DT-Web

DB00293 - Raltitrexed


Identification
Name Raltitrexed
Accession Number DB00293 (APRD00430, EXPT01092)
Type small molecule
Description Raltitrexed (brand name Tomudex®) is a chemotherapy drug manufactured AstraZeneca Company, is an antimetabolite used in chemotherapy. It is an inhibitor of thymidylate synthase.
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 458.488
Groups approved
Monoisotopic Weight 458.126005146
Pharmacology
Indication For the treatment of malignant neoplasm of colon and rectum
Mechanism of action Raltitrexed is an antineoplastic Agents and folic acid antagonists. Raltitrexed inhibits thymidylate synthase (TS) leading to DNA fragmentation and cell death. It is transported into cells via a reduced folate carrier. Inside the cell Raltitrexed is extensively polyglutamated, which enhances thymidylate synthase inhibitory power and duration. Inhibition of this enzyme results in decreased synthesis of thymidine triphosphate which is required for DNA synthesis.
Absorption Not Available
Protein binding >93%
Biotransformation Raltitrexed is transported into cells via a reduced folate carrier. Inside the cell it is extensively polyglutamated by the enzyme folyl polyglutamate synthetase to polyglutamate forms.
Route of elimination Not Available
Toxicity Side effects include pale skin, troubled breathing, unusual bleeding or bruising, unusual tiredness or weakness, black, tarry stools, chest pain, chills, cough, fever, painful or difficult urination, shortness of breath, sore throat, sores, ulcers, or white spots on lips or in mouth, swollen glands, increase in bowel movements, loose stools, soft stools.
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions Not Available
Food Interactions Not Available

Targets


Thymidylate synthase
Name Thymidylate synthase
Gene Name TYMS
Pharmacological action yes
Actions inhibitor
References
  • Yin MB, Guo B, Panadero A, Frank C, Wrzosek C, Slocum HK, Rustum YM: Cyclin E-cdk2 activation is associated with cell cycle arrest and inhibition of DNA replication induced by the thymidylate synthase inhibitor Tomudex. Exp Cell Res. 1999 Feb 25;247(1):189-99. - Pubmed
  • Cao S, McGuire JJ, Rustum YM: Antitumor activity of ZD1694 (tomudex) against human head and neck cancer in nude mouse models: role of dosing schedule and plasma thymidine. Clin Cancer Res. 1999 Jul;5(7):1925-34. - Pubmed
  • Ferguson PJ, Collins O, Dean NM, DeMoor J, Li CS, Vincent MD, Koropatnick J: Antisense down-regulation of thymidylate synthase to suppress growth and enhance cytotoxicity of 5-FUdR, 5-FU and Tomudex in HeLa cells. Br J Pharmacol. 1999 Aug;127(8):1777-86. - Pubmed
  • Orlandi L, Bearzatto A, Abolafio G, De Marco C, Daidone MG, Zaffaroni N: Involvement of bcl-2 and p21waf1 proteins in response of human breast cancer cell clones to Tomudex. Br J Cancer. 1999 Sep;81(2):252-60. - Pubmed
  • Grem JL, Sorensen JM, Cullen E, Takimoto CH, Steinberg SM, Chen AP, Hamilton JM, Arbuck SG, McAtee N, Lawrence D, Goldspiel B, Johnston PG, Allegra CJ: A Phase I study of raltitrexed, an antifolate thymidylate synthase inhibitor, in adult patients with advanced solid tumors. Clin Cancer Res. 1999 Sep;5(9):2381-91. - Pubmed
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
  • Yang Z, Waldman AS, Wyatt MD: DNA damage and homologous recombination signaling induced by thymidylate deprivation. Biochem Pharmacol. 2008 Oct 15;76(8):987-96. Epub 2008 Aug 19. - Pubmed
