Michaelson ◽  
Qingming Fang ◽  
Colin Campbell ◽  
Anthony E. Pegg ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cross Linking ◽  
Nitrogen Mustards ◽  
Dna Alkyltransferase

scholarly journals Cross-Linking of the Human DNA Repair ProteinO6-Alkylguanine DNA Alkyltransferase to DNA in the Presence of 1,2,3,4-Diepoxybutane

2006 ◽  
Vol 19 (5) ◽  
pp. 645-654 ◽  
Author(s):  
Rachel Loeber ◽  
Mathur Rajesh ◽  
Qingming Fang ◽  
Anthony E. Pegg ◽  
Natalia Tretyakova
Keyword(s):  
Dna Repair ◽  
Cross Linking ◽  
Human Dna ◽  
Dna Alkyltransferase

scholarly journals Cross-linking of the DNA repair protein O6-alkylguanine DNA alkyltransferase to DNA in the presence of cisplatin

DNA Repair ◽  
2020 ◽  
Vol 89 ◽  
pp. 102840
Author(s):  
Xun Ming ◽  
Erin D. Michaelson-Richie ◽  
Arnold S. Groehler ◽  
Peter W. Villalta ◽  
Colin Campbell ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cross Linking ◽  
Repair Protein ◽  
Dna Repair Protein ◽  
Dna Alkyltransferase

Nitrogen Mustards as Alkylating Agents: A Review on Chemistry, Mechanism of Action and Current USFDA Status of Drugs

2019 ◽  
Vol 19 (9) ◽  
pp. 1080-1102 ◽  
Author(s):  
Ghansham S. More ◽  
Asha B. Thomas ◽  
Sohan S. Chitlange ◽  
Rabindra K. Nanda ◽  
Rahul L. Gajbhiye
Keyword(s):  
Side Effects ◽  
Mechanism Of Action ◽  
Anticancer Agents ◽  
Nitrogen Mustard ◽  
Alkylating Agents ◽  
Cross Linking ◽  
Nitrogen Mustards ◽  
Information Leaflets ◽  
Anti Cancer ◽  
Approved Drugs

Background & Objective: :Nitrogen mustard derivatives form one of the major classes of anti-cancer agents in USFDA approved drugs list. These are polyfunctional alkylating agents which are distinguished by a unique mechanism of adduct formation with DNA involving cross-linking between guanine N-7 of one strand of DNA with the other. The generated cross-linking is irreversible and leads to cell apoptosis. Hence it is of great interest to explore this class of anticancer alkylating agents.Methods::An exhaustive list of reviews, research articles, patents, books, patient information leaflets, and orange book is presented and the contents related to nitrogen mustard anti-cancer agents have been reviewed. Attempts are made to present synthesis schemes in a simplified manner. The mechanism of action of the drugs and their side effects are also systematically elaborated.Results::This review provides a platform for understanding all aspects of such drugs right from synthesis to their mechanism of action and side effects, and lists USFDA approved ANDA players among alkylating anticancer agents in the current market.Conclusion: :Perusing this article, generic scientists will be able to access literature information in this domain easily to gain insight into the nitrogen mustard alkylating agents for further ANDA development. It will help the scientific and research community to continue their pursuit for the design of newer and novel heterocyclic alkylating agents of this class in the coming future.

scholarly journals Modulation of nitrosourea resistance in myeloid leukemias

Blood ◽  
1988 ◽  
Vol 71 (5) ◽  
pp. 1487-1494 ◽  
Author(s):  
SL Gerson ◽  
JE Trey
Keyword(s):  
Dna Repair ◽  
Therapeutic Index ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Biochemical Modulation ◽  
Repair Protein ◽  
Myeloid Leukemias ◽  
Dna Repair Protein ◽  
Dna Alkyltransferase

