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ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study.
The L1210:1565 cell line, which has greatly impaired reduced-folate/methotrexate transport and thus is resistant to methotrexate, was significantly cross-resistant to ICI D1694, suggesting that ICID1694 is dependent on this uptake mechanism for good cytotoxic potency in L 1210 cells.
ZD1694 (Tomudex): a new thymidylate synthase inhibitor with activity in colorectal cancer.
ZD1694 has antitumour activity in mice, although the high plasma thymidine in this species complicates: (1) the interpretation of therapeutic index; (2) tumour types in which activity is likely to be observed; and (3) translation of doses and schedules for clinical evaluation.
ICI D1694, an inhibitor of thymidylate synthase for clinical study.
The TS inhibitor, ICI D1694, is a highly potent inhibitor of tumour growth in vitro and in vivo. Uptake via the RFC and rapid metabolism to polyglutamate forms appear to be responsible for potency.
The role of the reduced-folate carrier and metabolism to intracellular polyglutamates for the activity of ICI D1694.
The results of short-exposure assays and in situ TS assays confirms that 7-methylation largely prevents the formation of a retained drug-form (polyglutamates), continuous exposure being necessary to maintain TS inhibition and cause a cytotoxic effect after removal of extracellular drug.
The biochemical pharmacology of the thymidylate synthase inhibitor, 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583).
Synthetic ICI 198583 polyglutamates were shown to be up to 100-fold more potent as inhibitors of isolated TS than the parent compound, which resulted in greater than 60% of the mice being cured and a 10-fold improvement in potency over CB3717.
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 cells, were made resistant to ZD1694 by continual exposure to incremental doses of the drug by finding cross-resistance was found to those compounds known to be active through polyglutamation.
The pharmacokinetics of the quinazoline antifolate ICID 1694 in mice and rats
Tissue distribution and excretion studies in mice suggested that biliary excretion predominated, confirming the results obtained in rats, and a more sensitive assay was developed that includes a solid-phase extraction step to define the third phase of ICI D1694 clearance in mice.
Cellular pharmacokinetics of ZD1694 in cultured human leukaemia cells sensitive, or made resistant, to this drug
The analysis of the cellular metabolism of a novel thymidylate synthase (TS) inhibitor, ZD1694, in MOLT-3 and K562 human leukaemia cell lines indicates that the cellular ability to produce the polyglutamate metabolites of ZD 1694 must influence the sensitivity of the tumour cells to this drug.
The effects of serine protease inhibitors on morphological differentiation of murine neuroblastoma cells (NB 15)
Morphological differentiation of neuroblastoma cells (NB15) was induced by cAMP effectors in the presence and absence of serine protease inhibitors and the effects of the protease inhibitor on growth and differentiation are discussed.
The measurement of polyglutamate metabolites of the thymidylate synthase inhibitor, ICI D1694, in mouse and human cultured cells.
A method is described for the measurement of the polyglutamates of the quinazoline thymidylate synthase inhibitor, N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-