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

@article{Aherne1998ComparisonOP,
  title={Comparison of plasma and tissue levels of ZD1694 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models.},
  author={G. Wynne Aherne and Erica N. Ward and N. Lawrence and Donna Dobinson and Simon Clarke and Helen L. Musgrove and Frances Sutcliffe and Trevor C. Stephens and Ann L. Jackman},
  journal={British Journal of Cancer},
  year={1998},
  volume={77},
  pages={221 - 226}
}
ZD1694 (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… 

Figures and Tables from this paper

Pharmacokinetic/pharmacodynamic study of ZD9331, a nonpolyglutamatable inhibitor of thymidylate synthase, in a murine model following two curative administration schedules.
  • G. Aherne, A. Hardcastle, A. Jackman
  • Biology, Medicine
    Clinical cancer research : an official journal of the American Association for Cancer Research
  • 2001
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 plasma pharmacokinetics and cerebrospinal fluid penetration of the thymidylate synthase inhibitor raltitrexed (TomudexTM) in a nonhuman primate model
TLDR
The elimination of raltitrexed is triexponential with a prolonged terminal elimination phase and the pharmacokinetic profile is consistent with extensive polyglutamation and intracellular retention of ralitrexe in humans.
Patterns of elevation of plasma 2'-deoxyuridine, a surrogate marker of thymidylate synthase (TS) inhibition, after administration of two different schedules of 5-fluorouracil and the specific TS inhibitors raltitrexed (Tomudex) and ZD9331.
  • H. Ford, F. Mitchell, A. Jackman
  • Biology
    Clinical cancer research : an official journal of the American Association for Cancer Research
  • 2002
TLDR
Both5-FU regimens inhibit TS, and prolonged TS inhibition is achieved by CI 5-FU without significant toxicity, which suggests that the mechanism of antiproliferative toxicity from bolus 5-fu/LV is partly non-TS mediated.
Raltitrexed (TomudexTM), a Highly Polyglutamatable Antifolate Thymidylate Synthase Inhibitor
TLDR
This chapter focuses on reviewing the medicinal chemistry path from these early compounds to the selection of Tomudex (Raltitrexed; ZD1694; Fig. 1) for clinical study.
Leucovorin rescue from raltitrexed (tomudex)-induced antiproliferative effects: in vitro cell line and in vivo mouse studies.
TLDR
In vitro cell studies are presented suggesting that the growth-inhibitory, and potentially cytotoxic, effects of RTX on populations of viable cells can be reversed by the delayed administration of LV, and a model is proposed where LV and/or its anabolic products can compete with RTX uptake into tissues and interfere with the homeostatic regulation of RTX polyglutamates.
Impact of polyglutamation on sensitivity to raltitrexed and methotrexate in relation to drug-induced inhibition of de novo thymidylate and purine biosynthesis in CCRF-CEM cell lines.
  • M. J. Barnes, E. Estlin, D. Newell
  • Biology, Medicine
    Clinical cancer research : an official journal of the American Association for Cancer Research
  • 1999
TLDR
It is demonstrated that polyglutamation is a critical determinant of the cellular pharmacology of both raltitrexed and MTX, markedly influencing potency in the case of raltitized and locus of action in the cases of MTX.
Clinical and Preclinical Pharmacokinetics of Raltitrexed
TLDR
It has not been possible to establish strong correlations between the plasma pharmacokinetics of raltitrexed and toxicity, and the cellular pharmacokinetic patterns may be more predictive, but delayed administration of folinic acid can assist in the recovery of animals from antiproliferative toxicity.
A simple and fast LC-MS/MS method with a very high sensitivity for the measurement of raltitrexed in human plasma.
  • Stefano Kim, A. Bisch, B. Royer
  • Biology
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
  • 2017
A Phase I study of raltitrexed, an antifolate thymidylate synthase inhibitor, in adult patients with advanced solid tumors.
TLDR
Raltitrexed clearance was independent of dose and was associated with the estimated creatinine clearance, and Asthenia, neutropenia, and hepatic transaminitis were dose-related and tended to occur more frequently when patients received three or more cycles of therapy.
...
1
2
3
...

References

SHOWING 1-10 OF 44 REFERENCES
ZD1694 (Tomudex): a new thymidylate synthase inhibitor with activity in colorectal cancer.
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.
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).
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.
TLDR
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.
Preclinical pharmacology of CB30900, a novel dipeptide inhibitor of thymidylate synthase, in mice.
CB30900 is a novel, potent thymidylate synthase inhibitor which can not be polyglutamated and may be active in cancers expressing low or defective folylpolyglutamate synthetase. Pharmacokinetics were
Folate-based thymidylate synthase inhibitors as anticancer drugs.
  • A. Jackman, A. Calvert
  • Biology, Chemistry
    Annals of oncology : official journal of the European Society for Medical Oncology
  • 1995
TLDR
A portfolio of novel compounds comprehensively addresses the potential of thymidylate synthase as a target for cancer chemotherapy.
...
1
2
3
4
5
...