chem of anti canncer agents 5

Sex Hormones

• Types of Hormones:

  • Androgens: Male sex hormones

  • Progestins: Hormones that regulate the menstrual cycle and maintain pregnancy

  • Oestrogens: Female sex hormones, primarily estradiol

Androgen Receptor (AR)

• Activation:

  • The AR is activated by binding any androgenic hormone.

  • Dihydrotestosterone (DHT) is a significantly more potent agonist of AR than testosterone.

• DHT Levels:

  • DHT levels are especially high in the prostate gland where there is an increased expression of the enzyme 5α-reductase.

  • Circulating DHT levels are relatively low, approximately 5-10% of testosterone levels.

• Relation to Progestin:

  • The AR is closely related to the progesterone receptor.

  • High doses of progestins can block AR activity.

• Synthesis of Androgens:

  • Androgens are produced in the testes, ovaries, and adrenal glands.

Estradiol

• Major Female Sex Hormone:

  • Estradiol is synthesized in ovarian follicles, testicles, adrenal glands, and liver.

Prostate Cancer: Hormone Therapy

• Dependency on Androgens:

  • Prostate cancer requires androgens for growth.

• Prostate Specific Antigen (PSA):

  • As the prostate enlarges, PSA levels increase.

• Selective Antagonists for AR:

  • These agents stop the growth of prostate cancer cells and include:

  • Flutamide

  • Cyproterone Acetate

  • Bicalutamide

• Androgen Deprivation Therapy (ADT):

  • ADT aims to reduce androgen formation and can help shrink tumors, serving as an alternative to surgery.

Androgen Deprivation Therapy

• Non-Steroidal Antiandrogens:

  • R-isomer is the active form.

  • Used for treating androgen-dependent conditions, feminization, and transgender treatments.

  • Typically administered multiple times per day due to a relatively short duration of action.

• Side Effects:

  • Common side effects for men undergoing hormone therapy for prostate cancer include:

  • Hot flushes

  • Loss of sexual ability

  • Weakened bones

  • Nausea

  • Enlarged and tender breasts

  • Fatigue

Prostate Cancer: Steroidal Therapy

• Steroidal Treatments:

  • Estradiol: A female hormone, used in palliative treatments for metastatic or progressive prostate cancer.

  • Estrone: The final metabolite product of estradiol metabolism.

  • Estramustine Phosphate:

  • A weak DNA alkylating agent similar to chlorambucil.

  • Strongly suppresses androgen production.

  • Cyproterone Acetate (Androcur):

  • A progestin-related antiandrogen.

• Treatment Efficacy:

  • None of these treatments are cures for prostate cancer but can significantly extend life expectancy.

• Related Side Effects:

  • Similar side effects to non-steroidal therapies, with the addition of carbamate as an electron-withdrawing group (EWG).

Breast Cancer: Hormone Therapy Using Tamoxifen

• ER+ Breast Cancer:

  • Estrogen promotes the growth of some breast cancer cells (ER+), as established through biopsy testing.

• Tamoxifen:

  • Functions as an antagonist but is classified as a Selective Estrogen-Receptor Modulator (SERM).

  • Acts as a partial agonist in the endometrium, which can be linked to the risk of endometrial carcinoma (carcinogenic potential).

  • Approved by the FDA for both prevention and treatment of breast cancer in both women and men.

  • Tamoxifen is a prodrug with minimal affinity for the estrogen receptor, metabolized in the liver to active metabolites.

  • Tamogel:

  • An active metabolite of Tamoxifen, with potential application as a topical treatment for breast cancer.

Breast Cancer in Post-Menopausal Women

• Estrogen Production:

  • Post-menopause, women do not produce estrogen from ovaries; however, small amounts are synthesized using aromatase enzymes.

• Aromatase Activity:

  • Aromatase is responsible for converting androgens to estrogens in fatty tissue, muscle, and skin.

• Aromatase Inhibitors:

  • Reversible Competitive Inhibitors:

  • Binding occurs at a CYP450 subunit of the enzyme, inhibiting estrone formation.

  • Examples:

  • Anastrozole

  • Letrozole (1,2,4-triazoles)

Quiz Questions

Prostate Cancer Statements: True/False

1. Statement Assessment:

   • (i) PSA levels usually increase slightly with age, not definitively indicative of prostate cancer.

   • (ii) Hormone therapy treatments use antagonists of the androgen receptor.

   • (iii) DHT is significantly less potent than testosterone as an agonist for AR (False).

   • (iv) Non-steroidal antiandrogens are taken orally multiple times per day.

2. Possible Answers:

   • A. (i) only

   • B. (i) and (ii)

   • C. (i), (ii) and (iv)

   • D. (ii), (iii) and (iv)

   • E. All are true

Tamoxifen and Tamogel Statements: True/False

1. Statement Assessment:

   • (i) The E-geometric isomer of Tamoxifen is presented.

   • (ii) Tamogel is a metabolite of Tamoxifen.

   • (iii) Tamoxifen is less effective than Tamogel in inhibiting estrogen.

   • (iv) Both drugs are more effective in treating post-menopausal women.

2. Possible Answers:

   • A. (i) only

   • B. (i) and (iv)

   • C. (i), (ii) and (iii)

   • D. (ii) and (iii)

   • E. (iv) only

Learning Outcomes

• Key Understandings:

  • Identification of main sex hormones and their physiological roles.

  • Awareness of high levels of 5α-reductase and DHT in the prostate.

  • Understanding that DHT is a potent agonist for AR.

  • Ability to explain androgen deprivation therapy for prostate cancer.

  • Knowledge of steroidal and non-steroidal drugs related to androgen deprivation therapy.

  • Familiarity with the structure-activity relationship of Estramustine and the function of the carbamate group.

  • Capacity to describe Tamoxifen's use in breast cancer and identify its active metabolite.

  • Comprehension of role and mechanism of aromatase and inhibitors in post-menopausal cancers.

  • Recognition of stereochemistry and geometric isomers' significance in major drugs.