2015 Antineoplastics

Critical Facts IconCRITICAL FACTS IV: Immune system modifiers
(if med school is a Minnesota forest with millions of trees,
these are the red pines)

  1. The vinca alkaloids (VINCRISTINE and VINBLASTINE), taxanes (PACLITAXEL) and epilones (IXABEPILONE) are mitotic spindle poisonsDespite their structural similarity, VINCRISTINE and VINBLASTINE have significantly different toxicities (VINCRISTINE=CNS; VINBLASTINE=Bone marrow suppression).

  2. As with many other natural product drugs, treatment with vinca alkaloids and taxanes commonly leads to the development of multi-drug resistance, due to increased expression of P-glycoproteinIXABEPILONE does not produce MDR, and is therefore approved for use in breast cancer patients who have failed anthracycline antibiotic and taxane treatments.

  3. The glucocorticoids DEXAMETHASONE and PREDNISONE are used as immunosuppressants in the treatment of many types of cancers --- specifically those that express the requisite receptors (e.g., prednisone-sensitive lymphomas).  When used in cancer chemotherapy, these agents are given in higher doses, using a “pulse” regimen, compared to their use in treating inflammatory diseases (asthma, arthritis, lupus, etc.).

  4. Immunosuppressive antibiotics are used to prevent rejection following bone marrow transplants (CYCLOSPORINE, TACROLIMUS) and as angiogenesis inhibitors (EVEROLIMUS, TEMSIROLIMUS).  These drugs are involved in 2 pathways that are involved in cell proliferation:  1) NFAT-mediated regulation of interleukin synthesis and 2) mTOR regulation of cell growth and angiogenesis

  5. As molecular targets are identified that distinguish cancer cells from normal cells, monoclonal antibodies and fusion proteins have been developed that can selectively recruit the immune system to destroy the cancer cells.  Currently, antibodies have been designed that target CDs (CD20 in NHL, and CD52 in B-CLL), and tyrosine kinase receptors (HER2, VEGF, EGFR) that are overexpressed in specific cancers.

  6. The cytokines used for cancer chemotherapy share some common characteristics.  They all have short half-lives, and are not cytotoxic by themselves they recruit immune cells to do the actual cell kill (which means the immune system has to recognize the tumour cells as foreign).  Despite their human origin, INTERLEUKIN 2, INTERFERON α and TUMOUR NECROSIS FACTOR α can have serious, even fatal, side effects.

  7. Bone marrow suppression is the dose-limiting complication of many antineoplastic drugs.  Recombinant forms of several lineage-dependent colony stimulating factors have been developed.  These factors activate specific progenitor cells, resulting in the production of:  ERYTHROPOIETIN red blood cells, FILGRASTIM (G-CSF) neutrophils, SAGRAMOSTIM (GM-CSF) granulocytes, eosinophils, basophils and monocytes and INTERLEUKIN 11 and ROMIPLOSTIM platelets.

  8. A significant spectrum of action exists among protein function inhibitors. At one end are drugs that target a unique aspect of a specific cancer type (such as L-ASPARAGINASE and IMATINIB); less specific are those that exploit overexpression of a particular protein (such as ERLOTINIB and GEFITINIB); and at the other end are drugs that are really targeting rapidly dividing cells and/or angiogenesis (like BORTEZOMIB, VORINOSTAT, SORAFENIB and SUNITINIB).

  9. One hallmark of malignant transformation is differentiation block.  Numerous chemicals --- including vitamin D and its analogues, retinoids (vitamin A derivatives such as TRETINOIN) and rexinoids (multifunctional nuclear retinoid X receptor ligands such as BEXAROTENE) --- can induce tumour cell differentiation, ultimately leading to apoptosis.
Email: Dr. Janet Fitzakerley | ©2015 University of Minnesota Medical School Duluth | Last modified: 10-may-15 6:13 PM