Anti-Neoplastics MTX, 5-FU, Hydroxyurea General • MTX, 5-FU, and Hydroxyurea block synthesis of thymidine (hexagonal pyrimidine plate) (thymidylate synthetase-methylates Dump) • dUMP is converted to dTMP (plate with dumplings, plate with "T" shaped chops1cks) thymidylate synthase (guy moving carbon sushi off 4-leaf boat) catalyzes the conversion of methylated THF to DHF (takes carbon from it to give to dUMP) (sushi boat with 4 leaves and a c-shaped carbon sushi becoming a boat with 2 leaves) and methylates dUMP to dTMP (transferring the carbon sushi from the boat to the dumpling plate) DHF (boat with 2 leaves) is then converted back to THF (boat with 4 leaves) by dihydrofolate reductase (add 2 hydrogens, so reducing) (sushi guy adding 2 leaves) THF is then re-methylated (gets a carbon) (addi1on of carbon sushi) • UDP is the precursor to pyrimidine nucleosides (UDP sign) DUP is converted to deoxy-UDP by ribonucleo1de reductase (guest list waitress) -S phase specific, since target rapidly dividing cells (blocks DNA Synthesis) Overview: Thymidylate Synthesis (pyrimidine in DNA): 1) UDP-> dUMP (by ribonucleotide reductase) ]- hydroxyurea 2) dUMP-dTMP (by thymidylate synthase) ]- 5 FU a. (needs THF -FOLATE) i. DHF->THF (by DHF reductase) ]- methotrexate (acts like folate) Antimetabolites Methotrexate (meat stick) (DHF Reductase) • a cytotoxic folate analog
• attacks rapidly dividing cells and inhibits proliferation of immune cells (torn an1body lantern) • blocks the conversion of DHF to THF by competitively inhibitng DHF reductase (meat chef blocking leaf-sushi guy) ( cant change DHF -> THF) ○ leads to buildup of DHF (buildup of 2-leaf boats) and decreased dTMP levels, decreased DNA synthesis cycle (Sushi phase sign) blocking DNA synthesis (chops1cks blocking ramen-DNA on sign) blocks the S phase of the cell (works • treats: ○ many types of malignancies (cracked crab) [Leukemias, lymphomas, breast, head and neck, lung] ○ used with misoprostol as an abortion method (blocks trophoblast, hindering implantation) ○ ectopic pregnancy (baby keychain) ○ molar pregnancy, trophoblastic tumors and choriocarcinoma (mole falling out of backpack), since rapidly turning over ○ psoriasis (silvery scale kneepads) (hyperproliferation of epidermis) [immunosuppressivealso stops proliferation of immune cells] ○ rheumatoid arthritis (bone lantern with flame)long term management- disease modifying rheumatic drugs. Inhibit proliferation of immune cells that contribute to chronic inflammation and long term joint destruction. [short term-NSAIDS/Glucocorticoids] -Immune Suppression- IBD, SLE, Vasculitis, Dermatomyositis • side effects ○ folate deficiency (falling leaves) leading to megaloblastic anemia (fireworks lantern) myelosuppression with pancytopenia (bone marrow depletion) and increased risk of infection (depleted bone serving tray, immunocompromised cane) ○ pulmonary fibrosis- gradual onset dyspnea, progress to symptoms at rest. PFT- restrictive, dec diffusion capacity, bilateral diffuse patterns of small
opacity, lower lobes. Honeycomb appearance (fibro1c lung bonsai tree) ○ hepatotoxicity (liver spot on apron)- direct damage to hepatocyte (elevated LFTs) ○ alopecia (bald guy) ○ mucositis- soreness of mouth (guy poking meat s1ck into his mouth) ○ reverse toxic effects with Leucovorin (lucky feline) a folinic acid § does not require DHF reductase § displaced MTX from binding sites to restore normal folate levels 5-Fluorouracil -Blocks thymidylate synthase ( full, 5-finger waiving guy in yellow) • a pyrimidine analog (empty hexagonal plate) -blocks thymidylate synthase (guy moving carbon sushi off 4-leaf boat) to block thymidine synthesis and DNA synthesis (5-FU complexes with THF to inhibit TS, stops the donation of Carbon, so can’t synthesize dTMP from dUMP) •blocks the S phase of the cell cycle (Sushi phase sign) blocking DNA synthesis (chops1cks blocking ramen-DNA on sign) ○ causes buildup of dUMP (buildup of dumpling plates) • used in many solid tumors (cracked crab)- colorectal cancer, breast, head, pancreas, basal cell carcinoma • side effects ○ loss of epithelium in intestines(rapidly dividing cells) leading to diarrhea (brown stained pants) ○ photosensi1vity (flashing camera)- cutaneous complications, hyperpigmentation ○myelosuppression with pancytopenia and increased risk of infec1on (depleted bone serving tray, immunocompromised cane) § worsened with Leaucovorin (falling lucky feline) Hydroxyurea blocks RIBONUCLEOTIDE REDUCTASE (hydrorock area in back le^)
-UDP- precursor to all dUMP, dTMP, pyrimidine synthesis • blocks ribonucleotide reductase (ribonucleotide reductase waitress list waitress being pushed aside) blocks the S phase of the cell cycle (Sushi phase sign) blocking DNA synthesis (chops1cks blocking ramen-DNA on sign) •blocks the S phase of the cell cycle (Sushi phase sign) blocking DNA synthesis (chops1cks blocking ramen-DNA on sign) •increases hemoglobin F (baby with hemoglobin coin) • treats CML, AML, head/neck cancer, melanoma, (cracked crab) • also treats veno-occlusive crises in sickle cell (zen sickle) ○ increases hemoglobin F (baby with hemoglobin coin) • side effects ○ GI upset, diarrhea (since rapidly dividing cells are targeted) -myelosuppression with pancytopenia and increased risk of infec1on (depleted bone serving tray, immunocompromised cane)
