Journal article
Contrasting Patterns of DNA Fragmentation Induced by Thymidylate Synthase Inhibitors, ZD1694 and AG-331
Oncology research, Vol.7(2), pp.73-81
01/01/1995
PMID: 7579730
Abstract
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-331).
The magnitude and size of DNA fragmentation indu ced 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 and nascent 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 breakage induced by 5-fluorouracil (FUra) was detected, similar to AG-331. The induction 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 DNA dsbs and cytotoxicity by ZD1694 and AG-331. These observations suggest that replicative DNA synthesis is an important factor in ZD1694- and AG-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.
Details
- Title: Subtitle
- Contrasting Patterns of DNA Fragmentation Induced by Thymidylate Synthase Inhibitors, ZD1694 and AG-331
- Creators
- Angeles PanaderoMing-biao YinWieland VoigtYoucef M Rustum
- Resource Type
- Journal article
- Publication Details
- Oncology research, Vol.7(2), pp.73-81
- Publisher
- Cognizant Communication Corporation
- PMID
- 7579730
- ISSN
- 0965-0407
- eISSN
- 1555-3906
- Language
- English
- Date published
- 01/01/1995
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359560802771
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