Anticancer Drugs Lecture Notes PDF

Lecture 8 Anticancer Drugs By Matin A. Mahmood M.Sc. Pharmacology & Toxicology Ph.D. Pharmacology 3. Cell cycle regulators Cell cycle regulators 1. +ve regulators Growth factors that act on protein kinase receptors 2. -ve regulat...

Lecture 8 Anticancer Drugs By Matin A. Mahmood M.Sc. Pharmacology & Toxicology Ph.D. Pharmacology 3. Cell cycle regulators Cell cycle regulators 1. +ve regulators Growth factors that act on protein kinase receptors 2. -ve regulators P53 BRCA1, BRCA2 4. CANCER CELL CYCLE KINETICS 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 (although cycling cells are more sensitive). CCS drugs are usually most effective when cells are in a specific phase of the cell cycle (Figure ). 5. Principles of Cancer Chemotherapy Cancer chemotherapy strives to cause a lethal cytotoxic event or apoptosis in the cancer cells that can arrest the progression of tumor growth. The attack is generally directed toward DNA or against metabolic sites essential to cell replication  Ideally, anticancer drugs should interfere only with cellular processes that are unique to malignant cells. Unfortunately, most traditional anticancer drugs do not specifically recognize neoplastic cells but, rather, affect all kinds of proliferating cells, both normal and abnormal. Therefore, almost all antitumor agents have a steep dose–response curve for both therapeutic and toxic effects. Newer agents are being developed that take a different approach to cancer treatment by blocking checkpoints and allowing the patient’s own immune system to attack cancer cells. Treatment strategies Goals of treatment The ultimate goal of chemotherapy is a cure (that is, long-term, disease-free survival). A true cure requires the eradication of every neoplastic cell. If a cure is not attainable, then the goal becomes control of the disease (prevent the cancer from enlarging and spreading) to extend survival and maintain quality of life. Thus, the individual maintains a “near-normal” existence, with the cancer treated as a chronic disease.  In either case, the neoplastic cell burden is initially reduced (debulked), either by surgery and/or by radiation, followed by chemotherapy, immunotherapy, therapy using biological modifiers, or a combination of these treatment modalities (Figure). In advanced stages of cancer, the likelihood of controlling the cancer is low, and the goal is palliation (alleviation of symptoms and avoidance of life-threatening toxicity). This means that chemotherapeutic drugs may be used to relieve symptoms caused by the cancer and improve the quality of life, even though the drugs may not extend survival. Cancer treatment options A. Surgery B. Radiation therapy C. Pharmacotherapy 1. Chemotherapy 2. Hormonal therapy 3. Immunotherapy D. Bone marrow transplantation E. Palliative (Symptomatic) therapy Indications for treatment When neoplasms are disseminated and are not amenable to surgery Chemotherapy Supplemental treatment to attack micrometastases Adjuvant following surgery and radiation treatment chemotherapy Given prior to the surgical procedure in an attempt Neoadjuvant to shrink the cancer chemotherapy Chemotherapy given in lower doses to assist Maintenance prolonging remission chemotherapy Treatment protocols Combination chemotherapy is more successful than single-drug treatment in most cancers for which chemotherapy is effective. Cytotoxic agents with different toxicities, and with different molecular sites and mechanisms of action, are usually combined at full doses. This results in higher response rates, due to additive and/or potentiated cytotoxic effects, and nonoverlapping host toxicities. In contrast, agents with similar dose-limiting toxicities, such as myelosuppression, nephrotoxicity, or cardiotoxicity, can be combined safely only by reducing the doses of each. Treatment protocols Advantages of combinations 1. Provides maximal cell killing within the range of tolerated toxicity, 2. Effective against a broader range of cell lines in the heterogeneous tumor population, and 3. Delay or prevent the development of resistant cell lines. Resistance to Anticancer Drugs Drug resistance is a major problem in cancer chemotherapy. Mechanisms of resistance include the following: 1. Increased DNA repair: responsible for resistance particularly in 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, 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. Resistance to Anticancer Drugs 4. Decreased activation of prodrugs: Resistance to the purine antimetabolites (mercaptopurine, thioguanine) can result from a decrease in the activity of the tumor cell enzymes needed to convert these prodrugs to their cytotoxic metabolites. 