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Biochemical and molecular effects of UCN-01 in combination with 5-fluorodeoxyuridine in A431 human epidermoid cancer cells.
- Source :
-
Anti-cancer drugs [Anticancer Drugs] 2002 Mar; Vol. 13 (3), pp. 259-70. - Publication Year :
- 2002
-
Abstract
- Concurrent and pre-exposure of A431 human epidermoid cancer cells to UCN-01, an investigational anticancer drug, with 5-fluoro--2'-deoxyuridine (FdUrd), which targets thymidylate synthase, produced more than additive cytotoxicty. A 24-h exposure to 10 nM FdUrd led to inhibition of TS, a 2.5-fold increase in total thymidylate synthase protein content, profound dTTP depletion and a 6.3-fold increase in the ratio of dATP to dTTP, but did not cause single-strand breaks in DNA. However, FdUrd enhanced UCN-01-associated DNA strand breaks. Concurrent thymidine exposure led to repletion of dTTP pools, and cytoprotection against FdUrd alone and with UCN-01. UCN-01 arrested cells in G1, decreased the percentage of FdUrd-treated cells in S phase and reduced FdUrd-DNA incorporation, suggesting the latter was not important for cytotoxicity. Delayed induction of high molecular mass DNA fragmentation and poly(ADP-ribose) polymerase cleavage was observed with the combination of UCN-01 and FdUrd. These findings suggest that while FdUrd-mediated deoxynucleotide imbalance alone was insufficient to induce apoptosis in this p53-mutant cell line, it magnified UCN-01's effects, most likely by interfering with DNA repair. The clinical evaluation of UCN-01 combined with 5-fluoropyrimidines may be of interest.
- Subjects :
- Carcinoma, Squamous Cell drug therapy
Carcinoma, Squamous Cell pathology
Cell Cycle drug effects
DNA Damage drug effects
DNA Fragmentation drug effects
DNA, Neoplasm drug effects
DNA, Neoplasm metabolism
Deoxyribonucleotides metabolism
Drug Combinations
Genes, p53
Humans
Lung Neoplasms drug therapy
Lung Neoplasms pathology
Polymerase Chain Reaction
RNA, Messenger metabolism
Staurosporine analogs & derivatives
Thymidylate Synthase genetics
Thymidylate Synthase metabolism
Tumor Cells, Cultured enzymology
Alkaloids pharmacology
Antimetabolites, Antineoplastic pharmacology
Cell Survival drug effects
Enzyme Inhibitors pharmacology
Floxuridine pharmacology
Thymidylate Synthase antagonists & inhibitors
Tumor Cells, Cultured drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0959-4973
- Volume :
- 13
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Anti-cancer drugs
- Publication Type :
- Academic Journal
- Accession number :
- 11984070
- Full Text :
- https://doi.org/10.1097/00001813-200203000-00008