The biochemical pharmacology of the thymidylate synthase inhibitor, 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583)

Jackman, Ann L.; Newell, David R.; Gibson, William A.; Jodrell, Duncan I.; Taylor, Gordon A.; Bishop, Joel A. M.; Hughes, Laura E.; Calvert, A. H.

doi:10.1016/0006-2952(91)90586-t

Cited by 61 publications

(42 citation statements)

References 21 publications

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“…Their measurement in tissue culture cells has been achieved previously after incubation with radiolabelled compounds followed by extraction and HPLC separation (Jolivet et al, 1982;Sikora et al, 1988;Pizzomo et al, 1989;Jackman et al, 1991c;Gibson et al, 1993). Similar methodology has been used to measure the polyglutamated forms of methotrexate in isolated human leukaemic blast cells (Goker et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…Polyglutamated forms of the quinazoline antifolates have previously been measured in vitro using radiolabelled drugs. Separation of polyglutamated metabolites by HPLC was followed by quantitation in fractions using radiochemical analysis (Jackman et al, 1991c;Gibson et al, 1993) or by measuring inhibition of TS (Sikora et al, 1988). In preliminary experiments, direct evidence of polyglutamation in tissues has been obtained by administration of radiolabelled drug to mice (Jackman et al, 1995a).…”

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confidence: 99%

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Comparison of plasma and tissue levels of ZD1694 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models

Aherne

Ward²,

Lawrence³

et al. 1998

Br J Cancer

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Summary ZD1 694 (Tomudex, raltitrexed) is a specific quinazoline antifolate thymidylate synthase inhibitor that relies on polyglutamation for high potency. Antibodies to ZD1694 have been used to establish a sensitive radioimmunoassay as an alternative to high-performance liquid chromatography (HPLC). The radioimmunoassay is reproducible, accurate and provides a means of determining low levels of ZD1694 in plasma (< 1 nM). By virtue of the high cross-reactivity of the antibodies with polyglutamated forms of ZD1 694, it is also possible to measure the total concentration of drug in tissues. Results obtained in L1210 mouse leukaemia cells and in mouse tissues were similar to those previously determined using radiolabelled drug. Pharmacokinetic studies in mice have confirmed that the compound is rapidly eliminated from the plasma and that there is a prolonged terminal elimination phase. ZD1694 was measured in plasma (0.56 ng ml-1; 1.2 pmol ml-') up to 7 days after a single i.p. dose of 100 mg kg-' ZD1 694. Liver, kidney and gut epithelium had a substantially higher level of ZD1 694 immunoreactivity than plasma. For example, 24 h after a single i.p. dose at 1, 10 and 100 mg kg-', total drug levels in the liver were 480, 325 and 152 times higher than plasma levels respectively. In kidney and gut epithelium, total drug levels at these doses were approximately 55 and 34 times those of plasma. The high tissue to plasma ratios were maintained for at least 7 days after administration. Similarly, high tissue to plasma ratios (> 100) were found in dogs treated with a clinically relevant dose of ZD1 694. These were maintained for 4 weeks in liver and kidney tissue (> 100). Total gastrointestinal concentrations of ZD1694 were approximately 10 times higher than plasma 3 days after administration, but levels were near to the limit of detection at 4 weeks. These results are consistent with extensive polyglutamation of ZD1 694 within tissues in both mice and dog and provide further support for the infrequent schedule that has been used clinically. Although it has not been possible to measure individual polyglutamated forms of ZD1 694, the radioimmunoassay provides a convenient means of assessing total drug levels in tissues and is currently the only method suitable for measuring the extent of drug retention in normal tissue and tumour biopsies obtained from patients treated with ZD1 694.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Comparison of plasma and tissue levels of ZD1694 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models

Aherne

Ward²,

Lawrence³

et al. 1998

Br J Cancer

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“…CB30865 also inhibited TS in a noncompetitive manner (K i = 110 nM ≅ K ies ). ZM198583 is reported to inhibit TS with an IC 50 of 50 nM (K i = 10 nM; Jackman et al, 1991). …”

Section: Inhibition Of Isolated Tsmentioning

confidence: 99%

“…Based on the structure of ZM198583 (2-desamino-2-methyl-N 10 -propargyl-5,8-dideazafolic acid; Jackman et al, 1991), these compounds have an aminomethyl 2-, 3-or 4-pyridine in place of the glutamate residue (Skelton et al, 1997). Their highly lipophilic nature [LogP (partition coefficient) ~ 3.5] suggests that they are likely to enter the cell by passive diffusion, and the absence of the glutamate ligand precludes intracellular polyglutamation.…”

