Cancer Chemotherapy Drugs PDF

Cancer Chemotherapy Dr. Lina Tamimi  Cancer is the second most common cause of death in the United States, accounting for 1 in 4 deaths. It is a disease characterized by: a defect in the normal control mechanisms of: 1. cell survival 2. Proliferation 3. differentiation. The inva...

Cancer Chemotherapy Dr. Lina Tamimi  Cancer is the second most common cause of death in the United States, accounting for 1 in 4 deaths. It is a disease characterized by: a defect in the normal control mechanisms of: 1. cell survival 2. Proliferation 3. differentiation. The invasive and metastatic processes and series of metabolic abnormalities associated with the cancer result in tumor-related symptoms and eventual death of the patient unless the neoplasm can be eradicated with treatment.  CAUSES OF CANCER 1. Environmental exposure is probably most important. Exposure to ionizing radiation, or chemical carcinogens (ex. tobacco smoke, azo dyes, aflatoxins, asbestos, benzene… 2. Several viruses: ex. hepatitis B (HBV) and hepatitis C (HCV) Epstein-Barr virus (EBV), also known as human herpesvirus 4 (HHV-4 ),HIV is associated with Hodgkin’s and non-Hodgkin’s lymphomas… 3. Mutations in oncogenes, Mutations or deletions in tumor suppressor genes. Anti cancer drugs  Cancer cell population kinetics 1. (cell cycle-specific [CCS] drugs): anticancer drugs exert their actions selectively on cycling cells most effective when cells are in a specific phase 2. (cell cycle-nonspecific [CCNS] drugs): kill tumor cells in both cycling and resting phases of the cell cycle (although cycling cells are more sensitive). Both types of drugs are most effective when a large proportion of the tumor cells are proliferating (ie, when the growth fraction is high).  Resistance to Anticancer Drugs 1. INCREASED DNA REPAIR An increased rate of DNA repair in tumor cells can be responsible for resistance and is particularly important for alkylating agents and cisplatin. 2. FORMATION OF TRAPPING AGENTS Some tumor cells increase their production of thiol trapping agents (eg, glutathione), which interact with anticancer drugs that form reactive electrophilic species. This mechanism of resistance is seen with the alkylating agent bleomycin, cisplatin, and the anthracyclines. 3. CHANGES IN TARGET ENZYMES Changes in the drug sensitivity of a target enzyme, dihydrofolate reductase, and increased synthesis of the enzyme are mechanisms of resistance of tumor cells to methotrexate. 4. DECREASED ACTIVATION OF PRODRUGS Resistance to the purine antimetabolites (mercaptopurine, thioguanine) and the pyrimidine antimetabolites (cytarabine, fluorouracil) can result from a decrease in the activity of the tumor cell enzymes needed to convert these prodrugs to their cytotoxic metabolites. 5. INACTIVATION OF ANTICANCER DRUGS Increased activity of enzymes capable of inactivating anticancer drugs is a mechanism of tumor cell resistance to most of the purine and pyrimidine antimetabolites. 6. DECREASED DRUG ACCUMULATION This form of multidrug resistance involves the increased expression of a normal gene (MDR1) for a cell surface glycoprotein (P-glycoprotein). This transport molecule is involved in the accelerated efflux of many anticancer drugs in resistant cells. CANCER TREATMENT MODALITIES  PRIMARY INDUCTION CHEMOTHERAPY Drug therapy is administered as the primary treatment for many hematologic cancers and for advanced solid tumors for which no alternative treatment exists. Although primary induction can be curative in a small number of patients who present with advanced metastatic disease (eg, lymphoma, acute myelogenous leukemia, germ cell cancer, choriocarcinoma, and several childhood cancers), in many cases the goals of therapy are palliation of cancer symptoms, improved quality of life, and increased time to tumor progression.  Adjuvant vs. Neoadjuvant Adjuvant chemotherapy is chemo that you get after your primary treatment, such as surgery or radiation. Neoadjuvant chemotherapy is chemo that you get before your primary treatment.  ADJUVANT CHEMOTHERAPY In the treatment of many solid tumors chemotherapy serves as an important adjuvant to local treatment procedures such as surgery or radiation. The goal is to: 1. reduce the risk of local and systemic recurrence 2. improve disease-free and overall survival.  NEOADJUVANT CHEMOTHERAPY The use of chemotherapy in patients who present with localized cancer for which alternative local therapy, such as surgery, exist is known as neoadjuvant chemotherapy. The goal is to render the local therapy more effective. CANCER CHEMOTHERAPEUTIC DRUGS  1. Alkylating agents The alkylating agents include: 1. nitrogen mustards (chlorambucil, cyclophosphamide, mechlorethamine) 2. nitrosoureas (carmustine, lomustine) 3. alkyl sulfonates (busulfan) 4. Other drugs that act in part as alkylating agents include: cisplatin, dacarbazine, and procarbazine.  