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Raltitrexed

Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Routes of administration	Intravenous
ATC code	L01BA03 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: Not available
Identifiers
IUPAC name N-amino}-2-thienyl)carbonyl]-L-glutamic acid
CAS Number	112887-68-0
PubChem CID	104758
IUPHAR/BPS	7403
DrugBank	DB00293
ChemSpider	94568
UNII	FCB9EGG971
KEGG	D01064
ChEMBL	ChEMBL225071
PDB ligand	D16 (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID0046482
ECHA InfoCard	100.180.242
Chemical and physical data
Formula	C21H22N4O6S
Molar mass	458.49 g·mol
3D model (JSmol)	Interactive image
SMILES O=C(c3sc(N(C)Cc2cc1C(=O)\N=C(/Nc1cc2)C)cc3)N(C(=O)O)CCC(=O)O
InChI InChI=1S/C21H22N4O6S/c1-11-22-14-4-3-12(9-13(14)19(28)23-11)10-25(2)17-7-6-16(32-17)20(29)24-15(21(30)31)5-8-18(26)27/h3-4,6-7,9,15H,5,8,10H2,1-2H3,(H,24,29)(H,26,27)(H,30,31)(H,22,23,28)/t15-/m0/s1 Key:IVTVGDXNLFLDRM-HNNXBMFYSA-N
(verify)

Raltitrexed (Thaltitrexed, Tomudex, TDX, ZD 1694) is an antimetabolite drug used in cancer chemotherapy. It is an inhibitor of thymidylate synthase, and is manufactured by AstraZeneca.

Uses

Used in treatment of colorectal cancer since 1998, it may also be used in the treatment of malignant mesothelioma. 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 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, GARFT and thymidylate synthase. Raltitrexed is fully active after polyglutamylation, 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 antimetabolites in use.

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

References

1. Widemann BC, Balis FM, Godwin KS, McCully C, Adamson PC (1999). "The plasma pharmacokinetics and cerebrospinal fluid penetration of the thymidylate synthase inhibitor raltitrexed (Tomudex) in a nonhuman primate model". Cancer Chemother. Pharmacol. 44 (6): 439–43. doi:10.1007/s002800051116. PMID 10550563. S2CID 9006510.
2. Zuidema PJ (1976). "". Ned Tijdschr Geneeskd. 120 (11): 477. PMID 1256598.
3. "Pharmacogenetics in Colorectal Cancer".
4. "EUROPEAN MEDICINES AGENCY DECISION on the granting of a product-specific waiver for raltitrexed (Tomudex)" (PDF). European Medicines Agency. January 27, 2009.
5. Calvert AH, Alison DL, Harland SJ, et al. (August 1986). "A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid, CB3717". J. Clin. Oncol. 4 (8): 1245–52. doi:10.1200/JCO.1986.4.8.1245. PMID 3734849.

• Thiophenes
• Mammalian dihydrofolate reductase inhibitors
• Antifolates
• Drugs developed by AstraZeneca
• Quinazolinones
• Lactams
• Thymidylate synthase inhibitors