Drug Information

Drug (ID: DG00018) and It's Reported Resistant Information

• Name: Raltitrexed
• Synonyms: Tomudex; 112887-68-0; ZD1694; ZD-1694; ICI-D1694; D-1694; ZD 1694; ICI D1694; UNII-FCB9EGG971; D1694; D 1694; CHEBI:5847; Raltitrexed (Tomudex); C21H22N4O6S; ZD-16; (2S)-2-[[5-[methyl-[(2-methyl-4-oxo-1H-quinazolin-6-yl)methyl]amino]thiophene-2-carbonyl]amino]pentanedioic acid; FCB9EGG971; CHEMBL225071; N-(5-(N-(3,4-Dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)-2-thenoyl)-L-glutamic acid; ICI-D-1694; NSC-639186; NCGC00229704-01; DSSTox_RID_81653; DSSTox_CID_26482; DSSTox_GSID_46482
• Indication:
  In total 1 Indication(s)
  Rectum cancer [ICD-11: 2B92]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Acute lymphocytic leukemia [ICD-11: 2B33]; [2]
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Colon cancer [ICD-11: 2B90]; [1]
  Osteosarcoma [ICD-11: 2B51]; [1]
• Target: Candida Thymidylate synthase (Candi TMP1); TYSY_CANAL; [1]
• Formula: C21H22N4O6S
• IsoSMILES: CC1=NC2=C(C=C(C=C2)CN(C)C3=CC=C(S3)C(=O)N[C@@H](CCC(=O)O)C(=O)O)C(=O)N1
• 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
• InChIKey: IVTVGDXNLFLDRM-HNNXBMFYSA-N
• PubChem CID: 135400182
• ChEBI ID: CHEBI:5847
• TTD Drug ID: D01KKQ
• VARIDT ID: DR00958
• DrugBank ID: DB00293

Type(s) of Resistant Mechanism of This Drug

  DISM: Drug Inactivation by Structure Modification

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Acute lymphocytic leukemia [ICD-11: 2B33]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Gamma-glutamyl hydrolase (GGH) [2]

• Resistant Disease: Acute lymphoblastic leukemia [ICD-11: 2B33.3]
• Molecule Alteration: Mutations; G667C; F589L-G595R
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: GGH signaling pathway; Regulation; N.A.
• In Vitro Model: REH cells; Bone marrow; Homo sapiens (Human); CVCL_1650
• In Vitro Model: Nalm-6 cells; Peripheral blood; Homo sapiens (Human); CVCL_0092
• Experiment for Molecule Alteration: Immunofluorescence staining assay; Western blot assay
• Experiment for Drug Resistance: Cell viability assay; MTX polyglutamated metabolite assay; Folate growth requirement assay
• Mechanism Description: A key cofactor of several enzymes implicated in DNA synthesis, repair, and methylation, folate has been shown to be required for normal cell growth and replication and is the basis for cancer chemotherapy using antifolates. gamma-Glutamyl hydrolase (GGH) catalyzes the removal of gamma-polyglutamate tails of folylpoly-/antifolylpoly-gamma-glutamates to facilitate their export out of the cell, thereby maintaining metabolic homeostasis of folates or pharmacological efficacy of antifolates. However, the factors that control or modulate GGH function are not well understood. In this study, we show that intact GGH is not indispensable for the chemosensitivity and growth of acute lymphoblastic leukemia (ALL) cells, whereas GGH lacking N-terminal signal peptide (GGH?deltaN) confers the significant drug resistance of ALL cells to the antifolates MTX and RTX. In addition, ALL cells harboring GGH?deltaN show high susceptibility to the change in folates, and glycosylation is not responsible for these phenotypes elicited by GGH?deltaN. Mechanistically, the loss of signal peptide enhances intracellular retention of GGH and its lysosomal disposition.

Osteosarcoma [ICD-11: 2B51]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-215 [1]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: Western blot analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.

Key Molecule: Thymidylate synthase (TYMS) [1]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: Western blot analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.

Colon cancer [ICD-11: 2B90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-215 [1]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.

Key Molecule: Thymidylate synthase (TYMS) [1]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.

References

• Ref 1: Molecular mechanism of chemoresistance by miR-215 in osteosarcoma and colon cancer cells. Mol Cancer. 2010 Apr 30;9:96. doi: 10.1186/1476-4598-9-96.
• Ref 2: A gamma-glutamyl hydrolase lacking the signal peptide confers susceptibility to folates/antifolates in acute lymphoblastic leukemia cells. FEBS Lett. 2022 Feb;596(4):437-448.