Medchem Exam 1 part 2

  1. Main differences between normal and cancer cells
    • Loss of cell growth
    • decreased cell differentiation
    • ability to invade surrounding tissue
    • ability to establish new growth at ectopic sites (metastasis)
  2. Goal of chemotherapy
    prevent cancer cells from multiplying, invading and metastasizing
  3. Why is cancer difficult to treat?
    • <100 different tumor types
    • cancer cells similar to normal cells
    • Tumor eradication elicits an immune response
    • Cancer drug toxicity
  4. Processes of controlling cell lifespan
    • cell proliferation
    • cell death
  5. Oncogene
    gene overexpressed in cancer cells
  6. retinoblastoma pathway
    • RB binds cyclin D and is phosphorylated by CDK4
    • Structure opens and releases Cyclin D
  7. Mutation of RB Pathway
    • Drives cell cycle much faster
    • 20-30% of cancer cases
    • 2nd major mutation
    • high [CDK4]
    • high [cyclin D]
    • low [P16]
  8. p53
    • transcription factor that functions as a "tumor suppressor"
    • senses DNA problems and stops cell cycle
    • -50% of cancer patients have mutated p53
    • -causes resistance to some types of chemotherapy
  9. p53 mediated apoptosis
    • Cancer drugs work by damaging DNA to induce p53 mediated apoptosis
    • -mutated p53 = drug may not work
  10. Phase specific drug
    Inhibits specific proteins or enzymes required for specific phases of the cell cycle
  11. Cell Cycle related drug resistance
    Only a fraction of cells are in the specific phase for the drug to act
  12. Biochemical related drug resistance
    • Altered metabolism
    • Decreased uptake of drug into cell
    • increased target
    • defective apoptosis
  13. pharmacologic related drug resistance
    • no receptors present
    • poor perfusion of large solid tumors
  14. Multi Drug Resistance
    • Decreased uptake mediated by P-glycoprotein
    • Increased glutathions which neutralize alkylating agents, platinum compounds and antibiotics
    • Decreased DNA topoisomerase II
  15. Drug Toxicity
    • Normal tissues undergo damage from anti-cancer drug
    • supplementary drugs allviate toxic effects or stimulate normal cells
  16. Dose Regimens
    • Do not use 2 phase specific drugs targeting the same phase
    • Combination therapy is more effective than monotherapy
  17. 3 reasons combination therapy is better
    • decrease resistance
    • decrease toxicity
    • target different cell cycle phases
  18. Five major classes of cancer drugs
    • Alkylating Agents
    • Antimetabolites
    • Natural Products
    • Miscellaneous Agents
    • Hormones and Antagonists
  19. Five types of Alkylating Agents
    • Nitrogen Mustards
    • Ethyleneimines
    • Alkyl sulfonates
    • Nitrosoureas
    • triazenes
  20. Two drug types that form adducts with DNA but do not alkylate
    • platinum complex
    • methylhydrazine
  21. Mechanism of Alkylating Agents
    • Produce cytotoxic, mutagenic and carcinogenic effects by reacting with cellular DNA
    • -N7 bond of guanine is susceptible to forming bonds with alkylating agents
    • -Alkylated guanine mispairs with thymine
    • Consequences trigger p53 mediated apoptosis
  22. Mechlorethamine***
    nitrogen mustards
  23. Cyclophosphamide
    prodrug which is activated by cytochrome p450 enzyme
  24. Cisplatin***
    • Platinum coordination complex
    • Very effective in testicular and ovarian cancer
    • Toxic to kidney and GI tract
  25. Mechanism of Action for platinum coordination complex
    • Enters cell via diffusion or active Cu2+ transporter
    • Covalently binds to nucleophilic sites on DNA
  26. Antimetabolites
    • Prevent biosynthesis or use of normal cellular metabolites
    • Drug closely related to structure of metabolite it antagonizes
    • S-phase specific
  27. 3 classes of antimetabolites
    • Folic Acid analogs
    • Pyrimidine analogs
    • Purine analogs
  28. Folic Acid Analogs
    • Methrotrexate inhibits dihydrofolate reductases (DHFR)
    • Undergoes conversion of polyglutamates which inhibit thymidylate synthesis
  29. Pyrimidine Analogs
    • Drug analogs of A,C and T must countain sugar group
    • -cannot be synthesized in the cell
    • Halogenated Pyrimidines
    • -Flourine
    • -Prevents methylation of 5 position by thymidylate synthase (TS)
  30. Resistance to 5-FU results from
    • Loss or decreased activity of enzymes necessary for activation of 5-FU
    • Amplification of TS
    • Mutation of TS that is not inhibited (most common)
    • Insufficient concentrations of cofactor required to lock TS in inactive state
    • -5,10-methylene tetrahydrofolate
  31. Cytarabine
    • Analog of 2'-deoxycytidine
    • Hinders rotation of pyrimidine base around nucleosidic bond and interferes with base stacking
    • Potent inhibitor of DNA polymerase
  32. Purine Analogs
    • Antiviral and anticancer
    • Substitution of S for O creates compounds that are readily converted to nucleotides and incorporated into DNA
  33. Adrenocorical suppressants
  34. Glucocorticoids
    bind to the glucocoricoid receptor and activate gene expression that leads to apoptosis

    used for acute leukemia in children and malignant lymphoma in children and adults
  35. Dexamethasone
    • glucocorticoid
    • suppress mitosis in lymphocytes
  36. Anti-Adrenal therapies for prostatic carcinomas
    • competitive inhibitors of androgen receptor
    • - AR blocker or Anti-androgens
    • -Steroidal or non-steroidal
  37. Gonadotropin-Releasing Hormone Agonsists
    • Cause surge in LH and FSH leading to negative feedback of gonadotropin release
    • complete androgen blockage
  38. Combination therapy of androgen blockers and GnRH-agonists
    Blocks androgens from adrenals and gonads
  39. Anti-Estrogen Treatments for Mammary Carcinomas
    • Selective estrogen-receptor modulators (SERMs)
    • Selective estrogen-receptor downregulators(SERDs)
    • Aromatase Inhibitors (AIs)
  40. Selective estrogen-receptor modulators (SERMs)
    • Tamoxifen
    • partially inactivated transcription of estrogen genes
  41. Selective estrogen-receptor downregulators (SERDs)
    • "Pure anti-estrogens"
    • Binds 100x stronger than tamoxifen to ER
    • -inhibits dimerization
    • -increases degredation
    • No transcription of estrogen genes will occur
  42. Aromatase Inhibitors (AIs)
    • Aromatase is responsible for conversion of androstenedion and testosterone to estrogens
    • 1st, 2nd and 3rd Generations
    • 3rd Gen has 2 types
    • -Type 1=binds irreversibly "suicide substrate"
    • -Type 2=binds reversibly
Card Set
Medchem Exam 1 part 2
Antineoplastic Agents