Raltitrexed (Thaltitrexed, Tomudex, TDX, ZD 1694) is an

antimetabolite An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolate ...

drug used in cancer

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...

. It is an inhibitor of thymidylate synthase, and is manufactured by

AstraZeneca AstraZeneca plc () is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, England. It has a portfolio of products for major diseases in areas includ ...

Uses

Used in treatment of colorectal cancer since 1998, it may also be used in the treatment of malignant

mesothelioma Mesothelioma is a type of cancer that develops from the thin layer of tissue that covers many of the internal organs (known as the mesothelium). The most common area affected is the lining of the lungs and chest wall. Less commonly the lining ...

. Raltitrexed is approved for use in Canada and some European countries, but is not approved by the US FDA.

Mechanism of action

Raltitrexed is chemically similar to

folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing a ...

and is in the class of chemotherapy drugs called folate antimetabolites, which inhibit one or more of three enzymes that use folate and derivatives as substrates:

DHFR Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry. In ...

, GARFT and

thymidylate synthase Thymidylate synthase (TS) () is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidine is one of the nucleotides in DNA. With inhibition of TS, an imbalance of deoxynucle ...

. Raltitrexed is fully active after

polyglutamylation Polyglutamylation is a form of reversible posttranslational modification of glutamate residues seen for example in alpha and beta tubulins, nucleosome assembly proteins NAP1 and NAP2. The γ-carboxy group of glutamate may form peptide-like bond wit ...

, which allows cellular retention of the drug. By inhibiting Thymidylate synthase (TS), thus 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. Inhibition of L1210 cell growth in culture IC₅₀ = 9 nM, is one of the strongest

s in use. Structure and phase I clinical trial of the precursor drug, CB3717, was described in 1986.

References

{{Chemotherapeutic agents Thiophenes Mammalian dihydrofolate reductase inhibitors Antifolates AstraZeneca brands Quinazolinones Lactams Thymidylate synthase inhibitors