Abstract Drug resistance in myeloid leukemias may be mediated by an increased capacity to repair chemotherapy-induced DNA damage. Some tumor cell lines that are resistant to nitrosoureas contain the DNA repair protein O6-alkylguanine-DNA alkyltransferase (alkyltransferase). This protects cells by removing cytotoxic, nitrosourea-induced O6-alkylguanine adducts. We measured the level of alkyltransferase activity in myeloid leukemic cells freshly obtained from patients to determine whether the alkyltransferase was an important factor in nitrosourea resistance in these cells and whether inactivation of this protein could sensitize leukemic cells to nitrosoureas. Myeloid leukemic cells from patients with acute nonlymphocytic leukemia and chronic myelogenous leukemia had higher levels of alkyltransferase than did myeloid precursors from normal donors (P less than .01). This difference did not appear to be due to the state of differentiation of the leukemic or normal cells. To show that this repair protein mediated nitrosourea resistance in leukemic cells, cells were treated with the modified base O6- methylguanine to selectively and irreversibly inactivate the alkyltransferase and then exposed to 1,3-bis (2-chloroethyl)-1- nitrosourea (BCNU). An 18-hour incubation in 0.5 mmol/L O6- methylguanine caused an 87% +/- 3.6% decrease in alkyltransferase activity in leukemic cells and a 73% +/- 8.6% decrease in normal myeloid precursors. After treatment with O6-methylguanine, clonogenic leukemic cells from ten different donors became much more sensitive to BCNU, with a decrease in the dose needed to reduce colony survival by 50% (LD50) of 6.3 +/- 1.4-fold. A lesser effect was seen on CFU-GM, BFU- E, and CFU-GEM where the LD50 decreased two- to threefold. These studies show that nitrosourea resistance in myeloid leukemic cells can be abrogated by inactivation of the DNA repair protein O6-alkylguanine- DNA alkyltransferase. This method of biochemical modulation of DNA repair will sensitize leukemic cells to nitrosoureas in vitro and has the potential of increasing the therapeutic index of nitrosoureas in this disease.

scholarly journals DNA repair protein O6-alkylguanine-DNA alkyltransferase is phosphorylated by two distinct and novel protein kinases in human brain tumour cells

2000 ◽  
Vol 351 (2) ◽  
pp. 393-402 ◽  
Author(s):  
Srinivas R. S. MULLAPUDI ◽  
Francis ALI-OSMAN ◽  
Jiang SHOU ◽  
Kalkunte S. SRIVENUGOPAL
Keyword(s):  
Dna Repair ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Casein Kinase Ii ◽  
Casein Kinase ◽  
Biochemical Modulation ◽  
Cell Extracts ◽  
Dna Alkyltransferase

We showed recently that human O6-alkylguanine-DNA alkyltransferase (AGT), an important target for improving cancer chemotherapy, is a phosphoprotein and that phosphorylation inhibits its activity [Srivenugopal, Mullapudi, Shou, Hazra and Ali-Osman (2000) Cancer Res. 60, 282–287]. In the present study we characterized the cellular kinases that phosphorylate AGT in the human medulloblastoma cell line HBT228. Crude cell extracts used Mg2+ more efficiently than Mn2+ for phosphorylating human recombinant AGT (rAGT) protein. Both [γ-32P]ATP and [γ-32P]GTP served as phosphate donors, with the former being twice as efficient. Specific components known to activate protein kinase A, protein kinase C and calmodulin-dependent kinases did not stimulate the phosphorylation of rAGT. Phosphoaminoacid analysis after reaction in vitro with ATP or GTP showed that AGT was modified at the same amino acids (serine, threonine and tyrosine) as in intact HBT228 cells. Although some of these properties pointed to casein kinase II as a candidate enzyme, known inhibitors and activators of casein kinase II did not affect rAGT phosphorylation. Fractionation of the cell extracts on poly(Glu/Tyr)-Sepharose resulted in the adsorption of an AGT kinase that modified the tyrosine residues and the exclusion of a fraction that phosphorylated AGT on serine and threonine residues. In-gel kinase assays after SDS/PAGE and non-denaturing PAGE revealed the presence of two AGT kinases of 75 and 130kDa in HBT228 cells. The partly purified tyrosine kinase, identified as the 130kDa enzyme by the same assays, was strongly inhibited by tyrphostin 25 but not by genestein. The tyrosine kinase used ATP or GTP to phosphorylate the AGT protein; this reaction inhibited the DNA repair activity of AGT. Evidence that the kinases might physically associate with AGT in cells was also provided. These results demonstrate that two novel cellular protein kinases, a tyrosine kinase and a serine/threonine kinase, both capable of using GTP as a donor, phosphorylate the AGT protein and affect its function. The new kinases might serve as potential targets for strengthening the biochemical modulation of AGT in human tumours.

Chromosome Alteration and Tumour Inhibition by Nitrogen Mustards: the Hypothesis of Cross-linking Alkylation

Nature ◽  
1950 ◽  
Vol 166 (4235) ◽  
pp. 1112-1113 ◽  
Author(s):  
J. J. BIESELE ◽  
F. S. PHILIPS ◽  
J. B. THIERSCH ◽  
J. H. BURCHENAL ◽  
SONJA M. BUCKLEY ◽  
...  
Keyword(s):  
Cross Linking ◽  
Nitrogen Mustards ◽  
Chromosome Alteration
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