Trimetrexate glucuronate

Trimetrexate glucuronate (NSC 352122) is a folic acid antagonist. Trimetrexate glucuronate affects DNA and RNA synthesis by inhibiting dihydrofolate reductase and preventing the synthesis of purine nucleotides and thymidylate. Trimetrexate glucuronate has potential anti-tumour activity[1].

Research Areas >> Cancer

Signaling Pathways >> Cell Cycle/DNA Damage >> Antifolate

Trimetrexate glucuronate (0.05-1 μM 6 h) results in a decrease in adenosine and guanosine acids and a significant increase in the pyrimidine nucleotide such as CTP, UTP of WI-L2 human lymphoblastoid cells in a dose-dependent manner[1]. Trimetrexate glucuronate (1 μM, 2 h) can reduce the level of dTTP by 29%, also decrease in the dGTP and dATP, while cause extensive inhibition of deoxyuridine incorporation into DNA in L1210 mouse leukemia cells[1].

Trimetrexate glucuronate (i.p., 100-225 mg/kg, daily, day 1, 5, 9) has antitumor activity in inbred DBA/2 mice with L1210 leukemia[1]. Animal Model: Inbred DBA/2 mice with L1210 leukemia[1] Dosage: 100, 150, 225 mg/kg Administration: Intraperitoneal injection; daily; day 1, 5, 9 Result: Showed the maximum lifespan T/C value of 171%. Animal Model: C57BL/6 mice with M5076 tumor[1] Dosage: 38, 62 mg/kg Administration: Intraperitoneal injection; daily; 1-9 days Result: Showed toxic (>10% early deaths) at high dose of 62 mg/kg and inactive (Lifespan T/C <130%) at lower dose of 38 mg/kg.

[1]. R C Jackson, et al. Biochemical pharmacology of the lipophilic antifolate, trimetrexate. Adv Enzyme Regul. 1984;22:187-206.

MOLECULAR WEIGHT :

563.63

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Human

DOSE/DURATION :

2027 ug/kg

TOXIC EFFECTS :

Vascular - BP lowering not characterized in autonomic section Gastrointestinal - other changes Blood - thrombocytopenia

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Human

DOSE/DURATION :

4054 mg/kg/3W-I

TOXIC EFFECTS :

Blood - changes in bone marrow (not otherwise specified)

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

60 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

50 mg/kg/5D-C

TOXIC EFFECTS :

Blood - changes in leukocyte (WBC) count Blood - changes in platelet count Related to Chronic Data - changes in testicular weight

MUTATION DATA

TYPE OF TEST :

DNA damage

TEST SYSTEM :

Rodent - mouse Leukocyte

DOSE/DURATION :

500 nmol/L

REFERENCE :

BCPCA6 Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- Volume(issue)/page/year: 40,1981,1990