ici-198583 has been researched along with thymidine-5--triphosphate* in 3 studies
3 other study(ies) available for ici-198583 and thymidine-5--triphosphate
Article | Year |
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Mechanisms of acquired resistance to the quinazoline thymidylate synthase inhibitor ZD1694 (Tomudex) in one mouse and three human cell lines.
Four cell lines, the mouse L1210 leukaemia, the human W1L2 lymphoblastoid and two human ovarian (CH1 and 41M) cell lines, were made resistant to ZD1694 (Tomudex) by continual exposure to incremental doses of the drug. A 500-fold increase in thymidylate synthase (TS) activity is the primary mechanism of resistance to ZD1694 in the W1L2:RD1694 cell line, which is consequently highly cross-resistant to other folate-based TS inhibitors, including BW1843U89, LY231514 and AG337, but sensitive to antifolates with other enzyme targets. The CH1:RD1694 cell line is 14-fold resistant to ZD1694, largely accounted for by the 4.2-fold increase in TS activity. Cross-resistance was observed to other TS inhibitors, including 5-fluorodeoxyuridine (FdUrd). 41M:RD1694 cells, when exposed to 0.1 microM [3H]ZD1694, accumulated approximately 20-fold less 3H-labelled material over 24 h than the parental line. Data are consistent with this being the result of impaired transport of the drug via the reduced folate/methotrexate carrier. Resistance was therefore observed to methotrexate but not to CB3717, a compound known to use this transport mechanism poorly. The mouse L1210:RD1694 cell line does not accumulate ZD1694 or Methotrexate (MTX) polyglutamates. Folylpolyglutamate synthetase substrate activity (using ZD1694 as the substrate) was decreased to approximately 13% of that observed in the parental line. Cross-resistance was found to those compounds known to be active through polyglutamation. Topics: Animals; Antineoplastic Agents; Carrier Proteins; Deoxyuracil Nucleotides; Drug Resistance; Female; Folate Receptors, GPI-Anchored; Folic Acid; Folic Acid Antagonists; Humans; Kinetics; Leukemia L1210; Lymphocytes; Methotrexate; Mice; Neoplasm Proteins; Ovarian Neoplasms; Peptide Synthases; Polyglutamic Acid; Proteins; Quinazolines; Receptors, Cell Surface; Thiophenes; Thymidylate Synthase; Thymine Nucleotides; Tumor Cells, Cultured | 1995 |
The duration of the inhibition of thymidylate synthase in intact L1210 cells exposed to two different classes of quinazoline analogues.
Topics: Animals; Antineoplastic Agents; Cell Division; Deoxyuracil Nucleotides; Drug Screening Assays, Antitumor; Folic Acid; Folic Acid Antagonists; Leukemia L1210; Mice; Quinazolines; Structure-Activity Relationship; Thiophenes; Thymidylate Synthase; Thymine Nucleotides | 1993 |
Inhibition of 2-desamino-2-methyl-10-propagyl-5,8-dideazafolic acid cytotoxicity by 5,10-dideazatetrahydrofolate in L1210 cells with decrease in DNA fragmentation and deoxyadenosine triphosphate pools.
5,10-Dideazatetrahydrofolate (DDATHF) is an antifolate drug, the cytotoxic effects of which can be fully reversed by hypoxanthine, suggesting that DDATHF exerts its effects by inhibiting de novo purine biosynthesis. ICI198583 is a quinazoline based inhibitor of thymidylate synthase. In this study we examine the interaction between treatment of mouse leukaemic L1210 cells with these drugs. The addition of DDATHF with ICI198583 was correlated with a decrease in ICI198583 cytotoxicity in a dose dependent manner. This protection was associated with a decrease in DNA fragmentation, and a drop in intracellular dATP pools. These results support the hypothesis that inhibitory effects on de novo purine biosynthesis by inhibitors of dihydrofolate reductase may limit cytotoxicity, and indicate that a rise in dATP pools may be an important cytotoxic signal. Topics: Animals; Antineoplastic Agents; Cell Cycle; Cell Survival; Deoxyadenine Nucleotides; DNA, Neoplasm; Drug Antagonism; Folic Acid; Folic Acid Antagonists; Hypoxanthine; Hypoxanthines; Leukemia L1210; Mice; Tetrahydrofolates; Thymine Nucleotides; Tumor Cells, Cultured | 1991 |