  • Chen VJ, Bewley JR, Andis SL, Schultz RM, Iversen PW, Shih C, Mendelsohn LG, Seitz DE, Tonkinson JL: Cellular pharmacology of MTA: a correlation of MTA-induced cellular toxicity and in vitro enzyme inhibition with its effect on intracellular folate and nucleoside triphosphate pools in CCRF-CEM cells. Semin Oncol. 1999 Apr;26(2 Suppl 6):48-54. - Pubmed
  • Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. - Pubmed
DTHybrid score 0.766
Folylpolyglutamate synthase, mitochondrial
Name Folylpolyglutamate synthase, mitochondrial
Gene Name FPGS
Pharmacological action unknown
Actions antagonist
References
  • Innocenti F, Ratain MJ: Update on pharmacogenetics in cancer chemotherapy. Eur J Cancer. 2002 Mar;38(5):639-44. - Pubmed
DTHybrid score 0.4333

Predictions


Id Partner name Gene Name Score
24 Thymidylate synthase TMP1 0.766
2626 Thymidylate synthase thyA 0.766
2729 Thymidylate synthase thyA 0.766
5352 Thymidylate synthase THYA 0.766
365 Dihydrofolate reductase DHFR 0.1199
2381 Dihydrofolate reductase DFR1 0.1199
2833 Dihydrofolate reductase Not Available 0.1199
2931 Dihydrofolate reductase folA 0.1199
3544 Dihydrofolate reductase folA 0.1199
3682 Dihydrofolate reductase folA 0.1199
6642 Dihydrofolate reductase folA 0.1199
6756 Dihydrofolate reductase dfrA 0.1199
3639 Thymidine phosphorylase deoA 0.0784
3936 Thymidine phosphorylase TYMP 0.0784
2287 Bifunctional purine biosynthesis protein PURH [Includes: Phosphoribosylaminoimidazolecarboxamide formyltransferase ATIC 0.0255
1709 Canalicular multispecific organic anion transporter 2 ABCC3 0.0247
3611 Cytidine deaminase cdd 0.0234
3707 Cytidine deaminase cdd 0.0234
4211 Cytidine deaminase CDA 0.0234
2222 Equilibrative nucleoside transporter 1 SLC29A1 0.0231
2320 Thymidine kinase, cytosolic TK1 0.0231
2164 Multidrug resistance-associated protein 4 ABCC4 0.023
4773 Deoxycytidine kinase DCK 0.0196
5818 Folate receptor alpha FOLR1 0.0185
1302 Dihydropyrimidine dehydrogenase [NADP+] DPYD 0.018
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0176
1043 Trifunctional purine biosynthetic protein adenosine-3 [Includes: Phosphoribosylamine--glycine ligase GART 0.0165
1729 Solute carrier family 22 member 6 SLC22A6 0.0164
293 Gamma-glutamyl hydrolase GGH 0.016
6148 Multidrug resistance-associated protein 7 ABCC10 0.0157
1588 Multidrug resistance protein 1 ABCB1 0.0145
243 Ribosyldihydronicotinamide dehydrogenase [quinone] NQO2 0.0145
3917 Methylenetetrahydrofolate reductase MTHFR 0.0142
1650 Heme carrier protein 1 SLC46A1 0.0137
4757 Cytochrome P450 2C9 CYP2C9 0.0133
2567 Thymidylate synthase thyX thyX 0.0128
4275 PCZA361.16 Not Available 0.0128
4276 DNA polymerase III subunit epsilon dnaQ 0.0128
2410 Deoxyuridine 5'-triphosphate nucleotidohydrolase dut 0.0127
2490 Deoxyuridine 5'-triphosphate nucleotidohydrolase dut 0.0127
738 Monocarboxylate transporter 1 SLC16A1 0.0119
6155 ATP-binding cassette transporter sub-family C member 11 ABCC11 0.0114
2555 Pol polyprotein pol 0.0114
3242 Pol polyprotein gag-pol 0.0114
3471 Pol polyprotein gag-pro-pol 0.0114
5256 Pol polyprotein pol 0.0114
6469 Pol polyprotein gag-pol 0.0114
6565 Pol polyprotein Not Available 0.0114
1353 DNA topoisomerase 1 TOP1 0.0114
3552 DNA topoisomerase 1 topA 0.0114
6143 Solute carrier family 22 member 7 SLC22A7 0.0103
6160 Solute carrier organic anion transporter family member 3A1 SLCO3A1 0.0103
6040 6-phosphogluconate dehydrogenase, decarboxylating PGD 0.0102
