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Titolo:
CONTRASTING PATTERNS OF DNA FRAGMENTATION INDUCED BY THYMIDYLATE SYNTHASE INHIBITORS, ZD1694 AND AG-331
Autore:
PANADERO A; YIN MB; VOIGT W; RUSTUM YM;
Indirizzi:
ROSWELL PK CANC INST,GRACE CANC DRUG CTR,DEPT EXPTL THERAPEUT,ELM & CARLTON ST BUFFALO NY 14263 ROSWELL PK CANC INST,GRACE CANC DRUG CTR,DEPT EXPTL THERAPEUT BUFFALONY 14263
Titolo Testata:
Oncology research
fascicolo: 2, volume: 7, anno: 1995,
pagine: 73 - 81
SICI:
0965-0407(1995)7:2<73:CPODFI>2.0.ZU;2-D
Fonte:
ISI
Lingua:
ENG
Soggetto:
DOUBLE-STRAND BREAKS; METASTATIC COLORECTAL-CARCINOMA; MOUSE FM3A CELLS; GROWTH-INHIBITION; ICI D1694; DEATH; CYTOTOXICITY; MECHANISMS; ICI-D1694; ACID;
Keywords:
ZD1694; AG-331; THYMIDYLATE SYNTHASE; DNA FRAGMENTATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
38
Recensione:
Indirizzi per estratti:
Citazione:
A. Panadero et al., "CONTRASTING PATTERNS OF DNA FRAGMENTATION INDUCED BY THYMIDYLATE SYNTHASE INHIBITORS, ZD1694 AND AG-331", Oncology research, 7(2), 1995, pp. 73-81

Abstract

The patterns of DNA fragmentation were evaluated following a brief exposure (2 h) of the human ileocecal adenocarcinoma cell line, HCT-8, to several specific thymidylate synthase inhibitors, a quinazoline (ZD1694) and benz[cd]indole-containing molecule (AG-33 I). The magnitude and size of DNA fragmentation induced by the two agents were assessed by alkaline elution for DNA single-strand breaks (ssbs), and by pulsed-and constant-field gel electrophoresis for DNA double-strand breaks (dsbs). Both agents induced dose-dependent DNA dsbs. While AG-331 induced ssbs and dsbs only in nascent DNA, ZD1694 affected both genomic andnascent DNA. The fragments of newly synthesized and genomic DNA, estimated by pulsed-field gel electrophoresis assay, were associated with the bands in the range of 0.05 to 1.1 and 1.1 to 5.7 megabases, respectively. 5-fluoro-2'-deoxyuridine (FdUrd), like ZD1694, produced both mature and nascent DNA fragmentation, whereas only nascent DNA breakageinduced by 5-fluorouracil (FUra) was detected, similar to AG-331. Theinduction of both mature and nascent DNA fragmentation by ZD1694 and FdUrd appears to correlate with the higher, but similar, potency of these agents. Aphidicolin, a DNA polymerase inhibitor, protects from DNAdsbs and cytotoxicity by ZD1694 and AG-331. These observations suggest that replicative DNA synthesis is an important factor in ZD1694- andAG-331-induced DNA fragmentation and, subsequently, cell growth arrest. The results indicate that although the new antimetabolites investigated herein were developed and extensively evaluated as specific and potent thymidylate synthase inhibitors, DNA damage appears to be an important additional determinant of drug effect. The newly synthesized DNA appears to be a common sensitive target of FUra, FdUrd, ZD1694, and AG-331; whereas the induction of mature DNA fragmentation is associated exclusively with FdUrd and ZD1694.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 01/10/20 alle ore 14:21:42