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Flashcards in Pharm of Chemo agents: Sweatman Deck (15)
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1

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.

2

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

3

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)

4

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.

5

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.

6

How do we tx triple neg. BrCa
ER-, PR-, HER-2/neu-

conventional chemo

7

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

8

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

9

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

10

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

11

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

12

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.

13

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.

14

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*

15

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)