Immunoreactive dUMP and TTP pools as an index of thymidylate synthase inhibition; effect of tomudex (ZD1694) and a nonpolyglutamated quinazoline antifolate (CB30900) in L1210 mouse leukaemia cells.

@article{Aherne1996ImmunoreactiveDA,
  title={Immunoreactive dUMP and TTP pools as an index of thymidylate synthase inhibition; effect of tomudex (ZD1694) and a nonpolyglutamated quinazoline antifolate (CB30900) in L1210 mouse leukaemia cells.},
  author={G. Wynne Aherne and Anthea Hardcastle and Florence I. Raynaud and Ann L. Jackman},
  journal={Biochemical pharmacology},
  year={1996},
  volume={51 10},
  pages={
          1293-301
        }
}
The inhibition of thymidylate synthase (TS) as a drug development target has received much attention in recent years, and several compounds have reached clinical evaluation. During drug development, the effectiveness of target inhibition can be assessed by determination of the perturbations of deoxythymidine 5-triphosphate (TTP) and deoxyuridine 5'-monophosphate (dUMP) pools in drug-treated cells. Rapid, sensitive, and reproducible radioimmunoassays for TTP pools and immunoreactive dUMP pools… 
Comparison of plasma and tissue levels of ZD1694 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models.
TLDR
Although it has not been possible to measure individual polyglutamated forms of ZD1694, 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 ZD 1694.
Deoxyuridine triphosphatase (dUTPase) expression and sensitivity to the thymidylate synthase (TS) inhibitorD9331
TLDR
DUTPase expression and activity were elevated (approximately 3-fold) in two variants of a human lymphoblastoid cell line with acquired resistance to TS inhibitors, further suggesting an important role for this enzyme in TS inhibited cells.
Pharmacokinetic/pharmacodynamic study of ZD9331, a nonpolyglutamatable inhibitor of thymidylate synthase, in a murine model following two curative administration schedules.
TLDR
The results suggest that antitumor activity is dependent on attaining adequate drug concentrations to affect dTTP pools as well as on the duration of effective drug levels.
The ability to accumulate deoxyuridine triphosphate and cellular response to thymidylate synthase (TS) inhibition
TLDR
Although loss of viability can be mediated through dTTP deprivation alone, the uracil misincorporation pathway resulted in an earlier commitment to cell death, the relevance of this latter pathway in the clinical response to TS inhibitors deserves further investigation.
Trifluorothymidine Resistance Is Associated with Decreased Thymidine Kinase and Equilibrative Nucleoside Transporter Expression or Increased Secretory Phospholipase A2
TLDR
Resistance induction to TFT can lead to different mechanisms of resistance, including decreased TK protein expression and enzyme activity, decreased hENT expression, as well as (phospho)lipid metabolism.
Low folate conditions may enhance the interaction of trifluorothymidine with antifolates in colon cancer cells
TLDR
The combination of TFT with the antifolates AG337, ZD1694 and GW1843 is mainly additive when the drugs are given simultaneously and this is mediated by an additive TS inhibition and DNA damage.
Raltitrexed (TomudexTM), a Highly Polyglutamatable Antifolate Thymidylate Synthase Inhibitor
Folic acid has, over the past 50 yr, formed the basis of an enormous amount of medicinal chemistry aimed at finding improved anticancer agents. This stemmed from the discovery of aminopterin (AMT)
Preclinical cellular pharmacology of LY231514 (MTA): a comparison with methotrexate, LY309887 and raltitrexed for their effects on intracellular folate and nucleoside triphosphate pools in CCRF-CEM cells.
TLDR
It is concluded that LY231514 was distinct from methotrexate, LY309887 and raltitrexed based on their metabolic effects in CCRF-CEM cells, and that in this cell line the inhibitory effects of LY 231514 were exerted primarily against the thymidylate cycle and secondarily against de novo purine biosynthesis.
Activity and substrate specificity of pyrimidine phosphorylases and their role in fluoropyrimidine sensitivity in colon cancer cell lines.
TLDR
In conclusion, overlapping substrate specificity was found for TP and UP in the cell lines, in which both enzymes were responsible for converting TdR and Urd, and 5'DFUR.
Determinants of trifluorothymidine sensitivity and metabolism in colon and lung cancer cells
TLDR
It was found that despite a high rate of TFT phosphorolysis, cells with high TP expression are not more resistant to TFT, while TPI did not increase TFT sensitivity, and the synthesis of radioactive TFT metabolites was studied.
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References

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TLDR
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.
Quinazoline thymidylate synthase inhibitors: methods for assessing the contribution of polyglutamation to their in vitro activity.
TLDR
These assays were validated using a series of quinazoline-based TS inhibitors with well-defined activity for TS, folypolyglutamate synthetase (FPGS) and the reduced-folate cell membrane carrier (RFC).
157 ESTIMATION OF THE IN VITRO AND IN VIVO INHIBITORY EFFECTS OF ANTIFOLATES UPON THYMIDYLATE SYNTHASE (TS) IN WHOLE CELLS
TLDR
Measuring the drug/target interaction in intact cells has allowed us to identify analogues which are considerably more potent in vivo TS inhibitors, including 2-methoxy, CB3717, desamino, and 2-methyl analogues respectively.
Biochemical effects of folate-based inhibitors of thymidylate synthase in MGH-U1 cells
TLDR
C2-desamino C2-methyl dideazafolates are potent TS inhibitors, survival is correlated with inhibition of TS for the folate-based TS inhibitors and the biochemical consequences of TS inhibition include increased dUMP and dUrd levels.
Rapid determination of thymidylate synthase activity and its inhibition in intact L1210 leukemia cells in vitro.
TLDR
There was a good correlation between tritium release, cellular uptake, and incorporation of [2-14C]dUrd into DNA, suggesting that competition for uptake and/or phosphorylation may contribute to the overall effects of certain nucleoside analogues on cellular dTMP synthase activity measured using the tritanium release assay.
A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid, CB3717.
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TLDR
CB3717 has activity in heavily pretreated patients and the maximum tolerated dose was in the region of 600 mg/m2 with renal toxicity being dose limiting, although the inter-patient variation did not allow a precise definition.
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TLDR
A portfolio of novel compounds comprehensively addresses the potential of thymidylate synthase as a target for cancer chemotherapy.
Mechanisms of acquired resistance to the quinazoline thymidylate synthase inhibitor ZD1694 (Tomudex) in one mouse and three human cell lines.
TLDR
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.
Modulation of anti-metabolite effects. Effects of thymidine on the efficacy of the quinazoline-based thymidylate synthetase inhibitor, CB3717.
TLDR
In vitro studies of protection by dThd against CB3717 cytotoxicity were carried out in an attempt to quantify this reversal, and it was demonstrated that even the minimum level of d Thd achieved in vivo was still in excess of that required for protection fromCB3717 toxicity in vitro.
Potentiation of quinazoline antifolate (CB3717) toxicity by dipyridamole in human lung carcinoma, A549, cells.
TLDR
Dipyridamole could exacerbate the nucleotide pool imbalance caused by CB3717, thereby potentiating its toxicity, and inhibition of nucleoside efflux may be an important aspect of its potentiation.
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