4604 Liver carboxylesterase 1 CES1 0.0101
6150 Solute carrier organic anion transporter family member 4C1 SLCO4C1 0.01
2251 Thymidylate kinase tmk 0.0098
2254 Thymidylate kinase DTYMK 0.0098
3522 Thymidylate kinase tmk 0.0098
702 UMP-CMP kinase CMPK1 0.0098
3478 Glucose-1-phosphate thymidylyltransferase rmlA 0.0097
4277 Glucose-1-phosphate thymidylyltransferase rmlA 0.0097
6020 Aldehyde oxidase AOX1 0.0094
6158 Solute carrier organic anion transporter family member 1C1 SLCO1C1 0.009
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.0089
360 Ribonucleoside-diphosphate reductase large subunit RRM1 0.0087
6171 Solute carrier family 28 member 3 SLC28A3 0.0085
509 Thymidine kinase TK 0.0085
570 Thymidine kinase TK 0.0085
2559 Thymidine kinase TK 0.0085
3430 Thymidine kinase tdk 0.0085
3518 Thymidine kinase TK 0.0085
5301 Thymidine kinase tdk 0.0085
5771 Thymidine kinase ORF36 0.0085
7009 Thymidine kinase ORF36 0.0085
5691 DTDP-4-DEHYDRORHAMNOSE 3,5-EPIMERASE RMLC rmlC 0.0084
3361 Serpin B5 SERPINB5 0.0084
5694 Transcription antiterminator licT licT 0.0084
4924 Cytochrome P450 2C8 CYP2C8 0.0083
587 Serum albumin ALB 0.0082
6157 Solute carrier organic anion transporter family member 1B3 SLCO1B3 0.0081
1024 Solute carrier family 22 member 11 SLC22A11 0.0076
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.007
862 Multidrug resistance-associated protein 1 ABCC1 0.007
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.0068
56 Delta-aminolevulinic acid dehydratase ALAD 0.0067
2356 Delta-aminolevulinic acid dehydratase hemB 0.0067
3613 Delta-aminolevulinic acid dehydratase hemB 0.0067
3674 Delta-aminolevulinic acid dehydratase hemB 0.0067
6142 Solute carrier family 22 member 8 SLC22A8 0.0066
2286 Isocitrate dehydrogenase [NADP] icd 0.0063
2302 Isocitrate dehydrogenase [NADP] icd 0.0063
2771 Isocitrate dehydrogenase [NADP] icd 0.0063
4226 Uridine phosphorylase 2 UPP2 0.0061
4026 Aspartyl aminopeptidase DNPEP 0.0061
4024 Mitochondrial glutamate carrier 2 SLC25A18 0.0061
4025 Mitochondrial glutamate carrier 1 SLC25A22 0.0061
4021 Probable glutamyl-tRNA synthetase, mitochondrial EARS2 0.0061
4023 N-acetylglutamate synthase, mitochondrial NAGS 0.0061
1047 Excitatory amino acid transporter 2 SLC1A2 0.0061
4022 Glutamate--ammonia ligase domain-containing protein 1 LGSN 0.0061
1912 Excitatory amino acid transporter 1 SLC1A3 0.0061
4016 Excitatory amino acid transporter 5 SLC1A7 0.0061
4019 Excitatory amino acid transporter 4 SLC1A6 0.0061
664 Glutamate decarboxylase 2 GAD2 0.0061
3890 Glutamate decarboxylase 2 GAD2 0.0061
924 Glutamate receptor, ionotropic kainate 3 GRIK3 0.0061
919 Glutamate receptor, ionotropic kainate 4 GRIK4 0.0061
915 Delta 1-pyrroline-5-carboxylate synthetase ALDH18A1 0.0061
920 Glutamate receptor, ionotropic kainate 5 GRIK5 0.0061
4017 5-oxoprolinase OPLAH 0.0061
922 Glutamate receptor 4 GRIA4 0.0061
927 Metabotropic glutamate receptor 8 GRM8 0.0061
925 Metabotropic glutamate receptor 4 GRM4 0.0061
926 Metabotropic glutamate receptor 7 GRM7 0.0061
4020 Glutamyl aminopeptidase ENPEP 0.0061
4018 Glutamate receptor delta-2 subunit GRID2 0.0061
4027 Glutamate receptor delta-1 subunit GRID1 0.0061
4534 Cytohesin-2 CYTH2 0.0061
4225 Uridine phosphorylase 1 UPP1 0.0059
3668 Maltose-binding periplasmic protein precursor malE 0.0059
5692 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B PDE1B 0.0054
2592 Beta-galactosidase lacZ 0.0053
413 Amidophosphoribosyltransferase PPAT 0.0051