Mechanism of action CCNS drugs (Cell-cycle nonspecific) They form reactive molecular species that alkylate nucleophilic groups on DNA bases, particularly the N-7 position of guanine. This leads to cross-linking of bases, abnormal base- pairing, and DNA strand breakage. Resistance increased DNA repair decreased drug permeability production of trapping agents such as thiols.  adverse effects generally dose-related occur primarily in rapidly growing tissues such as bone marrow, gastrointestinal tract, and reproductive system. Nausea and vomiting can be a serious issue with a number of these agents.  2. Antimetabolites The antimetabolites are structurally similar to endogenous compounds and are: 1. folic acid antagonists (methotrexate) 2. purines (mercaptopurine, thioguanine) 3. pyrimidines (fluorouracil, cytarabine, gemcitabine). CCS drugs: Cell-cycle specific acting primarily in the S phase of the cell cycle. The antimetabolites also have immunosuppressant actions  2.1. Methotrexate MOA an inhibitor of dihydrofolate reductase (DHF reductase). This action leads to a decrease in the synthesis of: 1. Thymidylate 2. purine nucleotides 3. amino acids and thus interferes with nucleic acid and protein metabolism  Methotrexate toxicity Common adverse effects of methotrexate include: 1. bone marrow suppression 2. toxic effects on the skin and gastrointestinal mucosa (mucositis). 3. Long-term use led to hepatotoxicity and to pulmonary infiltrates and fibrosis leucovorin rescue administration of folinic acid (leucovorin) to reduce toxic effects of methotrexate on normal cells  Remember antifungal FLUCYTOSINE 2.2. Fluorouracil (5-FU) 1. Fluorouracil is converted in cells to 5-fluoro-2′-deoxyuridine-5′- monophosphate (5-FdUMP) inhibits thymidylate synthase and leads to “thymineless death” of cells. 2. FdUMP continues into DNA……. inhibits DNA synthesis and function 3. 5-fluorouridine-5′-triphosphate (FUTP), another 5-FU metabolite, into RNA interferes with RNA processing and function. Resistance decreased activation of 5-FU increased thymidylate synthase activity reduced drug sensitivity of this enzyme  2.3. Cytarabine (ARA-C) the most specific for the S phase of the cell cycle. Cytarabine (cytosine arabinoside) is a pyrimidine antimetabolite. kinases Ara-CTP DNA polymerases inhibition.  2.4. Gemcitabine Gemcitabine is a deoxycytidine analog converted into the active diphosphate and triphosphate nucleotide form. 1. Gemcitabine diphosphate appears to inhibit ribonucleotide reductase and thereby diminish the pool of deoxyribonucleoside triphosphates required for DNA synthesis. 2. Gemcitabine triphosphate can be incorporated into DNA, where it causes chain termination  3. NATURAL PRODUCT ANTICANCER DRUGS CCS drugs 1. vinca alkaloids (vinblastine, vincristine, vinorelbine) 2. podophyllotoxins (etoposide, teniposide) 3. camptothecins (topotecan, irinotecan) 4. taxanes (paclitaxel, docetaxel).  3.1. vinca alkaloids 1. Vinblastine 2. Vincristine 3. Vinorelbine MOA They block the formation of the mitotic spindle by preventing the assembly of tubulin dimers into microtubules. They act primarily in the M phase of the cancer cell cycle. Resistance increased efflux of the drugs from tumor cells via the membrane drug transporter.  Disassembly Assembly NO mitotic spindle  3.2. podophyllotoxins: Etoposide and Teniposide Etoposide: a semisynthetic derivative of podophyllotoxin MOA induces DNA breakage through its: inhibition of topoisomerase II. The drug is most active in the late S and early G2 phases of the cell cycle. Teniposide is an analog with very similar pharmacologic characteristics  3.3. camptothecins: Topotecan and Irinotecan MOA produce DNA damage by inhibiting topoisomerase I. They damage DNA by inhibiting an enzyme that cuts and relegates single DNA strands during normal DNA repair processes.  3.4. Taxanes: Paclitaxel and Docetaxel MOA interfere with the mitotic spindle. The taxanes act differently from vinca alkaloids, since they prevent microtubule disassembly into tubulin monomers.  Taxanes Disassembly Assembly NO mitotic spindle  4. Antibiotics This category of antineoplastic drugs is made up of several structurally dissimilar microbial products and includes: 1. Anthracyclines 2. Bleomycin 3. mitomycin  4.1. Anthracyclines CCNS drugs Doxorubicin Daunorubicin Idarubicin Epirubicin Mitoxantrone MOA intercalate between DNA base pairs inhibit topoisomerase II generate free radicals. block the synthesis of RNA and DNA cause DNA strand scission. Membrane disruption also occurs.  