1. Methotrexate
    Cures trophoblastic choriocarcinoma
    • Folate Antagonists
    • decreases DNA synthesis
    • **Teratogenic, myelosuppression, and GI distress
  2. Antimetabolites
    • Interfere with nucleic acid production by:
    • • inhibiting enzymes →↓ synthesis of NTPs
    • •substituting for normal purines or pyrimidines
    • • killing cells in S phase
  3. Mechanism of action for anticancer drugs
    • (A) Covalent DNA Binding Drugs
    • (B) Noncovalent DNA Binding Drugs
    • (C) Antimetabolites
    • (D) Inhibitors of Chromatin Function
    • (E) Drugs Affecting Endocrine Function
  4. Covalent DNA-binding drugs(Alkylating Agents)
    -CCNS drugs that form electrophilic compounds that covalently bind alkyl groups to DNA
  5. 1) nitrogen mustards2) nitrosoureas3) platinum compounds
    Covalent DNA-binding drugs(Alkylating Agents)
  6. Consequences of alkylation
    1. Cross-linkage2. Depurination3. Excision repair of DNA4. Mispairing of bases
  7. Mechlorethamine
    -used in combination therapy for Hodgkin’s lymphoma
    • Nitrogen mustard
    • Alkylation
    • -bifunctional alkylator-very reactive and unstable
    • toxicity: myelosuppression
  8. Cyclophosphamide
    -used in combination: lung, breast and ovarian cancer
    • nitrogen mustard (alkylation-covalently find alkyl groups to DNA)
    • -less toxic ring structure
    • -bioactivated by P450s in liver
    • -toxicity: myelosuppression
  9. BCNU and CCNU
    -lipid-soluble: used for brain tumors
    • -nitrosoureas (alkylation-covalently find alkyl groups to DNA)
    • -alkylating agents -interstrand x-links in DNA
    • -toxicity: GI distress, myelosuppression, CNS dysfunction
  10. Cisplatin
    -used in combination, cures testicular cancer
    • Platinum compound (Alkylation, not really)-binds itself to DNA
    • -technically not an alkylating agent (no alkyl groups, but Cl- leaves)
    • -inorganic Pt compounds that bind to DNA → cross-links andadducts
  11. Anthracyclines & Bleomycin
    -in combination for a wide range of solid tumors and leukemia
    • Free radicals/intercalation (act on DNA)
    • noncovalent DNA binding drug
    • DNA intercalation and  Free radical damage of DNA
    • -planar drugs, intercalate with DNA-form tight drug-DNA interactions
    • Toxicity: -*cardiac toxicity (anthracyclines, e.g. doxorubicin)-*pulmonary fibrosis (bleomycin)
  12. Fluorouracil (5-fluorouracil, 5-FU)
    -used for common solid tumors (e.g. colorectal, pancreatic ca.)
    • antimetabolite (folate antagonist)-substitutes normal purines/pyridmidines, and inhibits enzymes -> decrease NTP synth, kills cells in S phase
    • -resembles uracil and thymine
    • -incorporates into RNA
    • -inhibits thymidylate eynthase and RNA processing
    • -toxicity: nausea, vomiting, diarrhea, oral and GI ulcers
  13. Etoposide
    -used in combination Rx of lung, prostate and testicular tumors
    • Topoisomerase Inhibitors (inhibit chromatin fun'c-prevent DNA replication and mitosis)
    • -stabilizes topo II-DNA complex-causes DNA strand breaks-lethal to cells in S and G2 Phases
    • -resistance due to ↑ drug efflux and ↑ topoisomerase levels
  14. Vinca alkaloids and Taxanes
    Use:-both used in combination with other drugs to treat lymphomas & many carcinomas
    • Microtubule Inhibitors
    • -VA: bind tubulin -> decrease MT formation
    • -Taxanes: stabilize MTs
    • Resistance: due to ↑ drug efflux & mutated tubulin
    • -Toxicity: -*peripheral neuropathy (MT are necessary for nervous conduction)
  15. Tamoxifen
    -effective in treatment of ER +ve breast cancer-may be useful as preventative agent
    • -affect Endocrine Function (Rationale: -tumor growth is modified by steroid hormones and antagonists)
    • Estrogen Receptor (ER) Antagonists → death of estrogen-dependent breast cancer cells
    • Toxicity: few side-effects
  16. Prednisone
    • -Act on steriod hormone receptors (Glucocorticoids)
    • • cytotoxic (by apoptosis) to leukemia and lymphoid cells
    • • used in combination with other drugs to treat various leukemias and lymphomas
    • -anti-inflammatory too
  17. Letrozole
    • effective in treatment of ER +ve breast cancer
    • -act on steriod hormone receptor (aromatase inhibitor)
    • -inhibit aromatase preventing conversion of androgens to estrogens
    • Toxicity: GI effects, hot flashes
  18. Principles of combination chemotherapy
