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Classes of cell cycle specific and cell cycle non-specific drugs
- Cell Cycle Specific
- Antimetabolites
- Topoisomerase Inhibitors
- Microtoubule Poisons (Plant Alkaloids)
- Signal Transduction Inhibitors
- Cell Cycle Non-Specific
- Alkylating Agents
- Antitumor Antibiotics
- Biologics (Hormone inhibitors, corticosteroids, biologic antineoplastics)
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The 3 classes of Plant Alkaloids
- Vinca Alkaloids (Vincristine and Vinblastine)
- Taxanes (Paclitaxel and Docetaxel)
- Podoohyllotoxins (Etoposide)
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3 Alkylating Agents
- Mechlorethamine
- Cycophosphamide
- Cis-Platin
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What is the mechanism of action for alkylating agents?
They covently interact with and bind DNA (typically cross-link), thus blockign access to DNA
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Which intercellular protein pumps foregin materials out of the cell and is associated with resistance?
P-glycoprotein
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Irinotecan
- Topoisomerase Inhibitor (CCS)
- Allows topoisomerase I to make cuts, but prevents reannealing; causes DS breaks
- S-G2 checkpoint arrest
- Pro-drug converted by esterase to SN-38
- UGT1A1 converts it to SN-38G to get rid of it
- Hematologic effects at higher doses
- Dose limiting diarrhea and n/v
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Methotrexate (folate analog)
- Antimetabolite (CCS)
- DHFR inhibitor--blocks the production of bases
- S-G2 arrest
- Oral, IV
- Rescue with folinic acid
- Hepatotoxicity
- Resistance associated
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5-FU/Cytarabine/Gemcitibine
- Antimetabolite (CCS)
- Pyrimidine analog--far mroe toxic than purines with more adverse side effects
- 5-FU-->thymine-less death
- Cy and Gem are cytosine analogs-chain terminators
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6-mercaptopurine/6-thioguanine
- Antimetabolites (CCS)
- Purine Analogs--less severe side effects
- Oral
- Myelosuppression only at higher doses
- Resistance from increase in alkaline phosphatase
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Imatinib
- Signal Transduction inhibitor (CCS)
- Blocks PDGFR, thereby blocking BCR-ABL and other tyrosine kinases
- Most recent and selective chemo because normal cells do not have these
- Myelosuppressive, hepatotoxic, and edema
- Use for CML and GIST
- Takes fatal diseae and makes it manageable--resistance associated
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Gefitinib
- Signal Transduction Inhibitor (CCS)
- Blocks EGF
- Used in non-small cell lung cancer
- Oral
- Fever/dyspnea
- Takes fatal disease and makes it manageable--resistance associated
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Vina Alkaloids (Vincristine and Vinblastine)
- Plant Alkaloids (CCS)
- Inhibit microtubule polymerization
- Metaphase arrest with no mitotic spindles
- IV
- Excreted in feces
- Cristine: peripheral neuropathy
- Blastine: n/v, alopecia, myelosuppression
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Taxanes (Paclitaxel and Docetaxel)
- Plant Alkaloids (CCS)
- Don't allow microtubules to dissociate
- Metaphase arrest with mitotic spindles
- IV
- Dissolved in Cremophor detergent--causes most negative side effects
- Pre-treat with analgesics and anti-inflammatories
- n/v, myelosuppression, hypersensitivity
- Used in solid tumors
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Podophyllotoxins (Etoposide)
- Plant Alkaloids (CCS)
- Topoisomerase II inhibitor--allows it to make cut but prevents reannealing--DS breaks
- S-G2 arrest
- Oral and IV
- n/v and myelosuppression
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Mechlorethamine
- Alkylating Agent (CCNS)
- Nitrogen mustard--highly reactive
- IV only--subcutaneous causes necrosis
- M of MOPP
- Used for Hodgkin's
- n/v and myelosuppression
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Cyclophosphamide
- Alkylating agent (CCNS)
- Metabolized to acrolein
- n/v, myelosuppression, alopecia, and hemorrhagic cystitis (treat with forced hydration or Mesna)
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Cis-platin
- Alkylating Agent (CCNS)
- Bifunctional platinating agent; x-links DNA to block synthesis
- IV
- severe n/v and renal toxicity (treat with 1 L IV first)
- Carboplatin and Oxaliplatin are similar
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Anthracyclines (Doxarubicin and Daunorubicin)
- Antitumor Antibiotics (CCNS)
- Squeeze between bps so topoisomerase can't come in
- Can cause strand breaks; generates free radicals
- Metabolized in liver
- Minimize effects of free radicals with Dexazoxane
- Myleosuppression, GI distress, alopeica, long-term cardiotoxicity
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Bleomycin
- Antitumor antibiotic (CCNS)
- Binds DNA--strand breaks--free radicals
- Only active in G2 phase (CCS)
- Hypersensitivity and dose-limiting pulmonary toxicity (long term) and fibrosis
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Aromatase inhibitors (Anastrazole and Letrozole)
- Hormone Inhibitors (CCNS)
- Aromatase converts androgen to estrogen and this inhibits process
- Specific for ER+ cancers
- Orally
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SERMS (Tamoxifen)
- Selective estrogen receptor antagonists (ER+)
- ER antagonist in breast tissue, agonist in endometrium, which is why 5+ years on this increases risk for ovarian cancer
- Orally
- Problem: CYP2D6 metabolizes tamoxifen more quickly than receptors do
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Androgen Receptor Antagonists (Flutamide)
- Hormone Inhibitor (CCNS)
- Block androgen intercellular functioning
- Use with radiation for prostate cancer
- Orally
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Hydrocortisone and Prednisone
- Corticosteroids (CCNS-Biologic)
- Suppress proliferation of immune cells
- Orally
- For lymphomas and leukemia
- Diabetes, immune suppression, myelosuppression
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Interferon-alpha
- Biologic Antineoplastics (CCNS)
- Cytokine produced by WBCs--jacking up immune function--didn't work that well
- Fever, chills, anorexia, weakness
- For hematologic malignancies, metastatic melanomas, and renal cell carcinoma
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Trastuzumab
- Biologic Antineoplastic (CCNS)
- Antibody targeting HER2 and EGF receptors
- IV
- Can not cross BBB
- Hypersensitivity and cardiomyopathy
- Stops proliferation, but does not eliminate tumor
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What are the tyrosine kinase receptor inhibitors?
Sutinib, temsirolimus, erlotini, cetuximab, bevatuzumab, and sorafenib
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Sutinib
- Multiple receptor tyrosine kinase inhibitor (PDGFR, VEGFR, and FLT3)
- Results in cell death and reduced angiogenesis
- no tumor regression
- GIST and renal cell carcinoma
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Temsirolimus
- mTOR inhibitor
- Stops proliferation and angiogenesisi by preventing synthesis of VEGF
- G1 cell cycle arrest
- no tumor regression
- kidney cancer
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Erlotinib
- EGFR inhibitor
- palliative drug for metastatic lung cancer
- <10% response rate to drug
- No tumor regression
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Cetuximab
- Bifunctional: EGFR inhibitor and antibody dependent cell cytotoxicity (helps body recognize and target cancer cells)
- Colon cancer
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Bevatuzumab
- VEGFR inhibitor
- Colon cancer
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Sorafenib
- VEGFR1-3 and RAF-1 inhibitor (Involved in signaling pathway, thereby shutting down ERK and MEK)
- Colon cancer
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