Anticancer drugs: chemotherapy

Hormonal treatment  Hormone-receptor positive (hormone dependent) forms of breast, prostate and ovarian cancer are subject to hormonal treatments.  The hormonal treatments often follow surgery and/or radiation and/or chemotherapy as an adjuvant treatment.

Hormonal treatment strategies  The idea behind the majority of hormone-based cancer treatments is to starve the cancer cells of the hormonal signals that would otherwise stimulate them to divide by: blocking the activity of the hormone in the target cell (steroid hormone receptor blockers) or by preventing the production of the hormone.

Hormonal treatment strategies: GnRH superactive agonists and antagonists  The most efficient strategy is supression of hormone synthesis by the analogs of gonadotropin-releasing hormone (GnRH = gonadoliberin, a hypothalamic neurohormone)  also named luteinizing hormone-releasing hormone (LH-RH) superactive agonists and antagonists  At the pituitary, GnRH interacts with its receptors and stimulates the synthesis and secretion of the gonadotropins, folicle-stimulating hormone (FSH), and luteinizing hormone (LH). These processes are controlled by the size and frequency of GnRH pulses, as well as by feedback from androgens and estrogens.

Hormonal treatment strategies: GnRH superactive agonists and antagonists  LH stimulates the testes to produce testosterone, which is metabolized to 5α-dihydroxytestosterone (DHT) by the enzyme 5α-reductase. In the adult, DHT acts as the primary androgen.  In women, LH stimulates the release of estrogens from the ovaries.

Hormonal treatment strategies: GnRH superactive agonists  GnRH superactive agonists overstimulate the receptors  Negative feedback principle: the GnRH receptors are down-regulated. Subsequently, the gonadal receptors for LH and FSH are reduced.  In men, the reduction in LH leads to rapid suppression of testosterone release from the testes.  In women it leads to suppression of estrogen release from the ovaries.  The concentrations of estrogen and androgens decrease to castrate levels = pharmacological castration GnRH agonists GnRH

Hormonal treatment strategies: GnRH superactive agonists  The pituitary cells, will initially respond to the stimulation of hypothalamic hormone analogues by increased GnRH secretion = the flush effect  Treatment should therefore not be initiated without previous therapy with receptor blockers (antiandrogen treatment or antiestrogen for breast cancer) over a few days.

Hormonal treatment strategies: GnRH superactive agonists  Goserelin is an GnRH agonist available as a 1-month depot and a long-acting 3-month depot.  Goserelin is used to treat hormone-sensitive cancers of the prostate and breast (in pre-/perimenopausal women) and some benign gynaecological disorders (endometriosis, uterine fibroids and endometrial thinning). In addition, goserelin is used in assisted reproduction.  Other GnRH: leuprolide, buserelin, nafarelin …

Hormonal treatment strategies: GnRH antagonists Bind to receptors for gonadoliberins and block sex hormone release after 6-12 h without the flush effect Degarelix, cetrorelix,….

Hormonal treatment strategies: GnRH superactive agonists and antagonists Indications: advanced prostate cancer used to relieve pain caused by metastatic prostate cancer  In prostate cancer, up to 70% of remissions are obtained using this treatment and their mean duration is around one to three years (and much longer among certain patients). estrogen-receptor positive advanced or metastatic breast cancer  in breast cancer, this treatment is often instituted in order to obtain non-definitive castration for young patients in the hope of a return of normal menstruation

Hormonal treatment strategies: GnRH superactive agonists and antagonists  Adverse efects: hot flushes impotence (in almost all patients), loss of libido major hypogonadism mood disturbances osteoporosis obesity  If the treatment is stopped, the castration effect will slowly regress (in particular when treatment duration is short).

Hormonal treatment: Anti-hormones  Partial agonists or full antagonists of sex hormones at the particular intracelular receptors in cancer cells and many healthy organs/tissues. Selective Androgen Receptor Modulators (SARMs) are antagonists, work by interfering with the function of the androgen receptor.  used to treat prostate cancer Selective Estrogen Receptor Modulators (SERMs) are partial agonists, work by interfering with the function of the estrogen receptor.  used to treat breast cancer Antagonist of the estrogen receptors – fulvestrant  used to treat breast cancer

Selective Androgen Receptor Modulators (Anti-androgens)  Hormonal (steroidal) antiandrogen cyproterone acetate acts  on the hypothalamus as a progestin - down-regulates the secretion of LH and androgens by the testes and decreases circulating testosterone  blocks the androgen receptor of the prostate tumour cells and deprove cells from growth-promoting signals  besides hormonal AE, the most serious potential side effect is liver toxicity, and patients should be monitored for changes in liver enzymes

Selective Androgen Receptor Modulators (Anti-androgens)  Nonsteroidal antiandrogenes  via the preferential binding to the androgen receptors, SARM prevent the androgens from binding and therefore reduce their pro-growth activities  there is no marked decrease in the plasma testosterone concentration after nonsteroidal antiandrogens

Prostate Cancer - Selective Androgen Receptor Modulators (SARM's)  Flutamide has been largely replaced by newer members of this class, nilutamide and bicalutamide, due to a better side-effect profile. Other more agressive/effective therapies which lower testosterone levels, such as orchiectomy or GnRH-analogue administration, have more significant side effects. Compared to these therapies, treatment with SARMs exhibits fewer hot flashes, less effect on libido, less muscle wasting, fewer personality changes, and less bone loss. The most unplesant side effect is gynaecomastia (which may be painful) in approximately 60% of patients, diarrhoea, vomiting, modification of liver enzymes and visual disorders for one drug (nilutamide). Given the advanced age of many patients with prostate cancer, as well as other features, many men may choose SARM therapy alone for a better quality of life.

