Anti-Cancer Drugs 29 Mar 2024 PDF

ANTI-CANCER DRUGS DEPARTMENT OF PHARMACOLOGY  Cancer Cancer involves changes which enable cells to grow and divide without respect to normal limits, to invade and destroy adjacent tissues, and ultimately metastasize to distant sites in the body. PHASES OF CELL CYCLE ...

ANTI-CANCER DRUGS DEPARTMENT OF PHARMACOLOGY  Cancer Cancer involves changes which enable cells to grow and divide without respect to normal limits, to invade and destroy adjacent tissues, and ultimately metastasize to distant sites in the body. PHASES OF CELL CYCLE  LEARNING OBJECTIVES Explain Cancer cell cycle kinetics Classify Cell Cycle specific anticancer drugs. Explain the mechanism of action of 5- Fluorouracil, Methotrexate, Vincristine, Bleomycin Discuss clinical uses of these drugs. Discuss adverse effects of these drugs.  CANCER CELL CYCLE KINETICS CELL CYCLE-SPECIFIC [CCS] DRUGS These are those anticancer drugs which exert their actions selectively on cycling cells CCS drugs are most effective when cells are in a specific phase of the cell cycle CELL CYCLE-NONSPECIFIC [CCNS] DRUGS These are those anticancer drugs which kill tumor cells in both cycling and resting phases of the cell cycle CLASSIFICATION OF CELL CYCLE- SPECIFIC (CCS) DRUGS  ANTIMETABOLITES Pyrimidines analogues 5-Fluorouracil Capecitabine cytarabine Gemcitabine Purine Analogues Act on S phase of cel Mercaptopurine (6-MP) cycle Thioguanine (6-TG) Azathioprine Anti folate Methotrexate Pralatrexate  5-FLUOROURACIL (5-FU)-INTRODUCTION It is an antimetabolite anti-cancer drug Is an antagonist of pyrimidines It is a CCS drug, which act primarily in the S phase of the cell cycle. Similar drugs include cytarabine, gemcitabine  5-FLUOROURACIL (5-FU)- MODE OF ACTION Fluorouracil is converted in cells to 5-fluoro2′- deoxyuridine-5′- monophosphate (5- FdUMP) 5-FdUMP which inhibits thymidylate synthase Incorporation of FdUMP into DNA inhibits DNA synthesis and function  5-FLUOROURACIL (5-FU) -CLINICAL USES Colorectal cancer ( widely used) GI cancers Breast cancer Neck cancer Hepatocellular cancer  5-FLUOROURACIL (5-FU) -ADVERSE EFFECTS Myelosuppression, Diarrhea, Nausea and vomiting and Neurotoxicity. METHOTREXATE  METHOTREXATE-MODE OF ACTION Methotrexate is an inhibitor of dihydrofolate reductase. This action leads to a decrease in the synthesis of purine nucleotides, and amino acids Thus interferes with nucleic acid and protein metabolism  METHOTREXATE-CLINICAL INDICATIONS Effective against following cancers: Acute lymphocytic leukemia, Choriocarcinoma, Breast cancer, and Head and neck carcinomas. Also effective against certain inflammatory diseases, such as severe psoriasis and rheumatoid arthritis Abortive in Ectopic Pregnancy  METHOTREXATE-ADVERSE EFFECTS Common adverse effects of methotrexate include: Bone marrow suppression and Toxic effects on the skin and gastrointestinal mucosa (mucositis). The toxic effects of methotrexate on normal cells may be reduced by administration of folinic acid (leucovorin); this strategy is called leucovorin rescue. Long-term use of methotrexate has led to hepatotoxicity and pulmonary infiltrates and fibrosis.  VINCA ALKALOIDS-INTRODUCTION These are plant-derived CCS drugs Also called Natural product cancer chemotherapy drugs Include: Vinblastin Act on e M Vincristin phase e of cell Vinorelbi cycle ne  VINCRISTINE-MODE OF ACTION Vincristine block the formation of the mitotic spindle by preventing the assembly of tubulin dimers into microtubules. Interference with microtubule assembly, resulting in impaired mitosis and ultimately cell death occurs VINCRISTINE-MODE OF ACTION  VINCRISTINE-CLINICAL USES Acute lymphocytic leukemia Hodgkin’s and non-Hodgkin’s lymphoma Wilms’ tumor Neuroblastoma  VINCRISTINE-ADVERSE EFFECTS Vincristine does not cause serious myelosuppression but has neurotoxic actions and may cause: Areflexia, Peripheral neuritis, and Paralytic ileus BLEOMYCIN-INTRODUCTION Bleomycin is a cell cycle specific (CCS) anti- cancer drug active in the G2 phase of the tumor cell cycle It is an antitumor antibiotic.  BLEOMYCIN-MODE OF ACTION Bleomycin cause scission of DNA by an oxidative process A DNA–bleomycin–Fe2+ complex undergo oxidation to bleomycin– Fe3+. The liberated electrons react with oxygen to form superoxide or hydroxyl radicals, which, in turn cause DNA damage. BLEOMYCIN-CLINICAL USES Bleomycin is a component of drug regimens for Hodgkin’s lymphoma and testicular cancer. It is used for treatment of lymphomas Also used to treat squamous cell carcinomas.  BLEOMYCIN-ADVERSE EFFECTS The toxicity profile of Bleomycin includes: Pulmonary dysfunction (pneumonitis, fibrosis) Hypersensitivity reactions (chills, fever, anaphylaxis) Mucocutaneous reactions (alopecia, blister formation, hyperkeratosis).  SUMMARY Some anticancer drugs exert their actions selectively on cycling cells (cell cycle-specific [CCS] drugs), and others (cell cycle- nonspecific [CCNS] drugs) kill tumor cells in both cycling and resting phases of the cell cycle 5-Fluorouracil Inhibits thymidylate synthase, and its metabolites are incorporated into RNA and DNA, all resulting in inhibition of DNA synthesis and function and in RNA processing Methotrexate Inhibits DHFR, resulting in inhibition of synthesis of purine nucleotides Vincristine Interferes with microtubule assembly, resulting in impaired mitosis Bleomycin cause DNA strand breaks, and inhibit Cancer Chemotherapy 2  Learning objectives  Classify Cell Cycle non-specific and miscellaneous anticancer drugs.  