4.2. Bleomycin CCS drug active in the G2 phase MOA Bleomycin is a mixture of glycopeptides generates free radicals bind to DNA cause strand breaks inhibit DNA synthesis.  4.3. Mitomycin CCNS drug MOA metabolized by liver enzymes to form: alkylating agent that cross-links DNA.  5. Targeted therapy Tyrosine Kinase Inhibitors 1- Imatinib is an example of a selective anticancer drug whose development was guided by knowledge of a specific oncogene. MOA 1. It inhibits the tyrosine kinase activity of the protein product of the bcr-abl oncogene that is commonly expressed in chronic myelogenous leukemia (CML) associated with the Philadelphia chromosome translocation. preventing the transfer of a phosphate group to tyrosine on the protein substrate and the subsequent activation of phosphorylated protein. As the result, the transmission of proliferative signals to the nucleus is blocked and leukemic cell apoptosis is induced Tyrosine kinase 2- inhibit c-kit tyrosine kinase for treatment of gastrointestinal stromal tumors Resistance mutation of the bcr-abl gene. toxicity diarrhea, myalgia, fluid retention, and congestive heart failure. 2- Dasatinib newer anticancer 3- nilotinib kinase inhibitors 4- bosutinib 6. Hormonal chemotherapy  6.1. Growth Factor Receptor Inhibitors 1- Trastuzumab MOA a monoclonal antibody, recognizes a surface protein in breast cancer cells that overexpress the HER-2/neu receptor for epidermal growth factor. In about 1 of every 5 breast cancers, the cancer cells have a gene mutation that makes an excess of the HER2 protein toxicity nausea and vomiting, chills, fevers, and headache. cardiac dysfunction, including heart failure. 2. Cetuximab is a chimeric monoclonal antibody directed to the extracellular domain of the EGFR. epidermal growth factor receptor 3. Panitumumab is a fully human monoclonal antibody directed against the EGF (epidermal growth factor) 4. Gefitinib and erlotinib inhibitors of the EGFR’s tyrosine kinase domain 5. Bevacizumab a monoclonal antibody binds to vascular endothelial growth factor (VEGF) prevents it from interacting with VEGF receptors. VEGF plays a critical role in the angiogenesis required for tumor metastasis. 6. Rituximab a monoclonal antibody binds to a surface protein in non-Hodgkin’s lymphoma cells induces complement-mediated lysis direct cytotoxicity induction of apoptosis.  6.2. Gonadal Hormone Antagonists 1. Tamoxifen a selective estrogen receptor modulator blocks the binding of estrogen to receptors of estrogen- sensitive breast cancer cells tissue. You may have hormone therapy after surgery, chemotherapy, and radiation are finished The drug is used in receptor-positive breast carcinoma and has been shown to have a preventive effect in women at high risk for breast cancer. (use : GIVEN FOR 5 YEARS)  toxicity Because it has agonist activity in the endometrium, tamoxifen increases: 1. the risk of endometrial hyperplasia and neoplasia. 2. nausea and vomiting, hot flushes, vaginal bleeding, and venous thrombosis. 2. Toremifene: newer is an estrogen receptor antagonist used in advanced breast cancer. 3. Flutamide androgen receptor antagonist used in prostatic carcinoma toxicity include gynecomastia, hot flushes, and hepatic dysfunction  6.3. Gonadotropin-Releasing Hormone (GnRH) 1. Leuprolide Analogs 2. Goserelin 3. nafarelin ………………………………….effective in prostatic carcinoma. MOA When administered in constant doses so as to maintain stable blood levels, they inhibit release of: gonadotropin release pituitary luteinizing hormone (LH) follicle-stimulating hormone (FSH). toxicity Leuprolide may cause: bone pain, gynecomastia, hematuria, impotence, and testicular atrophy  Chemotherapy antidotes Agent Antidote Agents causing nausea and vomiting 5H3 ANTAGOINST ONDANSETRON , METOCLOPRAMIDE Methotroxate Folinic acid or folic acid Several chemotherapy agents can Dexrazoxane : It appears to inhibit cause cardiotoxicity. The most formation of a toxic iron-anthracycline commonly used cardiotoxic agents are complex. the anthracyclines, e.g. doxorubicin, epirubicin and paclitaxel. The monoclonal antibodies Trastuzumab (Herceptin) and bevacizumab (Avastin) capecitabine and 5-fluorouracil, the latter is often given as a continuous infusion can also be cardiotoxic. Cyclophosphamides Mesna Acute chemotherapy-related diarrhea The mainstays of pharmacologic therapy is opioids. Loperamide (Imodium) diphenoxylate- atropine (Lomotil) are the most commonly