Ans. d (Calcium leucovorin) (Ref. Harrison 18th/ p 476, 607)# Methotrexate inhibits dihydrofolate reductase, which regenerates reduced folates from the oxidized folates produced when thymidine monophosphate is formed from deoxyuridine monophosphate.# Without reduced folates, cells die a "thymineless" death.# N-5 tetrahydrofolate or N-5 formyltetrahydrofolate (leucovorin) can bypass this block and rescue cells from methotrexate, which is maintained in cells by polyglutamylation.METHOTREXATE - Side Effects:# In addition to bone marrow suppression and mucosal irritation, methotrexate can cause renal failure itself at high doses owing to crystallization in renal tubules; therefore high-dose regimens REQUIRE ALKALINIZATION OF URINE with increased flow by hydration.6# Less frequent adverse effects include reversible increases in transaminases and hypersensitivity-like pulmonary syndrome.# Chronic low-dose methotrexate can cause hepatic fibrosis.# When administered to the intrathecal space, methotrexate can cause chemical arachnoiditis and CNS dysfunction.# Trimetrexate is a methotrexate derivative that is not polyglutamylated and does not use the reduced folate carrier.# The effects of folate antagonists that inhibit dihydrofolate reductase can be counteracted by folinic acid (5-formyl tetrahydrofolate ) in a dose of 100 to 200 mg/d, which circumvents the block in folate metabolism by providing a form of folate that can be converted to 5,10-methylene THF.Methotrexate(Antimetabolite)# A folic acid analog that inhibits dihydrofolate reductase; decreased dTMP levels hinder DNA and thus protein synthesis# S-phase specificNeoplastic indications: leukemia, lymphomas, breast cancer, choriocarcinomaNonneoplastic indications; rheumatoid arthritis, psoriasis, termination of pregnancy (e.g., ectopic) Toxicities: suppresses bone marrow reversibly; folinic acid (leucovorin) is used to "rescue"; fatty change in liver