Nursing Pharmacology Chapter 33-34:  Anticancer Drugs

• Hormonal Anticancer Drugs: 

  • Introduction:

    • Cancer cell proliferation is influenced by hormones, with proliferation either regulated or hormonal dependent.¹ 

      • Glucocorticoids administration may reduce neoplastic cell proliferation as well as exhibit lympholytic (lymphocyte cell death promoting) properties.

      • Anticancer effects are associated with administration of:

        • Estrogen inhibitors

        • Androgen inhibitors

        • Steroid synthesis inhibitors

        • Gonadotropin-releasing hormone (GnRH) analogues or inhibitors.¹ 

      • Sometimes administration of these agents prolong survival and can delay or prevent tumor recurrence, for example in prostate cancer and breast cancer.

        • Hormonal Therapy in Breast Cancer⁸

          Attribution: Frenett G Hormonal therapy in breast cancer. https://www.youtube.com/watch?v=pD3aXpnkWwU (1/2014) Charlottecancer https://www.youtube.com/channel/UC-XsQzqbLoft0yHY59vNLVA

        • Modes of action of these agents include:¹ 

          • Interference with a "stimulatory axis" due to systemic androgens and estrogens

          • Hormone production inhibition

          • Inhibition of hormone-receptor association

          • Inhibition of gene expressions that enhance cancerous tumor growth.¹

    • Hormonal-based treatments are also used in managing "paraneoplastic syndromes" for example, carcinoid syndrome as well as cancer-caused symptoms such as anorexia.³

    • Glucocorticoids:

      • Glucocorticoids exert their pharmacological properties as a result of binding to a particular glucocorticoid receptor (GR or GCR) .^1,9 

        • This receptor belongs to a group of nuclear receptors that regulate transcription factors.

          • Other members of the "nuclear hormone receptor superfamily" in addition to the estrogen receptor include:² 

            • Progesterone receptor (PR)

            • Androgen receptor (AR)

            • Glucocorticoid receptor (GR)

            • Mineralocorticoid receptor.

          • This receptor grouping, moreover, also includes nonsteroidal nuclear hormone receptors including:

            • Retinoids

            • Vitamin D (deltanoids)

            • Thyroid hormones.²

          • Following glucocorticoid binding in the cytosol, the glucocorticoid receptor-glucocorticoid comples relocates to the cell nucleus, where the complex induces changes in gene expression.

            • Glucocorticoid Receptor Binding and Transcription¹⁰

              Attribution:  Heltzer MD Wolf IM Sanchez ER Witchel SF DeFranco DB Glucocorticoid Receptor Physiology Endocrine and Metabolic Disorders 8(4):  321-330 December 2007 This figure corresponds to Figure 2. https://link.springer.com/article/10.1007%2Fs11154-007-9059-8 https://www.semanticscholar.org/paper/Glucocorticoid-receptor-physiology-Heitzer-Wolf/e5d6228f27d0c0ac7eb1b976f196884fbc9dd005

            • These changes in sensitive cells promote apoptosis and anti-cell division responses (antiproliferative).

              • Anti-proliferative responses manifest in reduced lymphocyte mitosis.

              • Furthermore, lympholytic effects are also prominent.

                • Because of these actions, glucocorticoids are effective in treating childhood acute leukemia and malignant lymphoma in both children and adults.

                  • Glucocorticoid administration, used to treat lymphoblastic or undifferentiated childhood leukemia, may result in rapid clinical improvement.

                • Hematological remissions are described in about 1/3 of pediatric patients.

                  • Unfortunately, remission duration may be brief and may occur earlier with glucocorticoids compared to anti-metabolite antineoplastic drugs.

                    • As a result, initial treatment may involve both prednisone and vincristine with subsequent treatment with an anthracycline drug or methotrexate and L-asparaginase.¹ 

      • Estrogens: 

        • High-dose estrogen administration is an effective agent for treating breast cancer.¹  

          • Antineoplastic effects of estrogen may be associated with drug -induced apoptosis noted in endocrine-resistant disease.

          • Estrogen signaling may also be inhibited by antiestrogens.

          • A prominent antiestrogen is tamoxifen.

          • Other ways of interfering with estrogen -related signaling is by direct reduction of estrogen synthesis by agents classified as aromatase inhibitors (AI) and gonadotropin-releasing hormone (GnRH) structural analogs.

            • These analogs have advantages in terms of both effectiveness and patient tolerance.

              • Furthermore, these agents have superseded estrogens or androgens for breast cancer management.

          • The presence of estrogen receptor (ER) and progesterone receptor (PR) on neoplastic breast cancer cells increase the likelihood of hormonal therapy response.

            • Breast cancer tumors that are positive (expressing) ER⁺ or positive (expressing) PR⁺ and also exhibit human epidermal growth factor receptor HER2/neu amplification show somewhat lower response to antiestrogen protocols.

              •  Breast cancers not expressing ER or PR are not responsive to hormonal treatment.¹ 

        • Estrogen and Related Agents: Structures:

          • There are three endogenous, naturally occurring estrogens:

            • Estradiol

            • Estrone

            • Estriol.

          • The structures are produced by testosterone and anthracenedione aromatization (respectively)