5.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. AE of ACD: General AE Specific AE 1. BM toxicity (myelosuppression) Specific for each drug 2. Impaired wound healing 3. Loss of hair (alopecia) 4. Damage of GI epithelium ( including oral and mucus membranes) 5. Hepatotoxicity 6. Sterility 7. Teratogenicity & carcinogenicity because many cytotoxic drug are mutagens Classes of Anticancer Drugs Alkylating Agents Hormone Antagonists Protein Kinase Antimetabolites Inhibitors Monoclonal Cytotoxic Antibiotics Antibodies Microtubule Inhibitors Miscellaneous Agents 1- Alkylating agents Nitrogen mustard : Chlorambucil, Cyclophosphamide Nitrosoureas : Carmustine Platinum compounds: Cisplatin Mechanism of action : DNA cross linking  Alkylation of DNA is probably the crucial cytotoxic reaction that is lethal to the tumor cells. Alkylating agents do not discriminate between cycling and resting cells, even though they are most toxic for rapidly dividing cells. They are used in combination with other agents to treat a wide variety of lymphatic and solid cancers. In addition to being cytotoxic, all are mutagenic and carcinogenic and can lead to secondary malignancies such as acute leukemia A. Cyclophosphamide Most commonly used alkylating agent It is a prodrug (requires biotransformation by hepatic CYP450 to be activated) Uses: 1. As anticancer drug; e.g. in breast cancer 2. As immunosuppressant e.g. RA. AE General : BM suppression, hepatotoxicity, alopecia Specific : hemorrhagic cystitis caused by metabolite (acrolein). Can be ameliorated by increasing fluid intake and sulfhydryl donors e.g. N-acetyl cysteine, Mesna. These agent react with acrolein forming non-toxic metabolite. 2- Cisplatin Contains central platinum atom Mechanism of action DNA cross linking Concentrated in kidney & genital tissue Uses: Testicular and ovarian tumors ( IV infusion) AE: General: BM depression(mild), hepatotoxicity, alopecia, severe NV Specific: Nephrotoxicity- sensory hearing loss- peripheral neuropathy 2. Antimetabolites Antimetabolites are structurally related to normal compounds that exist within the cell. They generally interfere with the availability of normal purine or pyrimidine nucleotide precursors, either by inhibiting their synthesis (Methotrexate) or by competing with them in DNA or RNA synthesis (6MP, 5-FU). S phase (cell cycle specific). The vitamin folic acid plays a central role in a variety of metabolic reactions and is essential for cell replication. Classes of Antimetabolites Folic acid antagonists: Methotrexate Purine analogues : 6 mercaptopurine Pyrimidine analogues: 5- Fluorouracil Theses drugs interfere with certain metabolic processes Methotrexate 1. Mechanism of action MTX is structurally related to folic acid and acts as an antagonist of the vitamin by inhibiting mammalian dihydrofolate reductase (DHFR), the enzyme that converts folic acid to its active, coenzyme form, tetrahydrofolic acid (FH4) (Figure). The inhibition of DHFR can only be reversed by a 1000-fold excess of the natural substrate, dihydrofolate (FH2), or by administration of leucovorin, which bypasses the blocked enzyme and replenishes the folate pool. Methotrexate However, in addition to inhibiting DHFR, it also inhibits thymidylate synthase and other enzymes involved in folate metabolism and DNA synthesis.  2. Therapeutic uses MTX, usually in combination with other drugs, is effective against acute lymphocytic leukemia, breast cancer, bladder cancer, and head and neck carcinomas. In addition, low-dose MTX is effective as a single agent against certain inflammatory diseases, such as severe psoriasis and rheumatoid arthritis. All patients receiving MTX require close monitoring for possible toxic effects.  