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confidence: 99%

A novel class of lipophilic quinazoline-based folic acid analogues: cytotoxic agents with a folate-independent locus

et al. 1999

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Thymidylate synthase (TS; EC 2.1.1.45) is a critical enzyme in the de novo synthesis of thymidylate (dTTP) and has long been recognized as a target for chemotherapeutic intervention. Of interest has been a class of quinazoline-based compounds that fall into three general biochemical sub-type of antifolate TS inhibitor; those which:1. are transported into the cell via the reduced folate carrier (RFC) and are subsequently polyglutamated by folylpolyglutamate synthetase (FPGS; EC 6.3.2.17), e.g. Tomudex TM (raltitrexed; ZD1694; reviewed in Jackman et al, 1996a) 2. use the RFC but which do not undergo intracellular polyglutamation, e.g ZD9331 (Jackman et al 1995c, 1997a) 3. do not interact with the RFC or FPGS, which may either retain the 'classical' (glutamate-containing) structure of antifolates Jackman et al, 1997b;Melin et al, 1997) or be 'non-classical' lipophilic derivatives (Skelton et al, 1994a(Skelton et al, , 1994b).This latter sub-type was originally developed with the aim of achieving good TS inhibition whilst circumventing resistance due to defective RFC and/or polyglutamation mechanisms in tumours. Based on the structure of ZM198583 (2-desamino-2-methyl-N 10 -propargyl-5,8-dideazafolic acid; Jackman et al, 1991), these compounds have an aminomethyl 2-, 3-or 4-pyridine in place of the glutamate residue (Skelton et al, 1997). Their highly lipophilic nature [LogP (partition coefficient) ~ 3.5] suggests that they are likely to enter the cell by passive diffusion, and the absence of the glutamate ligand precludes intracellular polyglutamation.The pyridine derivatives were generally good inhibitors of isolated mammalian TS (IC 50~ 0.1-2 µM). However, although compounds with the 2-or 4-pyridine structure targeted TS (at least partially) in W1L2 human lymphoblastoid cells, those with the 3-pyridine configuration did not, since they were active in the presence of exogenous salvageable thymidine (dThd; Jackman et al, 1996b; Skelton et al, 1997). They were also active against cell lines resistant to antifolates due to elevated TS or dihydrofolate reductase (DHFR) enzyme levels (Skelton et al, 1997). Furthermore, there were analogues in the 3-pyridine series which were extremely potent inhibitors of in vitro tumour cell growth (IC 50~ 1 nM). For example, substitution with Cl or Br at the C7 position of the quinazoline ring was found to improve growth inhibitory potency against L1210 and W1L2 cell lines bỹ 100-fold (Skelton et al, 1997). A detailed account of structure-activity relationships will be given elsewhere (Skelton et al, manuscript in preparation). Thus, based on its good growth inhibitory potency (W1L2 72 h IC 50 = 0.0028 µM) and apparently folate-independent mechanism, the 7-bromo-3-pyridine derivative CB30865 (ZM242421, p-[N-(7-bromo-3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]-N-(3-pyridylmethyl)benzamide; Figure 1) was selected for further in vitro studies.A novel class of lipophilic quinazoline-based folic acid analogues: cytotoxic agents with a folate-independent locus LA ...

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“…Several thymidylate synthase inhibitors have entered clinical trials as antitumor agents, notable among them being CB3717 (PDDF) [4], ZD1694 (Tomudex) [5] and LY231514 [6]. All of these are "classical" antifolates, i.e.…”

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confidence: 99%

Synthesis of novel, nonclassical 2‐amino‐4‐oxo‐6‐(arylthio)ethylpyrrolo[2,3‐d] pyrimidines as potential inhibitors of thymidylate synthase

Gangjee

Dubash

Kisliuk

2001

Journal of Heterocyclic Chem

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A novel series of 14 nonclassical 6-substituted pyrrolo [2,3-d]pyrimidines 2a -2n were designed as potential inhibitors of thymidylate synthase, based on previously reported 2-amino-4-oxopyrrolo[2,3-d]-pyrimidines 1a and 1b. The synthesis of the target compounds 2a-2n was accomplished by nucleophilic displacement of the mesylate 11 with appropriately substituted aromatic thiols. Most of the target compounds did not show inhibition of either Escherichia coli thymidylate synthase or recombinant human thymidylate synthase at the concentrations tested. However, compounds 2h (2,4-dichloro), 2j (3,4-dichloro) and 2m (4-nitro) did show 25%, 40% and 35% inhibition of human thymidylate synthase at 23 µM, 23 µM and 24 µM, respectively. These observations are in accordance with previous reports, which suggest that strong electron withdrawing substituents on the side chain aromatic ring are conducive to inhibition of thymidylate synthase.

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The biochemical pharmacology of the thymidylate synthase inhibitor, 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583)

Cited by 61 publications

References 21 publications

Comparison of plasma and tissue levels of ZD1694 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models

Comparison of plasma and tissue levels of ZD1694 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models

A novel class of lipophilic quinazoline-based folic acid analogues: cytotoxic agents with a folate-independent locus

Synthesis of novel, nonclassical 2‐amino‐4‐oxo‐6‐(arylthio)ethylpyrrolo[2,3‐d] pyrimidines as potential inhibitors of thymidylate synthase

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