1. hormones and hormonal antagonists

2. hormones
1- Prednisone:
Cushing syndrome (hypersecretion of cortisol) show lymphocytopenia & decreased lymphoid mass
Since they have inhibitory effects on lymphocytes proliferation, they are used in leukemia and lymphomas
Prednisone is a potent synthetic anti-inflammatory corticosteroid with less mineralocorticoid activity than cortisol
The hormone-dependency of tumors treated with steroids is, in general, related to the presence of steroid receptors in the malignant cells
The number of receptors can be estimated in biopsy specimens and this provides a guide to the potential efficacy of hormone therapy

3. Prednisone Mechanism of action: Mechanism of resistance:
Prednisone is a prodrug, should be metabolized by 11-β-hydroxysteroid dehydrogenase giving prednisolone
Prednisolone binds to a receptor that triggers a specific proteins
Mechanism of resistance:
Absence of receptor protein
Mutation that lowers receptor affinity for the hormone
Defect in the stage of gene expression

4. Prednisone Side effects: Infection due to immunosuppressant effects
Ulcers
Hyperglycemia
Osteoporosis
Change in mood (euphoria or psychosis)

5. Hormones 2- Oestrogens: Two important uses:
Fosfestrol (a prodrug activated by acid phosphatase in prostatic tissue to yield stilboesterol).
block the production of LH; thereby decreasing the synthesis of androgenic hormones and so the effect of androgens in androgen-dependent prostatic tumors.
They produce serious side effects: thromboemboli, myocardial infarction, strokes, hypercalcemia, gynecomastia & impotence
Used in postmenopausal woman with breast cancer: why?: to recruit resting mammary cancer cells into the proliferating pool of cells, thus allowing a greater killing efficacy of the cytotoxic drugs which are then given.

6. Hormones 3- Progestogens:
They are useful in treating hormone-responsive breast and endometrial neoplasms
The main agents used are megestrol and medroxyprogesterone

7. hormones 4- Somatostatin analogues
Analogues of somatostatin such as octreotide and lanreotide
are used to relieve the symptoms of neuroendocrine tumours, including hormone- secreting tumours of the gastrointestinal tract such as, glucagonomas, carcinoid syndrome and gastrinomas.
These tumours express somatostatin receptors, activation of which inhibits cell proliferation as well as hormone secretion.

8. . Hormonal Antagonists 1- Antiestrogens
Tamoxifen
It is an estrogen antagonist, structurally related to diethylstilbestrol.
It has weak estrogenic effect and is classified as Selective Estrogen Receptor Modulator (SERM).
The ability to produce both estrogenic and antiestrogenic affects is most likely due to the interaction with other coactivators or corepressors in the tissue and the binding with different estrogen receptors, ER and ER
Subsequent to tamoxifen ER binding, the expression of estrogen dependent genes is blocked or altered resulting in decreased estrogen response.

9. Tamoxifen selectively inhibits the effects of estrogen on breast tissue, while selectively mimicking the effects of estrogen on bone (by increasing bone mineral density) and uterine tissues.
These qualities make tamoxifen an excellent therapeutic agent against breast cancer.
It is known to compete with estrogen by binding to estrogen receptors on the membrane of target cells, thus limiting the effects of estrogen on breast tissue.
Tamoxifen may also has other anti−tumor activities :affecting oncogene expression & promotion of apoptosis (cancer cell death)

11. Hormone Antagonists
Estrogen competes with tamoxifen. Therefore, in premenopausal women, the drug is used with gonadotropin- releasing analog such as leuprolide, which lowers estrogen level
The action is not related to any specific phase of the cell cycle
Metabolized into some estrogenic and antiestrogenic metabolites

12. Hormone Antagonists Tamoxifen
When used prophylatically, tamoxifen has been shown to decrease the incidence of breast cancer in women who are at high risk for developing the disease

13. Hormone Antagonists Mechanism of resistance
Decreased affinity to the receptor
Decreased number of receptors
The presence of dysfunctional receptors

14. Adverse Effects
CNS: Depression, light headedness, dizziness, headache, decreased visual acuity &retinopathy.
GI: Nausea, vomiting
Hematological: Hypercalcemia
GU: Vaginal bleeding, vaginal discharge & menstrual irregularities
Dermatologic: Hot flashes, skin rash
Potentially more serious are hyperplastic events in the endometrium, which may progress to malignant changes, and the risk of thromboembolism.

15. fulvestrant (Faslodex®), binds to the ER and promotes its destruction, thereby reducing ER levels inside cells

16. Hormonal Antagonists 2- Anti-Androgen
Flutamide & cyproterone
Antagonizes androgenic effects
approved for the treatment of prostate cancer

17. 3-Gonadotrophin-releasing hormone analogues
Goserelin, buserelin, leuprorelin and triptorelin, can, under certain circumstances, inhibit gonadotrophin release used to treat advanced breast cancer in premenopausal women and prostate cancer.

18. 4- Aromatase Inhibitors
Aminoglutethimide
Anastrozole
Letrozole

19. Aminoglutethimide Mechanism of Action
It inhibits synthesis of pregnenolone (a precursor of estrogen) from cholesterol
Inhibits the synthesis of estrone and estradiol by inhibiting aromatase enzyme that converts androstenedione to estrone
It takes place in liver, fat, muscle, skin and breast tissue, including breast malignancies
Because the drug also inhibits hydrocortisone synthesis, which evokes a compensatory rise in adrenocorticotropic (ACTH) secretion to overwhelm the blockade of the adrenal, the drug is usually taken with hydrocortisone

21. Aminoglutethimide Toxicity
Dizziness
Lethargy
Visual blurring
Rash
Therapeutic Uses
ER- positive metastatic breast cancer

22. Anastrozole & Letrozole
A new selective nonsteroidal inhibitor of aromatase.
Treats advanced estrogen positive breast cancer that is no longer responsive to tamoxifen.

23. Anastrozole & Letrozole
Advantage:
They are more selective on aromatase enzyme
They are more potent greater than 96% aromatase inhibition, compared to less than 90% with aminoglutethimide
They do not need to be supplemented with hydrocortisone