Anti-estrogens: Selective Estrogen Receptor Modulators (SERMs)  In ER+ breast cancer patients estrogens contribute to the growth and divison of the cancer cells.  The SERMs are non-hormonal drugs that bind to and block ER, preventing the action of estrogens. The blockage of estrogen in the target cells causes changes in gene expression, preventing cell division.  However, the SERMs are partial agonists and exert pro-estrogenic effects in certain tissues, particularly in the uterus.  Individual SERMs differ in their affinities to different forms of estrogen receptor (  and  ) and, therefore, their effects differ in various organs and tissues (have somewhat different side-effect profiles).

Breast Cancer - Selective Estrogen Receptor Modulators (SERMs)  Tamoxifen is currently used for the treatment of both early and advanced ER+ (estrogen receptor positive) breast cancer in pre- and post-menopausal women. Additionally, it is the most common hormone treatment for male breast cancer. It is also approved for the prevention of breast cancer in women at high risk of developing the disease. It has been further approved for the reduction of contralateral (in the opposite breast) cancer.

Breast Cancer - Selective Estrogen Receptor Modulators (SERMs)  Other SERMs: raloxifen, toremifen  While tamoxifen does decrease effects of estrogens in the breast, it unfortunately has a pro-estrogenic activity in the uterus, causing a rise in uterine cancer for tamoxifen-treated breast cancer patients that have not undergone a hysterectomy (but the benefit exceeds the risk).  Raloxifene appears to have less estrogenic efect in uterine tissues. Raloxifene has not been shown to increase less the risk of endometrial cancer or vaginal bleeding.  Patients being treated with SERM are also at increased risk for deep venous thrombosis and pulmonary embolism, and also for strokes. These events are serious but rare.  Hot flashes are increased by all SERMs.

Breast Cancer - Selective Estrogen Receptor Modulators (SERMs)  One known benefit of SERM treatment is that it exerts pro- estrogen effects in the bone  Bone turnover and postmenopausal osteoporosis respond favorably to all SERMs.

Estrogen receptor antagonist  Fulvestrant is a full antagonist at estrogen receptors with a stronger effect than that of SERMs.  It is an estrogen receptor antagonist with no agonist effects, which works both by down-regulating and by degrading the estrogen receptor.  It is administered as a once-monthly injection.  Free of adverse effects of SERMs.

Hormonal treatment: hormone synthesis inhibitors (enzyme inhibitors)  Inhibitors of enzymes involved in sex hormone synthesis/activation: 5 alfa-steroid reductase inhibitors: inhibit conversion of testosterone to more active androgen 5-dihydrotestosterone inhibitor of the cytochrom P17A1 (17-alfa-hydroxylase) abirateron  Used in prostate cancer Aromatase inhibitors: work by blocking the production of estrogen by the enzyme aromatase  Used in breast cancer

Hormonal treatment: 5 alfa-steroid reductase inhibitors 5 alfa-steroid reductase inhibitors: inhibit conversion of testosterone to more active androgen 5-dihydrotestosterone in the prostate cancer cell weak hormonal treatment well tolerated, frequently combined with nonsteroidal antiandrogen (bicalutamide)

Aromatase inhibitors  After menopause, women produce a consistent low level of estrogen (that is derived from andostenedione and testosterone produced in adrenal gland) via the enzyme aromatase which is a member of the cytochrome P450 superfamily of enzymes.  The enzyme transforms androstenedione to estrone and testosterone to estradiol.  The aromatase enzyme can be found in many tissues including gonads, brain, adipose tissue, placenta, blood vessels, skin, bone, endometrium as well as in tissue of endometriosis, uterine fibroids, breast cancer, and endometrial cancer.

Aromatase inhibitors  By blocking the action of this enzyme, aromatase inhibitors prevent the formation of estrogen.  There are two types of aromatase inhibitors that have been approved as treatment for postmenopausal women with estrogen-receptor positive metastatic breast cancer: Irreversible steroidal inhibitors such as exemestane Competitive non-steriodal inhibitors like anastrozole and letrozole

Hormonal treatment of prostate cancer: summary  The three main mechanisms of hormonal treatment for prostate cancer: Testosterone suppression physical or pharmacological (GnRH analogs) castration inhibition of androgen synthesis in castrate-resistant prostate cancer by 17-alfa-hydroxylase inhibitor abirateron Action of antiandrogens (SARMs) on the receptor for androgens. Inhibition of the synthesis of 5  -dihydrotestosterone by 5-  reductase inhibitors

Hormonal treatments: additive hormonal treatments  Additive therapy with high doses of synthetic estrogens (diethylstilbestrol, ethinylestradiol) supresses LH and sex hormones  It is no longer used in prostate and breast cancer due to AE (most important was an increased cardiovascular mortality)  High doses of gestagens (progestins) – derivatives of progesterone and 19-nortestosterone megestrol, medroxyprogesterone  Negative-feedback supression of sex hormone synthesis  uterine cancer  3-rd option in breast cancer in postmenopausal woman

Glucocorticoids  Glucocorticoids (prednisone, prednisolone, methylprednisolone, dexamethasone) G. induce apoptosis of lymphocytes G. reduce the activity of RNA polymerase  Use: acute leukemias, lymphoma and other hematological cancers