The pharmacology and toxicology of novel thymidylate synthase inhibitors, potential new anticancer agents
The pharmacology and toxicology of novel thymidylate synthase inhibitors, potential new anticancer agents
N18-propargyl-5,8-dideazafolic acid (CB3717) is a folate based inhibitor of the enzyme thymidylate synthase (TS). TS catalyses the de novo synthesis of the nucleotide dTMP. CB3717 was an active anticancer agent in clinical trials, but renal toxicity was dose limiting and precluded further study in man.
CB3717-nephrotoxicity was caused by its poor solubility at physiological pH. Solubility was enhanced by substitution for the 2-amino group and surprisingly this modification enhanced cytotoxicity, despite reducing affinity for TS. The 2-methyl substitution (ICI 198583) was the most active agent against the L1210 in vitro. Numerous analogues of ICI 198583 have been synthesised and screened. A shortlist of 5 analogues was selected for further evaluation, including the pharmacokinetics and toxicological studies outlined in this thesis.
Initial pharmacokinetic studies were performed in both mice and rats. These identified rapid plasma clearance (generally biphasic), with rapid excretion of intact compound, predominantly in the bile. A more sensitive HPLC assay has been developed, in order to define further the pharmacokinetics of these compounds, and used to identify a third phase of plasma clearance.
A technique for measuring glomerular filtration rate in mice was developed and used to confirm that the shortlisted compounds are devoid of renal toxicity. Hepatic toxicity was caused by all the shortlisted compounds, although at doses much higher than those causing antiproliferative effects in vivo.
Review of these pharmacokinetic and toxicity data contributed significantly to the selection of one compound, D1694, from the shortlist and this compound should commence clinical evaluation in late 1990.
University of Southampton
1990
Jodrell, Duncan Ian
(1990)
The pharmacology and toxicology of novel thymidylate synthase inhibitors, potential new anticancer agents.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
N18-propargyl-5,8-dideazafolic acid (CB3717) is a folate based inhibitor of the enzyme thymidylate synthase (TS). TS catalyses the de novo synthesis of the nucleotide dTMP. CB3717 was an active anticancer agent in clinical trials, but renal toxicity was dose limiting and precluded further study in man.
CB3717-nephrotoxicity was caused by its poor solubility at physiological pH. Solubility was enhanced by substitution for the 2-amino group and surprisingly this modification enhanced cytotoxicity, despite reducing affinity for TS. The 2-methyl substitution (ICI 198583) was the most active agent against the L1210 in vitro. Numerous analogues of ICI 198583 have been synthesised and screened. A shortlist of 5 analogues was selected for further evaluation, including the pharmacokinetics and toxicological studies outlined in this thesis.
Initial pharmacokinetic studies were performed in both mice and rats. These identified rapid plasma clearance (generally biphasic), with rapid excretion of intact compound, predominantly in the bile. A more sensitive HPLC assay has been developed, in order to define further the pharmacokinetics of these compounds, and used to identify a third phase of plasma clearance.
A technique for measuring glomerular filtration rate in mice was developed and used to confirm that the shortlisted compounds are devoid of renal toxicity. Hepatic toxicity was caused by all the shortlisted compounds, although at doses much higher than those causing antiproliferative effects in vivo.
Review of these pharmacokinetic and toxicity data contributed significantly to the selection of one compound, D1694, from the shortlist and this compound should commence clinical evaluation in late 1990.
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Published date: 1990
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Local EPrints ID: 462599
URI: http://eprints.soton.ac.uk/id/eprint/462599
PURE UUID: c932d1e4-3bfb-4f3c-b0f2-2ab725a69317
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Date deposited: 04 Jul 2022 19:30
Last modified: 04 Jul 2022 19:30
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Author:
Duncan Ian Jodrell
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