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הוראה בנושאי טיפול תרופתי בסרטן

הוראה בנושאי טיפול תרופתי בסרטן. מנגנוני פעולה ועמידות: Hormone therapy, cytokines & targeted therapy ערך: פרופ’ נ. חיים , מאי 2004 כתובת לשאלות והערות: n_haim@rambam.health.gov.il. Antiestrogens…. Progestins…. Antiestrogens.

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הוראה בנושאי טיפול תרופתי בסרטן

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  1. הוראה בנושאי טיפול תרופתי בסרטן מנגנוני פעולה ועמידות: Hormone therapy, cytokines & targeted therapy ערך: פרופ’ נ. חיים , מאי2004 כתובת לשאלות והערות: n_haim@rambam.health.gov.il

  2. Antiestrogens…. • Progestins….

  3. Antiestrogens • Block estrogen action by inhibiting estradiol binding to the ER. • Examples: -Tamoxifen: has also partial agonist activity -Selective ER modulators (SERMs), e.g. Raloxifene (Evista) -Faslodex….. Contd

  4. Fulvestrant (Faslodex) Classified as a “pure antiestrogen”: functions by destroying the estrogen receptors (unlike tamoxifen does not have an agonist effect).

  5. Progestins • Indirect action on the hypothalamus-pituitary axis consisting of inhibition of gonadotropin-releasing hormone release. • Direct action resulting in the inhibition of cellular proliferation. • Examples: -Medroxyprogesterone acetate (Provera) -Megestrol acetate (Megace)

  6. Aromatase Inhibitors: • Selective aromatase inhibitors…. • Aminogluthetimide….

  7. Selective Aromatase Inhibitors-mechanism of action • In postmenopausal women the majority of estrogen is produced by aromatization of adrenal androgens in the peripheral tissues, such as fat and muscle. • The conversion of androstenedione to estrone in the peripheral tissues is catalyzed by aromatase, a complex enzyme consisting of cytochrome P-450 (CYP450) and a flavoprotein. • Conversion of androgens to estrogens is the rate-limiting step in the biosynthesis of estrogens. • Selective aromatase inhibitors compete with androgens for binding to the enzyme (competitive) or bind to the enzyme irreversibly (non competitive). Contd

  8. Selective Aromatase Inhibitors-mechanism of action (Contd) Non steroidal=Type II=reversible: • Anastrazole (Arimidex) • Letrozole (Femara) Steroidal=Type I=irreversible: • Exemestane (Aromasin) Smith IE and Dowsett M. N Engl J Med 348: 2431-42, 2003 (Review)

  9. Aminogluthetimide Aminogluthetimide is a non selective aromatase inhibitor. Although it inhibits aromatization of androgens to estrogens, its main action is inhibition of adrenal steroidogenesis at early steps (inhibition of the synthesis of aldosterone, cortisol ,and androgenes).

  10. Androgens…. • Anti-androgens…. • Ketoconazole…. • LHRH analogues….

  11. Androgens Possible anti-tumor effect in breast cancer: inhibition of gonadotropin-relrasing hormone (negative biofeedback), and , therefore, inhibition of estrogen production.

  12. Anti-androgens Steroidal anti-androgens: • Inhibition of nuclear androgen binding; • Suppression of gonadotropin production by a negative biofeedback mechanism and , therefore, suppression of gonadal androgen production. • Example: cyprosterone acetae (predominant activity=competitive inhibition of androgen at the receptor level). (megestrole acetate-a progestational compound- also inhibit androgen production via a negative feedback production, and , therefore, act as anti-androgen). Contd

  13. Anti-androgens (Contd) Non-steroidal anti-androgenes: • Do not suppress gonaotropins and testosterone production, but are specific inhibitors of nuclear androgen binding (bind to cytosol androgen receptors and competitively inhibit binding of androgenes). • Examples: -Flutamide (Eulexin) -Bicalutamide (Casodex)

  14. Ketoconazole High doses inhibit gonadal and adrenal steroidogenesis by inhibiting the P-450-dependent enzyme system.

  15. Luteinizing hormone-releasing hormone (LHRH) analogues • Gonadotropin hormone-releasing hormone (GHRH) is responsible for the synthesis and release of the pituitary hormones, LH and FSH. • Initial stimulatory phase, which is associated with depletion of pituitary LH stores. Initial rise in LH and testosterone, which lasts for approximately 7 days, followed by progressive decrease in the hormone levels, reaching nadirs after approximately 4 weeks. • Examples: -Goserelin (Zoladex) -Leuprolide acetate

  16. Cytokines: • Interferon alpha…. • Interleukin 2….

  17. Cytokines • Soluble proteins or glycoproteins produced by mononuclear cells of the immune system that have regulatory actions on other cells of the immune system or target cells involved in immune reactions • True hormones, acting on other cells at a distance from the secretory cells

  18. Interferon alpha • Direct effects: antiprolifetrative and differentiating • Composite: results in alterations in tumor cell surface antigen expression. • Indirect: effects on immune system and antiangiogenic effect

  19. Interleukin 2 • Induction of activated T-cell proliferation • Stimulation of cytotoxicity in NK and T cells • Acting as cofactor in activating macrophages and B cells

  20. Targeted therapy-Monoclonal antibodies: • Trstuzumab (Herceptin)…. • Rituximab (Mabthera)…. • CAMPATH-1H (Alemtuzumab)…. • Avastin (Bevacizumab)….

