Detail of "19916-73-5"

Reference

In vitro evaluation of temozolomide combined with x-irradiation

In vitro evaluation of temozolomide combined with x-irradiation. Wedge, Stephen R.; Porteous, Julia K.; Glaser, Mark G.; Marcus, Kim; Newlands, Edward S. (Dep. Medical Oncol., Charing Cross Hospital, London W6 8RF, UK). Anti-Cancer Drugs, 8(1), 92-97 (English) 1997 Rapid Science Publishers. CODEN: ANTDEV. ISSN: 0959-4973. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Section cross-reference(s): 8 The in vitro cytotoxicity of 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazine-4(3H)-one (temozolomide) with concurrent x-irradn. was examd. in a human glioblastoma cell line (U373MG) as a potential radio-chemotherapeutic treatment for malignant glioma. The combination was also examd. in a human colorectal adenocarcinoma (Mawi) which had 100-fold greater O6-alkylguanine-DNA alkyltransferase (AGT) activity, a DNA-repair protein which confers resistance to temozolomide. A comparison of IC50 values indicated U373MG to be more sensitive to temozolomide than Mawi, but slightly more resistant to x-irradn. (unpaired two-tailed t-test). Temozolomide and x-irradn. proved largely additive in U373MG by isobologram anal. (50% iso-effect) and the addn. of 10 mM temozolomide to 1-2 Gy of x-irradn. increased cell kill by 2.There are some commonly used reagents with their cas registry numbers 19916-73-5 and 92767-51-6 in this article.5- to 3.0-fold. However, the combination was antagonistic in Mawi: and effect attributed to AGT induction by x-irradn. as the antagonism was removed by coincubation with the AGT inhibitor O6-benzylguanine (O6-BG 1 mM; 24 h). O6-BG did not affect the radiation dose-response curve, but significantly increased temozolomide cytotoxicity. In conclusion, the combination of temozolomide with radiation is at best additive, but could nonetheless be of considerable therapeutic benefit in glioma, particularly if administered for prolonged periods. If AGT induction compromises the efficacy of this therapy, it may be circumvented with an appropriate inhibitor such as O6-BG. .

Interaction of mammalian O6-alkylguanine-DNA alkyltransferases with O6-benzylguanine

Interaction of mammalian O6-alkylguanine-DNA alkyltransferases with O6-benzylguanine. Loktionova, Natalia A.; Pegg, Anthony E. (The Milton S. Hershey Medical Center, Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA). Biochemical Pharmacology, 63(8), 1431-1442 (English) 2002 Elsevier Science Inc. CODEN: BCPCA6. ISSN: 0006-2952. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Section cross-reference(s): 7 Human O6-alkylguanine-DNA alkyltransferase (hAGT) activity is a major factor in providing resistance to cancer chemotherapeutic alkylating agents. Inactivation of hAGT by O6-benzylguanine (BG) is a promising strategy for overcoming this resistance. Previous studies, which have focused on the region encompassed by residues Pro138 to Gly173, have identified more than 100 individual mutations located at 23 discrete sites at which alterations can render AGT less sensitive to BG. The authors have now extended the examn. of possible sites in hAGT at which alterations might lead to BG resistance to include the residues from Val130 to Asn137, which also make up part of the binding pocket into which BG is postulated to fit. A further 21 mutations located at positions Gly132, Met134, Arg135, and Gly136 were found to lower sensitivity to BG. Mutants R135L, R135Y, and G136P were the most strikingly resistant, with a 50-fold increase in the amt. of BG needed to obtain 50% inactivation. These results therefore increase the no. of sites at which BG resistance can occur in response to a single amino acid change to 27. Although mammalian AGTs are very similar in amino acid sequence, mouse AGT (mAGT) is significantly less sensitive to BG than rat AGT (rAGT) or hAGT.There are some commonly used reagents with their cas registry numbers 77271-19-3 and 19916-73-5 in this article. Construction of chimeric proteins in which portions came from the rAGT and the mAGT indicated that the difference in inactivation resided solely in the amino acids located in the sequence from residues 150 to 188. Individual mutations of the three residues where rAGT and mAGT differ in this region showed that the principal reason for the reduced ability of the mAGT to react with BG was the presence of a histidine residue at position 161, which is occupied by asparagine in rAGT and hAGT. These expts. indicate that many minor changes in amino acids forming all parts of the nucleoside binding pocket of AGT can alter its ability to react with BG and that the possibility that polymorphisms or variants may occur reducing the effectiveness of combination therapy with BG and alkylating agents must be considered. .