Explain the mechanism of action of, Cyclophosphamide, Doxorubicin, Imatinib, Transtuzumab, Tamoxifen.  Discuss clinical uses of these drugs.  Discuss adverse effects of these drugs. Which is an antimetabolite a) Cyclosporine b) Methotrexate c) Etoposide d) Vinblastine Classification  Cyclophosamide Alkylating agents CCNS  MECHANISM OF ACTION An activated form of cyclophosphamide, phosphomide mustard, alkylates, or binds, to DNA. Its cytotoxic effect is mainly due to cross-linking of strands of DNA and RNA, and to inhibition of protein synthesis MECHANISM OF ACTION  Clinical uses Breast cancer Ovarian cancer Non- Hodgkin's lymphoma Chronic leukemia Neuroblastoma Testicular carcinoma Cancer of bladder, lung and ovary Advanced colon cancer  Side effects Myelosuppression Alopecia Hemorrhagic cystitis (metabolite acroline) Cardiac dysfunction Pulmonary toxicity  Imatinib (Tyrosine kinase inhibitor) Tyrosine kinase inhibitor A tyrosine kinase inhibitor (TKI) is a drug that inhibits tyrosine kinases Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. Imatinib is a specific inhibitor of a number of tyrosine kinase enzymes.  Clinical uses Used for various types of cancer Chronic myelogenous leukemia (CML) Acute lymphocytic leukemia Gastrointestinal stromal tumors (GIST) Chronic eosinophilic leukemia (CEL)  Side effects Common side effects include vomiting, diarrhea, muscle pain, headache, and rash Severe side effects may include fluid retention, gastrointestinal bleeding, bone marrow suppression, liver problems, and heart failure  Trastuzumab Growth factor receptor inhibitors  Growth factor receptor inhibitors Drugs that target the growth factor receptors of cells. Drugs of this type include those that target the epidermal growth factor receptors of epidermal cells (EGFR inhibitors) and those that target vascular endothelial growth factor recepto rs (VEGFR inhibitors)  Trastuzumab Trastuzumab is a recombined humanized monoclonal antibody which binds to the extracellular domain of HER2 Trastuzumab is the first anti- HER2 antibody approved by Food and Drug Administration (FDA) in 1998 for the treatment of patients with HER2- overexpressed metastatic breast cancer  Mechanism of Action Trastuzumab is a monoclonal antibody targeting HER2, inducing an immune-mediated response that causes internalization and downregulation of HER2  Clinical use and Side Effects Breast cancer Side effects Cardiac dysfunction Headache. Diarrhea. Nausea. Chills. Fever. Heart problems. Infection. Insomnia. Anthracyclin (Doxorubicin) Antitumor Antibiotics  Doxorubicin MOA Oxygen free radical bind to DNA causes DNA breakage Inhibits topoisomerase 2 Clinical uses Lymphoma, Myelomas, Breast, Lung and ovarian, thyroid cancers (Doxorubicin) Acute leukemia (Dunonorubacin) (idarubicin) Breast cancer, gasteroesophgeal cancer (Epirubacin)  Side effects Alopecia Myleosuppression Cardiopathy (dose related)  Tamoxifen (Estrogen receptor modulator)  Tamoxifen Block binding of estrogen of estrogen receptor sensitive cell in breast tissues  Clinical uses Tamoxifen is used to treat breast cancer that has spread to other parts It is used to treat early breast cancer in women who have already been treated with surgery, radiation, and/or chemotherapy  Side effects Menopause-like symptoms, including hot flashes, night sweats and vaginal dryness. Weight gain (more common) or fluid retention (edema). Irregular or loss of menstrual periods. Leg swelling. Nausea. Skin rash.  Fluorouracil A 61-year-old man was found to have recurrent colon cancer. The primary tumor was removed 8 months previously, at which time adjuvant chemotherapy with fluorouracil and carboplatin was begun. The oncologist suspected that the cancer recurrence was related to resistance to fluorouracil. Which of the following mechanisms best explains the resistance to this drug? A. Decreased ability to phosphorylate pyrimidines B. Decreased activity of the cell efflux pump C. Increased intracellular concentration of a reduced folate D. Decreased activity of topoisomerase E. Decreased activity of thymidylate synthase  Methotrexate A 13-year-old boy suffering from acute lymphoblastic leukemia was admitted to the hospital for the third cycle of anticancer therapy, which included high-dose methotrexate. Which of the following drugs should be given to the patient to counteract methotrexate toxicity? A. Folic acid B. Cyanocobalamin C. Leucovorin D. Ferrous sulfate E. Oprelvekin F. Filgrastim  Doxorubicin A 61-year-old woman with advanced Hodgkin lymphoma began chemotherapy with the ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) regimen. Which of the following molecular actions most likely mediated the therapeutic effect of doxorubicin in the patient’s disease? A. It intercalates between DNA strands and inhibits topoisomerase II. B. It prevents microtubule disassembly into tubulin monomers. C. It prevents assembly of tubulin dimers into microtubules. D. It alkylates nucleophilic groups on DNA bases. E. It blocks the synthesis of both ribonucleotides and deoxynucleotides. Thank you