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46 Cards in this Set
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The main objectives of this lecture include knowing the rationale for use of hormonal and anti-hormonal therapy, the mechanism's of action and uses of these drugs in breast and prostate cancer, the pharmacodynamics and pharmacokinetics of the commonly used drugs, the metabolic pathways of anti-hormonal drugs and the side effects of the hormonal/anti-hormonal drugs.
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There are hormonal agents and anti-hormonal agents. The anti-hormonal agents are divided into drugs that target receptors and drugs that target hormone biosynthesis.
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Anti-cancer therapies include surgery, irradiation and chemotherapy
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Anti-cancer agents are split into those that affect DNA, Microtubules and Hormones. This lecture discusses hormones.
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How is hormone therapy used?
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Rarely to effect a cure.
More to mitigate symptoms. Commonly used after surgery, radiation therapy and/or chemotherapy. |
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Prednisolone and Dexamethasone are two glucocorticoids used in cancer therapy. Why are they used and how are they used?
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1) They are used in combination therapy for leukemia's and lymphoma's
2) They suppress lymphocytic proliferation and activity and cause lysis of lymphoid tissue with high levels of GC receptors 3) They can mitigate the side effects of other anti-cancer drugs |
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Describe the Pharmacokinetics of Prednisolone.
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Highly bioavailable orally
Highly Protein bound Short Half Life Taken with food or after meals Excreted in the urine |
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What are the major side effects of Prednisolone? (8)
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Increased Appetite
Irritability Insomnia Fluid Retention Heart Burn Muscle Weakness Impaired Wound Healing Increased Blood Sugar |
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Surgical Discoveries --> Removal of ovaries/testes produced clinical benefit in breast/prostate cancer patients --> Anti-hormonal therapy
However, once the testes were removed, men would still develop prostate cancer. Why? |
Androgen's are also synthesized by the adrenal route.
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How do GnRH agonists work?
Aromatase (CYP 19) Inhibitors? CYP 17 Inhibitors? Hormone Receptor Antagonists? |
GnRH agonists continually hit the pituitary (instead of in pulses), which suppresses the release of LH/FSH
Aromatase Inhibitors inhibit the conversion of androgen to estrogen CYP 17 Inhibitors inhibit androgen production from pregnanes HRA's inhibit hormone receptor binding |
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Name the 2 GnRH agonists
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Leuprolide
Gosereline |
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What are they used for?
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To treat Advanced metastatic breast and prostate cancers
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How is Luprolide adminsitered?
How is Goserelin administered? Describe the PK's of these agents. |
Luprolide is administered as daily or depot injections (every few months)
Goserelin is administered SC High biolavailability Low Protein Binding Short Half life |
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What are the side effects of these agents?
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DVT
Hot Flashes Gynecomastia Osteoporosis Transient Pain Sexual Dysfunction |
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What are the major drugs in anti-hormonal breast cancer therapy?
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SERM's - Raloxifene, Tamoxifen
Pure Anti-estrogen - Fulvestrant Pure anti-estrogen's are antagonistic regardless of tissue |
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What tissue is Tamoxifen selective for?
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Inhibits estrogenic effects in breast
Promotes estrogen effects in the endometrium and bone Only works in tumors that present with the Estrogen Receptor No benefit shown beyond 5 years |
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What is used for?
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Estrogen dependent breast cancer (competitively binds to ER) and now breast cancer prevention.
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Describe the PK's of Tamoxifen.
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High Biolavailability
Highly protein bound (SHBG) Long Half-life (5-7 days) Active Metabolite has 10 times the binding affinity for ER |
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What would be the difference in patients with normal and dysfunctional CYP2D6 regarding Tamoxifen?
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You need a functional CYP 2D6 to convert Tamoxifen to its active and 10 times more potent metabolite via Hydroxylation.
Those with a dysfunctional enzyme will not get the same effect. |
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What are the major adverse effects of Tamoxifen?
Minor? |
Risk of endometrial cancer
Cataracts Pulmonary Embolism Hot Flashes Abnormal Menstruation Vaginal Discharge |
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Where is Raloxifene selective?
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Anti-estrogenic in breast and uterus
Estrogenic in the bone |
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What is it used for?
