Imitation Folate Methotrexate, Leucovorin, 5-Fluorouracil, Hydroxyurea

1.1 "Imitation folate": methotrexate, leucovorin, 5-Fluorouracil, hydroxyurea CA can be treated with targeted radiotherapy, excision (local therapy) or systemic administration of cytotoxic drugs to eradicate or control proliferative cells, but affect systemic as well. CA cells produces larger amounts of DNA/RNA per unit time than most healthy cells, so affecting these pathways is highly attractive. These agents affect thymidine synthesis, particularly those affecting folate cycle. Thymidine is a pyrimidine deoxynucleotide (hexagonal plates), synthesized by thymidylate synthetase methylates dUMP → dTMP (dUMP dumplings single dumpling with T-shaped chopsticks). Process powered by folate cycle: Methylated THF (4 leaves + C-shaped sushi) converted to DHF (removing C-shaped sushi & knocking off 2 leaves). Catalyzed thymidylate synthetase. DHF converted back to THF by DHFR (adding back 2 leaves). THF is then methylated (adding back C-shaped sushi). Thymidine is only found in DNA. Ribonucleotides are synthesized first. So precursor to both thymidine & uracil is UDP (U Dining in? Please sign in!). Ribonucleotide reductase converts UDP deoxy-UDP, which is precursor molecule (wait list waitress crossing out oxy). Antimetabolites Methotrexate (MTX) (meat stix) Folate analog competitively & irreversibly binds to DHFR, preventing THF renewal (meat stick chef has blocked leaf boats) → Buildup of folate & DHF (boat jam). Results in blocking de novo synthesis of DNA, RNA, and key cellular proteins. Cell-cycle specific for S-phase (Sushi Phase, ramen DNA blocked by chopsticks) Indications Treats a range of malignancies including leukemias, lymphomas, breast cancer, head & neck cancer, lung CA (cracked cancer crab) Treats non-neoplastic conditions with abnormal cellular proliferation MTX + misoprostol as abortifacient (uterus-shaped backpack). Used for non-surgical treatment of early, unruptured ectopic pregnancy (baby keychain outside of uterus). Gestational trophoblastic neoplasia (choriocarcinoma, trophoblastic tumors, invasive molar pregnancy) most can be treated with short course of MTX (mole for molar pregnancy) Chronic inflammatory conditions, d/t immunosuppressive effects (torn antibody lantern) Disease modifying anti-rheumatic drug (DMARDs). Effects take a few weeks (joint lantern with inflammatory candle). May manage with glucocorticoids, NSAIDs for short term SSx relief Psoriasis (hyperproliferation of epidermis), as well as arthritis & nail disease (potentially d/t immunosuppressive effects) (silvery scaled kneepads) Other inflammatory conditions, including IBD, SLE, Vasculitides, dermatomyositis Adverse effects Folate deficiency (falling foliage) Megaloblastic (macrocytic) anemia d/t folate deficiency (blasting lanterns) Myelosuppression is the dose-limiting effect in high dosing needed for chemo. Causes immunosuppression (empty bone serving tray; immunocompromised cane) Pulmonary fibrosis (restrictive pattern) (restricted growth of lung-shaped bonsai tree) Hepatotoxicity, likely d/t direct cell damage (liver stain on apron). Monitor LFTS. Alopecia (bald chef) Stomatitis (burning mouth with hot meat) o Leucovorin rescue (folinic acid) can be used to reverse or prevent the worst of the adverse effects (maneki-neko, i.e.. lucky feline). Does not require DHFR for activation; displaced MTX from binding sites, restoring normal folate levels. 5-fluorouracil (5-FU) (full guy waving 5 fingers) Pyrimidine analog (hexagonal plates). Inhibits thymidylate synthase (guy blocking transfer of C-shaped sushi). Cell-cycle specific for S-phase (Sushi Phase, ramen DNA blocked by chopsticks) Metabolized to active form, 5-dUMP. Forms complex with thymidylate synthase & DHF. Results in buildup of dUMP (dumpling buildup) Indications CRC, breast, head & neck, liver, pancreas CA (cracked cancer crab) Topically for basal cell carcinoma Adverse effects Diarrhea d/t damage of intestinal epithelium (patron with messy pants) Cutaneous complications Photosensitivity (camera flash) Hyperpigmentation Number of other rashes Myelosuppression & pancytopenia immunosuppression (empty bone serving tray; immunocompromised cane) No leucovorin rescue here! (falling feline) Hydroxyurea (hydro-rock area) Inhibits Ribonucleotide reductase (inhibited wait list waitress). Cell-cycle specific for S-phase (Sushi Phase, ramen DNA blocked by chopsticks) Indications AML, CML, head & neck CA Sickle cell anemia, d/t ↑production of HbF (sickle by Zen garden; raising baby with Hb coin up) Adverse effects Myelosuppression & pancytopenia immunosuppression (empty bone serving tray; immunocompromised cane) Gl upset