hormones and hormonal antagonists

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

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

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

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.

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

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.

. 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.

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)

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

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

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

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.

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

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

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.

4- Aromatase Inhibitors Aminoglutethimide Anastrozole Letrozole

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

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

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

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