Porth's Essentials of Pathophysiology, 4e

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Cell and Tissue Function

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TargetedTherapy Researchers have been working diligently to produce drugs that selectively attack malignant cells while leaving normal cells unharmed. 66,67 The characteristics and capabilities of cancer cells have been used to establish a framework for the development of such targeted therapies, including those that disrupt molecular signaling pathways, inhibit angiogenesis, and harness the body’s immune system. The first targeted therapies were the monoclonal antibodies. Researchers are now working to design drugs that can dis- rupt molecular signaling pathways, such as those that use the protein tyrosine kinases. The protein tyrosine kinases are intrinsic components of the signaling pathways for growth factors involved in the proliferation of lymphocytes and other cell types. Imatinib mesylate is a protein tyro- sine kinase inhibitor indicated in the treatment of chronic myeloid leukemia (see Chapter 11). Angiogenesis is also being explored as a target for targeted cancer therapy. 66 One of the newerr antiangiogenic agents, bevacizumab, targets and blocks VEGF, which is released by many can- cers to stimulate proliferation of new blood vessels. ■■ The methods used in the detection and diagnosis of cancer vary with the type of cancer and its location. Because many cancers are curable if diagnosed early, health care practices designed to promote early detection, such as screening, are important. ■■ Diagnostic methods include laboratory tests for the presence of tumor markers, cytologic and histologic studies using cells or tissue specimens, and gene profiling methods, in addition to medical imaging. ■■ There are two basic methods of classifying tumors: grading according to the histologic or tissue characteristics, and clinical staging according to spread of the disease.TheTumor, Node, Metastasis (TNM) system for clinical staging of cancer uses tumor size, lymph node involvement, and presence of metastasis. ■■ Treatment of cancer can include surgery, radiation, or chemotherapy. Other therapies include hormonal, immunologic, and biologic therapies, as well as molecularly targeted agents that disrupt molecular signaling pathways, inhibit angiogenesis, and harness the body’s immune system.Treatment plans that use more than one type of therapy are providing cures for a number of cancers that a few decades ago had a poor prognosis, and are increasing the life expectancy in other types of cancer. SUMMARY CONCEPTS

humanized antibodies in which the murine regions that bind antigen have been grafted into human immunoglobu- lin (Ig) Gmolecules, and entirely human antibodies derived from transgenic mice expressing immunoglobulin genes. 65 Some monoclonal antibodies are directed to block major pathways central to tumor cell survival and proliferation, whereas others are modified to deliver toxins, radioiso- topes, cytokines, or other cancer drugs. Currently approved monoclonal antibodies include rituximab (Rituxan), a chimeric IgG monoclonal anti- body that targets the CD20 antigen on B cells and is used in the treatment of nonHodgkin lymphoma; beva- cozumab (Avastin), a humanized IgG monoclonal anti- body that targets vascular endothelial growth factor (VEGF) to inhibit blood vessel growth (angiogenesis) and is approved for treatment of colorectal, lung, renal, and breast cancer; and cetuximab (Erbitux), a chimeric monoclonal antibody that targets the epidermal growth factor receptor (EGFR) to inhibit tumor cell growth and is approved for treatment of colorectal cancer and squa- mous cell cancer of the head and neck. 64,65 Cytokines. The biologic response modifiers include cytokines such as the interferons and interleukins. The interferons appear to inhibit viral replication and also may be involved in inhibiting tumor protein synthesis, prolonging the cell cycle, and increasing the percentage of cells in the G 0 phase. Interferons stimulate NK cells and T-lymphocyte killer cells. There are three major types of interferons, alpha ( α ), beta ( β ), and gamma ( γ ), with members of each group differing in terms of their cell surface receptors. 63 Interferon- γ has been approved for the treatment of hairy cell leukemia, AIDS-related Kaposi sarcoma, and chronic myelogenous leukemia, and as adjuvant therapy for patients at high risk for recurrent melanoma. Interferon- α has been used to treat some solid tumors (e.g., renal cell carcinoma, colorectal cancer, carcinoid tumors, ovarian cancer) and hema- tologic neoplasms (e.g., B-cell and T-cell lymphomas, cutaneous T-cell lymphoma, and multiple myeloma). 62 Research now is focusing on combining interferons with other forms of cancer therapy and establishing optimal doses and treatment protocols. The interleukins (ILs) are cytokines that provide com- munication between cells by binding to receptor sites on the cell surface membranes of the target cells. Of the 18 known interleukins (see Chapter 15), IL-2 has been the most widely studied. A recombinant human IL-2 (rIL-2, aldesleukin) has been approved by the U.S. Food and Drug Administration (FDA) and is currently being used for the treatment of metastatic renal cell carcinoma and metastatic melanoma. 63 Adjuvants. Adjuvants are substances such as Bacillus Calmette-Guérin (BCG) that nonspecifically stimulate or indirectly augument the immune system. 63 Instillations of BCG, an attenuated strain of the bacterium that causes bovine tuberculosis, are used to treat noninva- sive bladder cancer after surgical ablation. It is assumed that BCG acts locally to stimulate an immune response, thereby decreasing the relapse rate.