2515 Amidophosphoribosyltransferase purF 0.0051
3714 Amidophosphoribosyltransferase purF 0.0051
830 Glutamate dehydrogenase 2, mitochondrial GLUD2 0.0051
4512 Cytochrome P450 3A4 CYP3A4 0.005
917 Glutaminase kidney isoform, mitochondrial GLS 0.005
5 Glutaminase liver isoform, mitochondrial GLS2 0.005
355 GMP synthase [glutamine-hydrolyzing] GMPS 0.005
4353 GMP synthase [glutamine-hydrolyzing] guaA 0.005
3991 Glutamine-dependent NAD(+) synthetase NADSYN1 0.005
3982 Phosphoribosylformylglycinamidine synthase PFAS 0.005
5261 Phosphoribosylformylglycinamidine synthase purL 0.005
3984 Probable glutamyl-tRNA(Gln) amidotransferase subunit B, mitochondrial PET112L 0.005
668 Glutamate--cysteine ligase regulatory subunit GCLM 0.005
315 Arginase-1 ARG1 0.005
625 Glutamate carboxypeptidase 2 FOLH1 0.0049
801 Kynurenine/alpha-aminoadipate aminotransferase mitochondrial AADAT 0.0048
3895 Kynurenine--oxoglutarate transaminase 3 CCBL2 0.0048
420 Glutamate decarboxylase 1 GAD1 0.0048
3900 Glutamate decarboxylase 1 GAD1 0.0048
665 Phosphoserine aminotransferase PSAT1 0.0048
4652 Phosphoserine aminotransferase serC 0.0048
382 Glutamate receptor, ionotropic kainate 1 GRIK1 0.0047
2347 Proto-oncogene serine/threonine-protein kinase Pim-1 PIM1 0.0046
916 Metabotropic glutamate receptor 1 GRM1 0.0046
1671 Excitatory amino acid transporter 3 SLC1A1 0.0044
923 Glutamate receptor 3 GRIA3 0.0044
3877 Growth-inhibiting protein 18 GIG18 0.0044
186 Glutamate--cysteine ligase catalytic subunit GCLC 0.0044
914 Formimidoyltransferase-cyclodeaminase FTCD 0.0044
201 Glutamate dehydrogenase 1, mitochondrial GLUD1 0.0043
448 Vitamin K-dependent gamma-carboxylase GGCX 0.0043
83 Alpha-aminoadipic semialdehyde synthase, mitochondrial AASS 0.0043
426 Aspartate aminotransferase, mitochondrial GOT2 0.0042
210 Bifunctional aminoacyl-tRNA synthetase [Includes: Glutamyl-tRNA synthetase EPRS 0.0041
763 Tyrosine aminotransferase TAT 0.0041
5493 Tyrosine aminotransferase Not Available 0.0041
735 Alanine aminotransferase 1 GPT 0.0041
3904 Alanine aminotransferase 2 GPT2 0.0041
541 cAMP-specific 3',5'-cyclic phosphodiesterase 4B PDE4B 0.004
505 Glutamate [NMDA] receptor subunit epsilon-3 GRIN2C 0.004
586 Aspartate aminotransferase, cytoplasmic GOT1 0.004
439 Glutamate [NMDA] receptor subunit epsilon-4 GRIN2D 0.004
6263 cAMP-dependent protein kinase catalytic subunit alpha PRKACA 0.004
242 Asparagine synthetase [glutamine-hydrolyzing] ASNS 0.0039
795 Branched-chain-amino-acid aminotransferase, mitochondrial BCAT2 0.0038
401 Glutamate [NMDA] receptor subunit zeta-1 GRIN1 0.0037
591 Glutamate [NMDA] receptor subunit 3B GRIN3B 0.0037
574 Branched-chain-amino-acid aminotransferase, cytosolic BCAT1 0.0037
33 Cystine/glutamate transporter SLC7A11 0.0036
705 Glutamate receptor 1 GRIA1 0.0036
464 Glutamate [NMDA] receptor subunit epsilon-2 GRIN2B 0.0036
3426 Glutamine synthetase glnA 0.0036
3987 Glutamine synthetase GLUL 0.0036
280 4-aminobutyrate aminotransferase, mitochondrial ABAT 0.0035
837 Glutamate [NMDA] receptor subunit epsilon-1 GRIN2A 0.0034
6136 Multidrug resistance-associated protein 5 ABCC5 0.0033
706 Glutamate [NMDA] receptor subunit 3A GRIN3A 0.0028
918 Glutamate receptor, ionotropic kainate 2 GRIK2 0.0027
6151 Monocarboxylate transporter 10 SLC16A10 0.0027
921 Glutamate receptor 2 GRIA2 0.0026
5718 Cytochrome P450 2A6 CYP2A6 0.0025
4200 Cytochrome P450 1A2 CYP1A2 0.002
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