3. Pharmacokinetics MTX is variably absorbed at low doses from the GI tract, but it can also be administered by intramuscular, intravenous (IV), and intrathecal routes Metabolite is less water soluble than MTX and may lead to crystalluria. Therefore, it is important to keep the urine alkaline and the patient well hydrated to avoid renal toxicity.  4. AE: General: BM depression, hepatotoxicity, teratogenicity, etc. Specific: megaloblastic anemia and mucosal ulceration Folinic acid must be supplied to prevent megaloblastic anemia (Folic acid 5 mg/d Is usually taken on "non-methotrexate day). 6-Mercaptopurine Mechanism of action: Interferes with purine nucleotide (adenine & guanine)synthesis thus inhibits DNA and RNA synthesis. Adverse effects: General: BM depression, hepatotoxicity, teratogenicity, etc. Specific:1. The enzyme thiopurine S-methyltransferase (TPMT), converts 6-MP into non-toxic compound. People with genetic deficiency of this enzyme are subjected to severe myelosuppression when take 6-MP 2. The enzyme xanthine oxidase breaks down 6- MP. Concomitant use of allopurinol (Xo inhibitor) with 6-MP can lead to severe toxicity. 3. Antibiotics Their cytotoxic action primarily due to their interactions with DNA, leading to disruption of DNA function A. Doxorubicin: It binds to DNA and RNA gyrase thus inhibits both DNA and RNA synthesis. Main adverse effect: Irreversible, dose-dependent cardiotoxicity NB Cardiotoxicity results from the generation of free radicals and lipid peroxidation. Can be managed the iron chelator dexrazoxane in protecting against the cardiotoxicity of doxorubicin B. Bleomycin: Cause direct DNA damage and fragmentation, Main adverse effects: pulmonary fibrosis C. Mitomycin C: It Is transformed to an alkylating agent that cause DNA cross-linking Main adverse effects: nephrotoxicity  Doxorubicin classified as anthracycline antibiotics. Therapeutic uses for these agents differ despite their structural similarity and apparently similar mechanisms of action. It is used in combination with other agents for treatment of sarcomas and a variety of carcinomas, including breast cancer, as well as for treatment of acute lymphocytic leukemia and lymphomas. 4. Microtubule Inhibitors The mitotic spindle is part of a larger, intracellular skeleton (cytoskeleton) that is essential for the movements of structures occurring in the cytoplasm of all eukaryotic cells. The mitotic spindle consists of chromatin plus a system of microtubules composed of the protein tubulin. The mitotic spindle is essential for the equal partitioning of DNA into the two daughter cells that are formed when a eukaryotic cell divides. Several plant-derived substances used as anticancer drugs disrupt this process by affecting the equilibrium thereby causing cytotoxicity. A. Vinca alkaloids: Vincristine Vinblastine They are of plant origin. Mechanism: bind to microtubule system (mitotic spindle) during metaphase and prevent cell division. They are cell cycle-specific Adverse effects: General: hepatotoxicity, alopecia, etc. Specific: Vinblastine: more BM depression but less neurotoxic Vincristine: less BM depression but causes peripheral neuropathy (CNS)  1. Mechanism of action These agents are cell cycle specific and phase specific, because they block mitosis in metaphase (M phase). Their binding to the microtubular protein, tubulin, blocks the ability of tubulin to polymerize to form microtubules. Instead, paracrystalline aggregates consisting of tubulin dimers and the alkaloid drug are formed. The resulting dysfunctional spindle apparatus, frozen in metaphase, prevents chromosomal segregation and cell proliferation B. Paclitaxel & Docetaxel Paclitaxel was the first member of the taxane family to be used in cancer chemotherapy. Paclitaxel has good activity against advanced ovarian cancer and metastatic breast cancer. Docetaxel is commonly used in prostate, breast, GI and lung cancers.  