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Alkylating Agents
- Damage DNA by adding alkyl group
- –Results in impaired cell reproduction
- Platinums
- Nitrogen Mustards
- –Cyclophosphamide, Ifosphamide, Melphalan, Chlorambucil
- •Side effects:
- –Myelosuppression
- –Nausea/Vomiting (severe and common)
- –Increased risk of secondary malignancies (AML and myelodysplasia)
- –Neurotoxicity: tremors, confusion and ataxia (chlorambucil and ifosphamide)
- –Hemorrhagic cystitis (cyclophosphamide)
- Temozolomide
- •Class: non-classic alkylating agent
- •Mechanism of action
- –Methylation of guanine residues in DNA which inhibit DNA, RNA, and protein synthesis
- •Side effects
- –Leukopenia, thrombocytopenia
- –N/V, anorexia
- –Headache, and dizziness
- –Elevated LFTs (40%)
- –Skin: rash, itching, photosensitivity
- –Increased incidence of PCP
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Anti Tumor Antibiotics
- •Dactinomycin
- •Mitomycin-C
- •Bleomycin: (testicular ca) oxidation of DNA produces free radicals
- –Pulmonary toxicity
- •Resistance: MDR
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Arsenic Trioxide
- •Mechanism of Action
- –Apoptosis of APL cells
- –Degradation of the fusion protein PML/RAR-a
- •Clinical Use: Acute Promyelocytic leukemia (APL)
- •Side Effects
- –CV: Prolonged QT interval
- –GI: Nausea, vomiting, diarrhea, or constipation
- –HA, myalgias, and bone pain
- –Leukocytosis (50% of pts)
- –Neuro: neuropathy, tremors, insomnia
- –Pulmonary: cough, SOB, pleural effusions
- –Electrolyte abnormalities
- –APL differentiation syndrome
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Trentinoin (ALL-Trans Retinoic Acid)
- •Mechanism: induces maturation of promyelocytes to myelocyte; thus decreasing proliferation
- •Clinical use: APL
- •Side effects
- –Vitamin A toxicity symptoms: HA, fever, bone pain,nausea, vomiting, sweating, dry skin, mucositis, rash
- –GI: abdominal pain, diarrhea or constipation
- –Neuro: dizziness, confusion, depression
- –Increasing leukocyte count
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Steroids
- •Prednisone
- •Dexamethasone
- •Action
- –Inhibit tumor growth (NHL)
- –Reduce inflammation
- –Reduce CNS edema
- –Antiemetic
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Tamoxifen
- Mechanism
- Competitively binds ER inhibiting transcriptional processes in breast cancer cells
- Systemic estrogen receptor modulator (SERM)
- Estrogen antagonist in breast cancer tissue
- Estrogen agonist in endometrium and bone
- Conversion by CYP2D6 to active drug 4-hydroxytamoxifen
- •Use(s): Pre/Postmenopausal women with ER+ breast cancer
- –History of ER+ DCIS/LCIS
- –Beneficial for prophylaxis in women at high risk of developing breast cancer.
- Serious risks: Thromboembolic events, endometrial cancers
- Adverse effects: Hot flashes, fluid retention, vaginal bleeding
- Drug interactions: Strong inhibitors of CYP2D6
- SSRI’s: Paxil>Prozac>Zoloft>>Effexor
- Genetics: CYP2D6 *10 genotype shown to have lower 4-OHT levels
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Aromatase inhibitors
- •Mechanism
- –Inactivates aromatase and blocks the conversion of adrenal androgens to estrogen
- •Common Toxicities
- –Hot flashes
- –Arthralgias (15%)
- –Headache
- –Flu-like symptoms
- •Examples
- –Anastrozole
- –Letrozole
- –Exemestane
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Fulvestrant
- •Mechanism
- –ER antagonist
- –Downregulates ER expression
- •Common Toxicities
- –Asthenia (25%)
- –Hot flashes (20%)
- –Flu-like symptoms (10%)
- –Headaches
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LHRH Antagonists
- •Common Toxicities
- –Hot flashes (50%)
- –Impotence (10%)
- –Decreased libido (10%)
- –Tumor Flare (20%) – increased bone pain, urinary retention or back pain
- •Examples
- –Leuprolide
- –Goserelin
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Antiandrogens
- •Mechanism
- –Binds to Androgen receptor and inhibits androgen uptake
- •Common Toxicities
- –Hot flashes
- –Decreased libido
- –Gynecomastia
- –Myalgias
- –Hepatotoxicity
- •Examples
- –Bicalutimide
- –Nilutamide
- –Flutamide
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