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Post-menopausal women at high risk of breast cancer
Post-menopausal women for osteoporosis prevention |
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Describe the PK's of Raloxifene
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It is rapidly absorbed by the GI, but its oral bioavailability is only 2%.
It is highly protein bound Has a half life of ~27 hours Rapidly metabolized via Glucuronidation |
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What are the side effects of Raloxifene?
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Major = Retinal Vascular Occlusion, VTE
Minor = Hot Flashes, Leg Cramps |
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What is MOA of Fulvestrant?
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It is a pure anti-estrogenic agent. It works by binding and preventing dimerization of the ER thereby causing downregulation and degredation.
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What is Fulvestrant use for?
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Tamoxifen resistant breast cancer
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Describe Fulvestrant's bioavailability.
How is it administered? |
Very poor bioavailability - very insoluble
It is administered IM once per month and cannot be given orally. |
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What is the side effect profile of Fulvestrant?
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Minimal - GI, HA, Hot Flashes
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Name the 4 Aromatase (CYP19) Inhibitors.
What are they used for? |
Anastrozole
Letrozole Exemestane Formestane Block the synthesis of estrogen Post-menopausal breast cancer |
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What is needed for the conversion of Androstenedione to Estrone?
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3 moles of molecular O2
3 moles of NADPH This reaction is unique to any other by its conversion from a non-aromatic ring to an aromatic ring |
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What is Anastrazole used for?
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1st line for Advanced Breast Cancer
Breast cancer metastasis in postmenopausal women with disease progress following anti-estrogen therapy. |
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Describe Anastrazole's PK profile.
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High bioavailability
Low protein binding Half life 45 hours |
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What are the major side effects of Anastrazole?
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Osteoporotic Fractures
Thrombophlebitis Hypercholesterolemia Profuse Vaginal Bleeding |
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What is Letrazole used for?
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Breast Cancer after surgery
Breast Cancer metastasis in postmenopausal women |
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Describe Letrazole's PK profile.
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High bioavailability
Low protein binding Half life 48 hours |
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What are the major side effects of Letrazole?
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Similar to that of Anastrazole.
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What is a key difference between Anastrazole/Letrazole and Exemestane?
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Anastrazole/Letrazole are non-steroidal and reversible
Exemestane is steroidal and irreversible |
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What are the indications for Exemestane?
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Same as Letrazole
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What are the side effects?
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Similar to that of Anastrazole/Letrazole
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Describe Exemestane's PK profile.
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Lower bioavailability - ~60%
Highly Protein Bound Half life 27 hours Bioavailability increases with fatty meals |
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90% of prostate cancers are androgen dependent.
What is the current gold standard therapy for prostate cancer? |
Surgical Castration and GnRH agonist therapy
Combination therapy of a GnRH agonist + antiandrogen therapy is more effective However, does not eliminate androgens from the adrenal glands. |
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Name the 3 most common anti-androgen agents used in prostate cancer.
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Flutamide
Nilutamide Bicalutamide Block Testosterone/DHT from binding Androgen Receptor. |
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What is Bicalutamide indicated for?
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Early non-metastatic prostate cancer
In combination with Surgical Castration or GnRH agonists in the treatment of advanced prostate cancer |
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Describe the PK profile of Bicalutamide.
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High Bioavailability
Highly Protein Bound Half life ~6 days |
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What are the side effects of Bicalutamide?
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Nausea
GI Disorders Hot Flashes Reproductive System Disorders |
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Prostate cancer cells develop resistance by increasing gene expression of androgens. This is why CYP 17 androgen biosynthesis inhibitors are important. What reactions are inhibited by CYP 17 enzymes?
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Progesterones to Androstenedione and DHEA which are converted to Testosterone and DHT.
In addition, Prostate cancer cells have the enzymes required to synthesize androgens from cholesterol de novo. |
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What is the use of Ketoconazole in PC therapy?
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It has non-selective CYP inhibitory actions. It is weak, but high doses can cause PC regression.
It's usefulness is limited by GI side effects and is second line therapy for PC. |
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Name the two other CYP 17 Inhibitors that are currently being developed.
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Abiraterone
Legaterone |
