Description
Tomudex was launched in Ireland, France, Luxembourg and the UK for
advanced colorectal cancer and it was prepared in a convergent manner (6 steps)
from diethyl L-glutamate and 6-bromomethyi-2-methyl-quinazolin4(3H)-one.
Tomudex is a highly selective inhibitor of thymidylate synthase (TS), the key enzyme
in the biochemical conversion of dUMP to dTMP. It enters the cell via the reduced
folatefmethotrexate cell membrane carrier and is converted to the polyglutamate
species by folylpolyglutamate synthase within 4h where it then binds to the folate
substrate site of TS. Clinically, it had a 29% response rate in patients with advanced
colorectal cancer. It is water soluble, can be administered as a single dose every
three weeks and had no hepto- or nephrotoxicity.
Chemical Properties
Yellow Crystalline Powder
Uses
Folate-based inhibitor of thymidylate synthase; rapidly and extensively metabolized to its more potent polyglutamate derivatives. Antineoplastic
Definition
ChEBI: ICI D1694 is a N-acyl-amino acid.
brand name
Tomudex (Zeneca).
Biochem/physiol Actions
Raltitrexed is a folate-based inhibitor of thymidylate synthase (TS) that is rapidly and extensively metabolized to its more potent polyglutamate derivatives. By inhibiting the formation of precursor pyrimidine nucleotides, raltitrexed prevents the formation of DNA and RNA, which are required for the growth and survival of both normal cells and cancer cells.
Clinical Use
Treatment of colorectal cancer when fluorouracil and
folinic acid cannot be used
Drug interactions
Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine, increased risk
of agranulocytosis.
Folic and folinic acid: impairs cytotoxic action -
avoid.
Metabolism
Raltitrexed is actively transported into cells and
metabolised to active polyglutamate forms.
The remainder of a dose is not metabolised and is
excreted unchanged, about 50% of a dose appearing in the
urine, and about 15% in the faeces.