Adverse effects The dose-limiting toxicities of paclitaxel and docetaxel are neutropenia and leukopenia. Peripheral neuropathy is also a common adverse effect with the taxanes. [Note: Because of serious hypersensitivity reactions (including dyspnea, urticaria, and hypotension), patients who are treated with paclitaxel should be premedicated with dexamethasone and diphenhydramine] 5. Hormones and Their Antagonists Some tumors are hormone dependent (e.g. breast and prostate cancers). Hormone antagonists are used in the treatment of these tumors. Tamoxifen is a selective estrogen modulator (SERM).  Tumors that are sensitive to steroid hormones may be either 1) hormone responsive, in which the tumor regresses following treatment with a specific hormone; or 2) hormone dependent, in which removal of a hormonal stimulus causes tumor regression. For a steroid hormone to influence a cell, that cell must have intracellular (cytosolic) receptors that are specific for that hormone.  1. Tamoxifen 2. Aromatase inhibitors Is an estrogen antagonist in the Aromatase is the enzyme that catalyzes breast but is an agonist in the the production of estrogens from the uterus and bone. adrenal cortex and peripheral tissues. It is used in the treatment of Anastrazole and letrozole (Femara) are estrogen receptor-positive competitive inhibitors of aromatase. breast cancer and for primary used for treatment of post menopausal prevention of breast cancer in women with estrogen receptor-positive women at high risk. breast cancer who have received two Adverse effects: it increases the to three years of tamoxifen and are risk of endometrial cancer and switched to them for completion of a thrombotic complications. total of five years of adjuvant hormonal therapy Antiandrogens 1. Flutamide 2 Cyproterone acetate It is potent blocker of It Inhibits testosterone action on testosterone receptors. target tissue. It Is used in the treatment of It Is NOT used in the treatment advanced prostate cancer. of prostate cancer but used in Adverse effects: hepatotoxicity. treatment of female hirsutism. 6. Tyrosine Kinase Inhibitors The tyrosine kinases are a family of enzymes that are involved in several important processes within a cell, including signal transduction and cell division. [Note: At least 50 tyrosine kinases mediate cell growth or division by phosphorylation of signaling proteins. They have been implicated in the development of many neoplasms.] The tyrosine kinase inhibitors are administered orally, and these agents have a wide variety of applications in the treatment of cancer Imatinib Erlotinib Vemuratenib They are small molecules used to target signaling pathway kinases of growth factors such as EGF PDGF, etc. thus prevent uncontrolled cell proliferation. Imatinib Inhibits the BCR-ABL tyrosine kinase This Inhibition blocks proliferation and promotes apoptosis in BCR -ABL-positive cell lines. Used for the treatment of Philadelphia chromosome -positive CML. Adverse effects: fluid retention and hepatotoxicity. 7. Monoclonal antibodies (-MAB) They are MABS designed to bind to specific protein targets on the surface of cancer cells or immune cells. They are given by IV infusion. NB: Premedication with antihistamine and acetaminophen is required.  Name Molecular target Indication Trastuzumab HER2 ( human epidermal HER2 positive breast (Herceptin®) growth) factor receptor cancer CD20 protein on the surface of Rituximab B-cell lymphoma B-cells Bevacizumab VEGF (vascular endothelial Colorectal cancer (Avastin®) growth factor) EGFR (Epidermal growth factor Cetuximab Colorectal cancer receptor) Dostarlimab PD-1 protein on the surface of Colorectal cancer (Jemberli®) T-cells 8. Miscellaneous Agents 1. Bortezomib is boron-containing tripeptide that inhibits cellular proteosome function. Malignant cells readily depend on suppression of the apoptotic pathway. For some reason, rapidly dividing cells are more sensitive than normal cells to this drug.it is used for treatment of multiple myeloma. 2. Biological response modifiers Agents that enhance the host's Immune response The interferons are endogenous glycoproteins with antineoplastic, immunosuppressive, and antiviral actions. Alpha-interferons are effective against a number of neoplasms, including hairy cell leukemia Thank you