Introduction

• Breast and prostatic cancer: palliation with sex hormone therapy

• Adrenal corticosteroid treatment-- useful in:

  • Acute leukemia

  • Myeloma

  • Lymphomas

  • Other hematologic cancers

  Pharmacological effects:

  • Steroid hormones bind to steroid receptors:

  • Efficacy of steroid treatment depends on specific receptor presence on malignant cell surface.

•  Clinical Use:Treatment of:

  • Female and male breast cancer

  • Prostatic cancer

  • Endometrial cancer of uterus

•  Adverse Effects:

  • Fluid retention (secondary to Na-retaining properties)

  • Androgens-masculinization (long-term use)

  • Estrogens-feminization (long-term use)

  • Adrenocortical steroids:

    • Hypertension

    • Diabetes

    • Enhanced susceptibility to infection

    • Cushingoid appearance

Estrogen and Androgen Inhibitors: (Tamoxifen and Flutamide)

• Tamoxifen: Breast cancer treatment

  • Oral administration.

  • Activity against progesterone-resistant endometrial neoplasm

  • Chemopreventive:  women -- high-risk for breast cancer

  • Mechanism of Action:

    • Competitive partial agonist-inhibitor of estrogen

    • Binds to estrogen-sensitive tissues (receptors present)

    • Best antiestrogen effect requires minimal endogenous estrogen presence {estradiol has a much higher affinity for the estrogen receptor than tamoxifen's affinity for the estrogen receptor}

    • Suppresses serum levels of insulin-like growth factor-1; and up-regulates local TGF-beta production. These properties may explain tamoxifen antitumor activity in melanoma and ovarian cancer.

  •  Adverse Effects:

    • Generally mild

    • Most frequent: hot flashes

    • Occasionally: fluid retention, nausea

  •  Clinical Use:

    • Advanced breast cancer

      • Most likely to be effective if:

        • Lack endogenous estrogens {oophorectomy; postmenopausal}

        • Presence of cytoplasmic estrogen receptor;presence of cytoplasmic progesterone receptorColeman

    • Prolongs survival {surgical adjuvant therapy} in postmenopausal women with estrogen receptor-positive breast cancer.

• Flutamide (Eulexin): prostatic cancer

  • Antagonizes remaining androgenic effects after orchiectomy or leuprolide treatment

Gonadotropin-Releasing Hormone Agonists (Leuprolide and Goserelin (Zoladex))

• Leuprolide and goserelin: synthetic peptide analogues of gonadotropin-releasing hormone (GnRH, LHRH)

  • Mechanism of Action: Analogues more potent.  These agents behave as GnRH agonists.

    • Pituitary effects: when given continuously, these drugs provide initial stimulation then inhibition of follicle-stimulating hormone and leutinizing hormone.

      • Causes reduced testicular androgen synthesis, the reason why these agents are effective in treating metastatic prostate carcinoma

•  Clinical Use: treating metastatic prostate carcinoma

  • Comparing leuprolide with diethylstilbestrol (DES):

    • Similar suppression of androgens synthesis and serum prostatic acid phosphatase (an index of metastatic tumor load, especially elevated in metastatic disease; however, increased levels may be found due to other conidtions, e.g. Paget's disease, multiple myeloma, and others.)

  •  Adverse Effects: Leuprolide less frequently causes:

    • Nausea

    • Vomiting

    • Edema

    • Thromboembolism

    • Painful gynecomastia

  • Leuprolide and goserelin: medication more costly, the more cost-effective given reduced frequency of complications.

Aromatase Inhibitors (Aminoglutethimide and Anastrozole (Arimidex))

• Aminoglutethimide: 

  • Mechanisms of action: Reduction in estrogen concentration

    • Aminoglutethimide: inhibitor of adrenal steroid synthesis ( blocks conversion of cholesterol to pregnenolone {first-step})

    • Aminoglutethimide inhibits extra-adrenal estradiol and estrone synthesis.

    • Aminoglutethimide inhibits an aromatase enzyme {catalyzes conversion of androstenedione to estrone}

      • This conversion may occur in fat.

  • Clinical Use:

    • Metastatic breast cancer (tumors contain estrogen or progesterone receptors)

      • Aminoglutethimide is administered with adrenalreplacement doses of hydrocortisone to ensure avoidance of adrenal insufficiency.

        • Hydrocortisone is used in preference to dexamethasone, because dexamethasone increases the degradation of aminoglutethimide.

    • Aminoglutethimide in combination with hydrocortisone: Second-Line Therapy for women treated with tamoxifen (aminoglutethimide causes more adverse side effects than tamoxifen)

• Anastrozole  (Arimidex): new, selective, nonsteroidal aromatase inhibitor.

  • Appears to have no effect on glucocorticoid or mineralocorticoid synthesis

  • Clinical Use:

    • Treatment of advanced estrogen-or progesterone-receptor positive non--tamoxifen responsive breast cancer

Salmon, S. E. and Sartorelli, A. C. Cancer Chemotherapy, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 881-911.