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 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 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.(ABSTRACT TRUNCATED AT 250 WORDS)
journal_name
Oncol Resjournal_title
Oncology researchauthors
Panadero A,Yin MB,Voigt W,Rustum YMsubject
Has Abstractpub_date
1995-01-01 00:00:00pages
73-81issue
2eissn
0965-0407issn
1555-3906journal_volume
7pub_type
杂志文章abstract：:The pre-mRNA splicing regulator serine-arginine protein kinase 1 (SRPK1), a member of the SR kinase family, plays an essential role in cancer development and various pathophysiological processes. However, its expression pattern and functions in renal cell carcinoma (RCC) remain unknown. Therefore, the aim of this stud...
journal_title：Oncology research
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doi：10.3727/096504016X14743324568129
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journal_title：Oncology research
pub_type： 杂志文章
doi：
更新日期：1995-01-01 00:00:00
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journal_title：Oncology research
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journal_title：Oncology research
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journal_title：Oncology research
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更新日期：1997-01-01 00:00:00
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journal_title：Oncology research
pub_type： 杂志文章
doi：
更新日期：1999-01-01 00:00:00
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journal_title：Oncology research
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doi：
更新日期：1998-01-01 00:00:00
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journal_title：Oncology research
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journal_title：Oncology research
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journal_title：Oncology research
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更新日期：1999-01-01 00:00:00
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journal_title：Oncology research
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更新日期：1997-01-01 00:00:00
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