    Drugs used in combination should:a) have some individual anti-tumor activityb) act by different mechanismsc) have different toxicitiesd) have minimal cross-resistance
  19. Mechanisms of drug resistance
    Mechanisms:1) Decreased drug accumulation2) Altered drug metabolism3) Altered drug targets4) Increased repair of DNA damage5) Formation of trapping agents6) Combinations of mechanisms
  20. Bevacizumab (Avastin)
    colon cancer
    • Bind VEGF (block VEGF receptor tyrosine kinase)
    • -VEGF needed for angiogenesis for nurtient and O2 delivery to tumor for expansion and metastasis
    • Clinical effects:- no side-effects- treats primary tumors and metastases- used in combination with other drugs
  21. Imatinib (Gleevec)
    – clinically effective in in chronic myelogenous leukemia(CML) as Abl is mutated
    • -anticancer drug
    • inhibit Ab1 tyrosine kinase -> decrease Ab1 function -> tumor cell death
  22. Tyrosine Kinase as a Target in anti-cancer drugs
    -interfere with signalling pathways that modulate mitogenesis,and angiogenesis (also cell motility, cell adhesion, invasion)
  23. restricted to ADR mediated by IgE
    Drug allergy
  24. secondary to the intended use of a drug
    Drug side-effects
  25. Type A (augmented) ADR
    • -Dose-dependent ADR
    • -can occur in all Pxs
    • -known mechanism
    • -reproducible experimentally
    • -elevated plasma drug levels
  26. inhibition of cyclooxygenase enzymes and GI ulceration
    • NSAID toxicity
    • (COX necessary for healthy gut, COX converts arachidonic acid) AA causes GI ulceration
  27. Exaggerated pharmacological effects of the drugon the intended target
    Pharmacological toxicity
  28. Doxorubicin toxicity
    • antibiotic used as an anticancer drug
    • -toxicity: heart failure due to free radical production in myocardium
  29. Aminoglycoside toxicity
    nephrotoxicity and ototoxicity (ie. gentamicin, tobramycin)
  30. Mechanism of antimalarial action Chloroquine
    Inhibit heme polymerase -> toxic build up of free heme in malaria parasite
  31. Anti-rheumatic activity of chloroquine
    ie. rheumatoid arthritis, lupus erythematosus
    • inhibits T-cell functions
    • -relatively high doeses used chronically -> many times these Pxs have ocular adverse effects
  32. Chloroquine toxicity to retina
    • -has affinity for MELANIN -> acculumates in RPE and PRs -> damages lysosomes -> cell loss
    • -retina parafoveal granularity of RPE (early)-> progression into retinopathy (chloroquine-related lesions) "Bull's Eye" maculopathy (late)
  33. Patients may have abnormal sensory responses and distortedcolour vision (late phase) with a yellow, green, or blue tinge toobjects, and coloured haloes around lights. The drugs arefound excreted in the tear film and can aggravate dry eyealong with possibly decreasing contact lens tolerance. Theycan also cause decreased accommodation and visual fielddefects.
    Chloroquine toxicity
  34. Point of toxicity for chloroquine?
    total lifetime dose of >1,250g
  35. Viruses are ____ ___ parasites
    • obligate intracellular
    • - no cell membrane or cell wall
    • - no metabolic processes -> use host cell’s machinery
    • - difficult to stop viral replication without harming host
  36. Px has HSV and you give them Vidarabine
    • Antiviral drug: Nucleoside analogue (adenosine)
    • -activated by virus-encoded thymidine kinase -> inhibits viral DNA polymerase
    • -use: HSV-associated dendritic or geographic epithelial keratitis
    • - adverse effects: stinging, burning, lacrimation,conjunctival hyperemia
    • - contraindications: hypersensitivity to drug
  37. Px has HSV keratitis and you give them Trifluridine
    • Antiviral drug: Nucleoside analogue (thymidine)
    • -inhibits thymidine synthetase -> inhibits DNA synthesis in virus and normal
    • -use: drug of choice for HSV keratitis(superior to vidarabine)
    • - adverse effects: HIGHLY TOXIC so only use topically, stinging, burning, conjunctival hyperemia,corneal erosion, keratitis sicca (- ptosis and lacrimal punctal occlusion may be permanent)
  38. Px has HSV and VZV and you give them Acyclovir
    • -Antiviral drug: Nucleoside analogue (guanosine)
    • - inhibits viral DNA polymerase following phosphorylation by a virus-encoded enzyme (thymidine kinase), so primarily affects virus-infected cells –extremely safe
    • (ORAL delivery)
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