  21. Trastuzumab (Herceptin) • HER= human epidermal growth factor receptor • HER2 proto-oncogene encodes the HER2 receptor • The HER2 protein is a transmembrane thyrosine kinase that is a member of the epidermal growth factor. • HER2 is overexpressed in 20-30% of human breast cancers (in the majority, HER2 overexpression is caused by amplification of the HER2 gene). Contd

  22. Trastuzumab (Herceptin) (Contd) Herceptin is humanized anti-HER2 MAB (95% human and 5% murine). It binds with the extracellular domain of the HER2 cell-surface receptor, thereby inhibiting the growth of breast tumor cells that over express HER2.

  23. Rituximab (Mabthera) CD20 antigen: • It is present in high levels on over 95% of B-cell non-Hodgkin’s lymphoma cells. • It is absent from critical host cells such as stem cell or early B-cell precursors. • The antigen does not internalize, is not shed from the cell surface, and does not circulate as free protein. • Evidence suggests that it has a biological function. Contd

  24. Rituximab (Mabthera) (Contd) Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen.

  25. CAMPATH-1H (anti-CD52 monoclonal antibody) (Alemtuzumab) • CD52 is cell surface antigen on lymphocytes & monocytes. • Campath is a humanized immunoglobulin G1 (IgG1) anti-CD52 monoclonal antibody that binds to the cell membrane of greater than 95% of all normal human blood lymphocytes , as well as to most B-and T –cell lymphomas. • Active in pts with advanced and chemotherapy resistant CLL. Osterborg A et al. J Clin Oncol 15: 1567-74, 1997 Frampton JE et al. Drugs 63: 1229-43, 2003

  26. Avastin (Bevacizumab) • Humanized anti- vascular endothelial growth factor (VEGF) monoclonal antibody. • VEGF has been shown to have central role in the control of angiogenesis and to be essential for the development of tumor vasculature. Gordon MS et al. J Clin Oncol 19: 843-50, 2001 Activity in phase I…. Kabbinavar F et al. J Clin Oncol 21: 60-5, 2003 Phase II with 5FU/LCV…..

  27. Targeted therapy-Epidermal growth factor receptor antagonists-low molecular weight inhibitors: • ZD1839 (Iressa)…. • Traceva…..

  28. Low-molecular weight inhibitors of the receptor`styrosine kinase • The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor of the ErbB family (= type I receptor tyrosine kinases=ErbB receptors) that is abnormally activated in many epithelial tumors. • This receptor family is comprised of the following 4 related receptors, that trigger downstream signaling pathways: HER1, HER2/neu,HER3, HER4. • Low-molecular weight tyrosine kinase inhibitors interfere with with receptor signaling by competing with ATP for binding to the tyrosine kinase portion of the receptor. Mendelsohn J and BaselgaJ. J Clin Oncol 21: 2787-99, 2003(Review)

  29. ZD1839=Gefitinib (Iressa) • HER= human epidermal growth factor receptor • HER1 (EGFR) activation starts a signal-transduction cascade that promotes tumor cell proliferation and has an important role in the survival and growth of many types of cancer. • Iressa is a small molecule that selectively inhibits HER1 tyrosine-kinase (HER1-TKI).

  30. Traceva • HER= human epidermal growth factor receptor • HER1 (EGFR) activation starts a signal-transduction cascade that promotes tumor cell proliferation and has an important role in the survival and growth of many types of cancer. • Traceva is a small molecule that selectively inhibits HER1 tyrosine-kinase (HER1-TKI).

  31. Imatinib (STI571)….

  32. Imatinib (STI571) (=Glivec) GIST: • Kit is a 145-KD transmembrane glycoprotein-a product of the c-kit gene. The proto oncogene is type III receptor tyrosine kinase (structurally related to PDGFs and M-CSF). • C-Kit is a mutated KIT receptor overexpressed in certain malignancies such as Gastrointestinal Stromal Tumors (GIST). It has tyrosine kinase activity. Contd

  33. Imatinib (STI571) (=Glivec) (Contd) • Kit mutation results in ligand independent activation of KIT tyrosine kinase activity and stimulation of downstream signaling pathways including MAP kinase, P13kinase and STAT pathways. • Imatinib (STI571) is 2-phenylaminopyrimidine derivative. • Imatinib inhibits tyrosine kinase activity of c-kit ,which is activated in GIST as a result of gene mutation (Imatinib is TKI=tyrosine kinase inhibitor). Heinrich MC et al. J Clin Oncol 20: 1692-703, 2002 (review) Contd

  34. Imatinib (STI571) (=Glivec) (Contd) CML: The mechanism of action is due to inhibition of the Bcr-Abl tyrosine kinase created by the Philadelphia chromosome abnormality in CML.

  35. Bisphosphonates….

  36. Bisphosphonates • Bisphosphonates are analogs of pyrophosphates in which a carbon atom replaces the central oxygen atom (and , therefore, the two phosphate groups are linked to the central carbon atom). • The P-C-P moiety of bisphosphonates is responsible for their strong affinity for divalent atoms, such as calcium ions, and for the skeleton.Contd

  37. Bisphosphonates (Contd) Antiresorptive properties: Inhibit osteoclastic bone resorption (lead to osteoclast inactivation, diminish osteoclast maturation, inhibit movement of osteoclasts to the bone surface where they resorb bone, induce apoptosis of osteoclasts) and therefore, reduce the occurrence of pathological fractures, bone pain, hypercalcemic episodes, and the need for radiation therapy and surgery in patients with osteolytic bone metastases. Contd

  38. Bisphosphonates (Contd) Direct antitumor effects: There is experimentalevidence of direct antitumor activity (see: Santini D et al. Ann Oncol 14: 1468-76, 2003, Review). Contd

  39. Bisphosphonates(Contd) • Pmidronate (Aredia) • Zolendronic acid (Zometa; Zomera (in Israel) • Clodronate (Bonefos)

  40. Sulpiride (Modal) • Dopamine receptor antagonist • PO 50 MG X 3 (or-including IM not more than 50 mg)

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