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Pharmacology 21b - Cytotoxic Drugs Anil Chopra 1. 2. 3. 4. 5. To be able to define the term ‘Cancer.’ To be able to describe the characteristics of cancer cells. To be familiar with the molecular basis of chemotherapy. To be able to discuss the potential targets for chemotherapy. To be able to identify the major classes of anticancer drugs and describe their mechanisms of action. » Cancer = a disease in which there is uncontrolled multiplication and spread within the body of abnormal forms of the body’s own cells Normal cells are turned into cancer cells via a series of complex genetic mutations Neoplasia = new growth Neoplasm which expresses uncontrolled proliferation only = benign Neoplasm which expresses uncontrolled proliferation, invasiveness and metastases = malignant Cancer is usually far advanced before the diagnosis is made – generally more than 2cm and near the surface » » » » » Cytotoxic drugs are drugs that modify the growth of cells and tissues. They are used in: Anti-cancer agents o To eradicate disease o Induce a remission o Control symptoms Control of immune responses in organ transplantation Management of autoimmune disease Drug Aims They tend to be anti-Proliferative and so do not affect the ability to invade or metastasise Are commonly used in combination – 2-6 drugs to increase effectiveness and reduce resistance Will affect all rapidly dividing tissues – hence side effects (e.g. bone marrow, GI epithelium, hair) The aim of chemotherapy is to eliminate/ block proliferation of neoplastic cells and inhibit their invasion and metastatic potential. Elimination of cells is achieved using very toxic chemicals that target rapidly proliferating cells. Blocking the proliferation of cells is aimed at stalling tumour growth and encouraging apoptosis and immunosurveillance (removal of abnormal cells by the immune system). Cancer cell have their own particular phenotypes: Disregard of signals to stop proliferating. Disregard of signals to differentiate. Capacity for sustained proliferation. Evasion of apoptosis. Ability to invade. Ability to promote angiogenesis Neoplasia: new growth Benign: uncontrolled proliferation only Malignant: uncontrolled proliferation with the potential to invade and metastasise. Cancers are difficult to treat because they are very similar to normal cells, need to be entirely eradicated to be gone and are normally diagnosed when they are very advanced. Tumour cells can be: Dividing (sensitive to anticancer treatment) No longer able to divide (not a problem) Resting in G0 phase (insensitive to anticancer treatment and could start dividing again after chemotherapy). Cytotoxic Drugs - Antiproliferative - Do not affect invasiveness - Used as combinations - Affect rapidly dividing normal cells as well as tumours. Alkylating Agents Names Nitrogen mustards: cyclophosphamide, melphalan, chloirambucil Methotrexate DHFR Usage DHFR Mode of Action They contain a carbonium ion which covalently bonds with nucleophiles. Their main target is guanine as it is the most electron rich (also adenine and cytosine) and interfere with transcription and replication by causing inter or intra chain cross-links. FH4(glu)n F(glu)n FH2(glu)n FH4(glu)n + 1-carbon unit Thymidylate synthetase O CH3 HN O O DTMP DUMP Fluorouracil HN O F N HN N R R O O N R Antimetabolites Names Methotrexate, fluorouracil, azathioprine Usage – Anti-cancer. Chemotherapy. Mode of action They block pathways in DNA synthesis, either as folate antagonists (methotrexate) interfering with synthesis of thymidilate; pyrimidine analogues (fluorouracil) interfere with 2’-deoxythymidylate synthesis or purine analogues (Azathioprine) which inhibits purine synthesis. Cytotoxic antibiotics Names Actinomycin , Doxorubicin, Bleomycin Usage – Anti-cancer. Chemotherapy. Mode of Action These work by directly interacting with DNA. Actinomycin D intercalates DNA and interferes with topoisomerase II. Doxorubicin inhibits DNA and RNA synthesis. Bleomycins are metal-chelating glycopeptide antibiotics that degrade DNA. Mitotic inhibitors (Plant derivatives) Names Podophyllotoxins: etoposide Vinva alkaloids: vincristine Usage – Anti-cancer. Chemotherapy. Mode of Action Etoposide inhibit DNA synthesis by causing cell cycle block at G2. The vinca alkaloids e.g. vincristine, act by binding to tubulin and inhibiting polymerisation into microtubules which therefore inhibits spindle formation at prophase of mitosis. Miscellaneous agents Usage – Anti-cancer. Chemotherapy. Name - Hyroxyurea, Mode of Action Hydroxyurea inhibits ribonucleotide reductase (essential for DNA synthesis). ___________________________________________________________________ Name - cisplatin Mode of Action - Cisplatin interacts with DNA causing guanine intrastrand crosslinks. Name - Procarbazine Mode of Action - Procarbazine inhibits DNA and RNA synthesis and interferes with mitosis at interphase, it is activated by cytochrome P450 and monoamine oxidase to alkylate DNA. Hormones Names Generally Gonadotrophin releaseing hormone analogues such as goserelin. Also prednisolone, fosfestrol, Tamoxifen. Usage Used in chemotherapy but not cytotoxic. Mode of Action Can inhibit tumours in hormone-sensitive tissues. GENERAL SIDE EFFECTS Myelotoxicity. Impaired wound healing. Depression of growth (children) Sterility. Teratogenicity. Loss of hair. Nausea and vomiting Affect rapidly dividing cells by inhibiting division; affect slowly dividing cells by inducing mutations which can induce secondary tumours. Immunopharmcology Cytotoxic drugs can also be used as immunosuppressants at much lower doses than used to treat cancer. These can be used in the prevention of transplant rejection. At these lower doses they have a relatively selective action on lymphocytes. Principally the anti-metabolites (methotrexazte, azathioprine) are used with the alkylating agents (cyclophosphamide)