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. Chemotherap ...

. 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 includin ...

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 and ...

and is in the class of chemotherapy drugs called

folate antimetabolite Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9). Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine ...

s, which inhibit one or more of three enzymes that use folate and derivatives as substrates: DHFR, 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 deoxynucleo ...

. 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 Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or on ...

, 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 L1210 is a mouse lymphocytic leukemia cell line which is derived from the ascitic fluid of 8-month-old female DBA/2 strain mice. While they are lymphocytic B-cells they are more like lymphoblasts in morphology, develop massive tumours in nude mice ...

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