Pharm of Prostate Cancer and Testicular Cancer: Sweatman Flashcards
Describe the source and importance of androgens and estrogens in hormonally-responsive prostatic tumors.
Testicular testosterone and locally produced DHT derived from DHEA from the adrenal cortex. These androgens stimulate the prostate tumor’s growth. Prostate cancer is the most hormone sensitive cancer.
Explain the available treatment options for prostate cancer.
::GnRH agonists/antagonists inhibit the production of androgens at the ant. pit.
::CYP17A1 inhibitors inhibit androgen production at the level of the testes and adrenal cortex by inhibiting 17a-reductase (17B-hydroxysteroid dehydrogenase).
::Androgen receptor antagonists will directly block the actions of androgens on the prostate cancer by competing for the receptors.
Recall the route of delivery, mechanism of action and adverse effects of:
AnRH agonists
Goserelin
Histrelin
Triptorelin
Leuprolide
ROD: Injection. Acts in 2-4 weeks. Will see initial flare of dz due to initial agonism (before negative feedback kicks in). To prevent, give concurrent androgen receptor blocking drugs.
MOA: Overstimulate GnRH receptors in ant. pit. —> negative feedback that inhibits FSH/LH/ACTH release
AEs: Decr bone mineral density, elevated serum lipids, weight gain, DM.
CNS: headache, fatigue, depression, [seizures and suicidal ideation (histerelin)]
Symptoms due do androgen insufficiency: reduced libido, sexual dfxn, gynecomastia.
Rarely, hepatotoxicity.
Explain treatment options for organ-confined and metastatic disease of testicular cancer.
Cisplatin used in ALL regimens.
Organ-confined:
Etoposide/cisplatin
Bleo/etopo/cisplatin
Bleo/mesna/ifosfamide/cisplatin
Mets:
Vinblastine/mesna/ifosphamide/cisplatin
Pacilitaxel/mesna/ifosfamide/cisplatin
Describe the mechanism of action and principal dose-limiting toxicities of the cytotoxic agents used commonly in the treatment of testicular cancer.
Bleomycin: double strand breakage. Pulm. fibrosis and derm tox.
Cisplatin- Nuclear and mitoch. DNA damage + O2 stress. Also, proapoptotic and pro p53. Renal tox. and ototox (in high doses)
Carboplatin- slower rxn w/ nuclear DNA. Less potent that cisp. *Thrombocytopenia. *
Etoposide- Stabilizes DNA + topo II —> Strand breakage leukopenia
Ifosfamide- metabolically activated alkylating agent (cross-linking) myelosuppression
Pacilitaxel- microtubule stabilizer myelosuppression
Vinblastine- microtubule DEstabilizer. neuropathy
Mesna- prevents hemorrhagic cystitis of ifosfamide’s breakdown product, acrolein. Bad taste in mouth, soft stools, h/a
Discuss the role of reactive oxygen species, ER stress and active cellular accumulation in the unusual organ toxicities produced by bleomycin and cisplatin, as it relates to testicular cancer.
Cisplatin produces ROS that kill cells needed for hearing (outer hair cells, etc)
Bleomycin stimulates production of ROS, chemokines/cytokines that recruit proinflammatory mediators and profibrotic mediators that result in pulm. fibrosis associated with bleo use.
Co-administration of anti-oxidants can help prevent negative ADEs.
Recall the route of delivery, mechanism of action and adverse effects of:
GnRH receptor antagonists
Degarelix
ROD: SC injection. Quick acting (3 days). Castration.
MOA: Blocks GnRH binding to GnRHr in ant. pit. —I LH/FSH secretion
AEs: Hot sweats, weight gain, inj site rxn, HTN, arthralgia, chills, fatigue, and impotence.
Elevated liver enzymes, QT prolongation
Recall the route of delivery, mechanism of action and adverse effects of:
Estramustine
Estramustine (alkylator bound to estradiol)
ROD: oral
MOA: targets Estramustine Binding Receptor on prostate cancer cells. Alkylating agent that blocks microtubule action. Testosterone levels depressed to to neg. feedback on HP axis.
AEs: gynecomastia, mastalgia, and CV risks due to increased levels of circulating estradiol.
Elevated hepatic enzymes and hyperbilirubinemia.
Recall the route of delivery, mechanism of action and adverse effects of:
Androgen receptor blockers
Bicalutamide
Enzalutamide
Flutamide
Nilutamide
MOA: blocks androgen receptor on cancer cells.
AEs: hypoandrogenic symptoms
HF/HTN, Resp. insufficiency (BBW), interstitial pneumonitis, incr. time to accomodate transition from light to dark: nilutamide
Blood dyscrasia: Flutamide/nilutamide
CNS: dizziness, insomnia, seizures (enzalutamide)
GI tox, aches, pains
All teratogens* except nilutamide
Male mediated teratogen, URTI: enzalutamide
Recall the route of delivery, mechanism of action and adverse effects of:
Sipuleucel-T
Sipuleucel-T
MOA: Stimulates T-cell mediated immunity against prostatic acid phosphatase (PAP)
AEs: Mild infusion rxns, fever/chills/dyspnea, n/v, paresthesias, citrate tox, fatigue.
Recall the route of delivery, mechanism of action and adverse effects of:
Abiraterone
Abiraterone
MOA: inhibits 17a-hydroxylase (CYP17)
AEs: produces increased mineralcorticoid state due to shunting of pregnenolone to mineralcorticoid production.
HTN, hypokalemia, fluid retention. Elevated liver enzymes.
Teratogen (Cat X).
Recall the route of delivery, mechanism of action and adverse effects of:
Docetaxel and Cabazitaxel
Mitoxantrone
Both Docetaxel and Cabazitaxel are taxanes (microtubule stabilizers)
Cabazitaxel penetrates BBB.
Need LFTs, KFTs.
Mitoxantrone + prednisone used for palliation of severe pain from advanced, hormone-refractory prostate cancer.
