Pharm of Chemo agents: Sweatman Flashcards
Describe the role of estrogens in breast and endometrial tumors and the molecular cross-talk between estrogen, progesterone and cell surface proliferative pathways.
Estrogen drives ER+ tumors.
Estrogen binds to ER and signals for cell proliferation via nuclear and cytoplasmic pathways.
Progesterone—> gene transcription
PR+ predictive of good prognosis bc PR represses ER.
Explain the treatment options for pre- and post-menopausal breast, and endometrial cancer, including carriers of BRCA1/2 mutations.
BRCA1: prophylactic mastectomy/oophorectomy. No estrogenic signaling, so SERMS are ineffective.
BRCA2: surgery described above +/- SERMS (tamoxifen, raloxifene)
ER+:
premen- remove ovaries, GnRH agonists/antagonists that downreg. HP axis control. SERMs block ER. Pure estrogen antagonists
postmen- aromatase inhibitors, SERMs, SERDs (pure antagonist, also reduces ER expression)
(ovaries no longer produce estrogen, so GnRH won’t matter)
HER2:
mAbs, nib, mTOR inhibitor
Rx for endometrial cancer: progestins
Explain the localized delivery techniques to treat ovarian and bladder cancer.
For ovarian cancer: Pts may receive intraperitoneal instillations of cisplatin in a 2L bolus that is drained off after 2 hrs.
Only used for localized cancer, no mets.
For bladder cancer: intravesicular instillations of mitocycin C (alkylating agent) and Bacillus Calmette-Guerin (BCG)* for 1-2 hrs weekly x6 wks
*BCG acts by activating an immune response (attracts APCs that activate NK cells, CTLs, etc. that kill the tumor cells)
Describe the drug treatment options to treat ovarian and bladder cancer.
Ovarian:
IP cisplatin
Adjuvant IV admin of conventional agents for mets
Bladder:
intravesicular instillations of mitocycin C (alkylating agent) and Bacillus Calmette-Guerin (BCG)
Chemo-radiation or systemic chemo for mets
Thiotepa (alkylator) may be used.
Discuss principal adverse effects when drugs are used either locally or systemically in the management of ovarian and bladder cancer.
Carboplatin/Cisplatin- allergy, myelo supp.
Carboplatin- less peripheral neuropathy than Cisplatin. More myelosupp.
Cisplatin- Ototoxicity, severe nephrotox, peripheral neuropathy
Cyclophosphamide- Hemorrhagic cystitis, anemia, infxn, pulm. fibrosis.
Doxorubicin- CHF, myelosuppression, extravasational necrosis
Mitomycin C- Cystitis, contact dermatitis, pancytopenia (IV admin), pulm. infiltrates
Pacilitaxel- hypersensitivity, myelosuppression, myalgia, arthralgia
Thiotepa- dysuria, urinary retention, hemorrhagic cystitis, renal dysfunction, pancytopenia (IV admin) Very low MW, so traverses bladder wall w/ great ease.
How do we tx triple neg. BrCa
ER-, PR-, HER-2/neu-
conventional chemo
Chemo MOA reminder: Carboplatin Cisplatin Cyclophosphamide Doxorubicin Mitomycin C Pacilitaxel Thiotepa
Carboplatin- DNA intrastrand crosslinks/adducts
Cisplatin- DNA intrastrand crosslinks/adducts
Cyclophosphamide- alkylating agent
Doxorubicin- Intercallator, free radical generator, Topo II inh.
Mitomycin C- alkylating agent
Pacilitaxel- microtubule stabilizer, inhibits depolymerization
Thiotepa- alkylator
Recall the route of delivery, mechanism of action and adverse effects of SERDs.
SERD (fulvestrant)-
ROD: IM, monthly
MOA: pure Estrogen antagonist, no estrogen effects. Impaired dimerization of ER, incr. turnover of ER, disfupted nuclear localization, degradation —> v ER levels
AE: PMS sx due to lack of estrogen responsiveness
Recall the route of delivery, mechanism of action and adverse effects of SERMs.
SERMs (Tamoxifen, raloxifene, toremifine)
ROD: Tam- daily PO, Ral- monthly IM
MOA: tissue specific estrogenic and anti-estrogenic effects. Good for bone growth, inhibitory for BrCa. CYP2D6 metab. for maximum effectiveness
AE: Teratogens
BBW: endometrial hypertrophy, vag. bleeding, endometrial cancer (tam)
Thromboembolic dz, stroke (both)
Toremifine- derivative of tam. estrogen ant. BBW: QT prolongation
Recall the route of delivery, mechanism of action and adverse effects of the Aromatase inhibitors.
Aromatase inhibitors: (anastrozole, letrozole, exemestane- steroid)
ROD: QD, orally
MOA: block CYP19A1 mediated production of estrone/estradiol, starving tumor of proliferative signaling.
AE: VMS, nausea, hair thinning, teratogens
Recall the route of delivery, mechanism of action and adverse effects of the mAbs.
mAbs: extracellular binders
trastuzumab- inhibits microtubules when internalized via HER2. BBW: multisystem organ failure. Diminished LVEF
pertuzumab- blocks HER2 dimerization. BBW: teratogen
ROD: IV q21 days
AE: GI upset, blood dyscrasias, asthenia, fatigue, alopecia, loss of appetite, peripheral edema, rash, weight gain, URTIs, pharyngitis, fatigue. infusion reactions
Rare: multiorgan system failure
Recall the route of delivery, mechanism of action and adverse effects of the RTK inhibitor.
nib: (lapatinib)- RTK inhibitor against HER1/2. binds intracellularly and competes with ATP.
ROD: IV
AE: GI tox, anemia, thrombocytopenia, hand-foot synd., rash pain, HA, back ache. QT prolongation
BBW: don’t use in pts w/ compromized liver. Lack of metabolism will lead to drug accumulation and probs.
Recall the route of delivery, mechanism of action and adverse effects of the mTOR inhibitor.
mTOR inhibitor: (Everolimus)
Used in conjunction with AI- exemestane.
MOA: complex w/ mTOR —I cell proliferation
BBW: opportunistic infections, neoplasia; lymphoma, SCC
AE: n/v/d/constipation. bld dyscrasias, hyperglycemia, hyperlipidemia, hypertriglyceridemia, elevated Cr and liver enzymes.
Recall the route of delivery, mechanism of action and adverse effects of the GnRH agonist
GnRH agonist: (Goserelin)
ROD: SQ inj. q28 days
MOA: inhibits estrogen release due to neg. feedback on hypothalamus.
AE: just like menopause. temporary incr. bone pain from mets during early use
Recall the route of delivery, mechanism of action and adverse effects of Progestins for endometrial cancer.
Progestins for endometrial cancer:
Medroxyprogesterone
MOA: binds to progestin receptors and blocks GnRH release
AE: menopause-like
Megestrol
MOA: Suppress Pit. LH release and enhances estrogen degradation.
AE: menopause-like. Weight-gain (appetite stimulant)
