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CHEMOTHERAPY

An introduction to pharmacy

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CHEMOTHERAPY

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  1. DRUGS USED IN CHEMOTHERAPY Dr. Kenneth Orimma B.Sc., M.Sc., M.B.B.S, D.I.R, D.M(Doctor of Medicine) Psychiatry

  2. Basics of chemotherapeutic agent action • Chemotherapeutic agents, also referred to as antineoplastic agents, are used to directly or indirectly inhibit the uncontrolled growth and proliferationof cancer cells. • They are classified according to their mechanism of action and include alkylating agent, antimetabolites, antibiotics, mitotic inhibitors, and protein kinase inhibitors • Chemotherapy is associated with a range of adverse effects (e.g., nausea, vomiting, immunosuppression, and impairedgrowth of healthy cells), and some agents increase the risk of secondary neoplasmdevelopment. • Forsome chemotherapeutic agents, specific detoxifying agents can be administered to avert preventable side effects (e.g., leucovorinafter application of methotrexate, mesnaafter cyclophosphamide application).

  3. Basics of chemotherapeutic agent action Kinetics • Chemotherapeutic agents are most active on cells with a high growth fraction, i.e., cells actively undergoing division (including normal cells, such as epithelial or bone marrow cells, as well as cancer cells) • The log-kill hypothesis is a mathematical model of chemotherapeutic agent action, equated according to which a given dose of a certain chemotherapeutic agent eliminates a constant fraction of cancer cells regardless of tumour size. Cell cycle specificity • Cell cycle-specific antineoplastic agents act on proliferating cells only during a specific phase of the cell cycle. • There is no cell-cycle specific antineoplastic agent that acts during the resting (G0) phase. • Cell cycle-nonspecific antineoplastic agents act on cells at any phase of the cell cycle, including the resting (G0) phase.

  4. Basics of chemotherapeutic agent action Resistance mechanisms: • cancer cells can develop resistance to chemotherapeutic agents via the following mechanisms; Mutations or altered expression of target cells • Increased rate of its DNA repair (e.g., this mechanism can cause resistance to alkylating agents) • Drug inactivation (e.g., some cancer cells can increase the synthesis of glutathione and other antioxidants, thus counteracting anthracyclines, which act through the generation of reactive oxygen species) • Alteration of apoptotic pathways (e.g., leukemic cells can increase the expression of antiapoptotic molecules such as Bcl-2 to escape chemotherapy-induced apoptosis. • Drug efflux (e.g., cancer cells can increase the expression of the MDR1 gene coding for P-glycoprotein which acts as the efflux transporter)

  5. Mechanisms of Action of Anti-Tumour Agents Chemotherapy Drugs Target Phases of the Cell Cycle: o S-Phase Specific – Interfere with DNA Synthesis o M-Phase Specific – Interfere with Cell Division o Phase-Nonspecific – Interferes with Cell Metabolism

  6. From the G1 phase, cells enter the DNA synthesis phase in which they replicate DNA

  7. Overview of Approaches to Chemotherapy: Typical Cytotoxic Agents: o Alkylating Agents: § (Disrupts DNA replication in Rapidly-Dividing Cells) o Antimetabolites: § (Provide cells with False Nuclear Substrates → Interferes with DNA Synthesis) o Cytotoxic Antibiotics: § (Directly Damages DNA →Disrupts DNA Replication/Transcription & Produces Free Radicals) o Plant alkaloids: § (Antimitotic Agents – Disrupts mitotic cellular machinery)

  8. Overview of Approaches to Chemotherapy: Hormones and Anti-Hormones: (Interfere with Hormone-Related Growth of Tumours) o Immunosuppressants: § Glucocorticoids – HAEMATOLOGICAL CANCERS: o Hormone Agonists: § Oestrogens § Progestogens o Hormone Antagonists: § Anti-Oestrogens – BREAST CANCER: • Selective Oestrogen Receptor Modulators (SERMs) • Selective Oestrogen Receptor Downregulators (SERDs) § Anti-Androgens – PROSTATE CANCER o Inhibitors of Hormone Synthesis: § GnRH-Receptor Agonists & Antagonists § Reductase Inhibitors § Aromatase Inhibitors

  9. Overview of Approaches to Chemotherapy: Thalidomide: o 1: Antiproliferative/Pro-Apoptotic Actions o 2: Inhibition of Cell-Adhesion Molecule expression on Bone-Marrow Stroma o 3: Inhibition of Angiogenesis (Cytokine mediated) o 4: Immunomodulation (Primarily ↑NK-Cell Activity)

  10. Overview of Approaches to Chemotherapy: Novel Chemotherapeutic Approaches: o Biological Response Modifiers: § Interferons: • Amplifies Cytotoxic Activity of the Immune System→ ↑NK, ↑T-Cell, ↑Macrophage Activity • Inhibits Cell Proliferation • AltersAntigen Expression on Tumour & Immune Cells § Interleukin-2: • In Vitro – Used to Stimulate Lymphocyte Proliferation & Cellular Immunity against an Introduced Tumour-Specific Antigen o Resultant Lymphocytes are Re-Infused into the Patient → Attack Tumour o Monoclonal Antibodies § Antibodies are Directed against Tumour-Cell Antigens → Lyses Tumour Cells Directly § Or, are Directed against Tumour-Cell Secretions → Denies tumour of Growth Factors

  11. Overview of Approaches to Chemotherapy: GENERAL SIDE EFFECTS: • Alopecia – (Hair Loss) • Nausea/Vomiting • Blisters, Sores • Myelosuppression • Impaired Healing • Stunted Growth (Children) • Organ Toxicity (Heart, Nervous System, Liver, Kidneys)

  12. Overview of Approaches to Chemotherapy: SPECIFIC SIDE EFFECTS: Antimetabolites side effects: § Hepatotoxicity Cytotoxic Antibiotics side effects: o Bleomycin: § Significant Cardiotoxocitity → Tachycardia, Arrhythmias, Hypotension, Pericardial Effusion, Congestive Heart Failure) Plant Alkaloids side effects: eg Vinca Alkaloids – Vincristine: § Neurotoxicity because it inhibits the microtubules needed for Axonal NT-Transport Thalidomide side egffects: o Severe Foetal Malformation (DO NOT take if Pregnant!)

  13. Overview of Approaches to Chemotherapy: GENERAL TREATMENT COMPLICATIONS Drug Resistance: o What is it? § Cells acquire mutations which provide resistance to treatment drugs o How can we get around this? § Multi-Drug approach § Change treatment Timeline → Reduce Adaptation Tumour Sanctuaries: o What is it? § Tumour cells are Inaccessible to Drugs due to: • Encapsulated Tumour • Quiescence (Ie: Non-dividing) o How can we get around this? § Radiotherapy § Surgery

  14. Overview of Approaches to Chemotherapy: Dose Exhaustion: o What is it? § Patient has reached the Maximum Therapeutic dose – (Any higher → Toxicity) § → Remaining cells re-establish malignancy o How can we get around this? § Multi-Drug Therapy § + Surgery/Radiotherapy Myelosuppression: o What is it? § Under-Proliferation of Myeloid Cells Neutrophils/Macrophages/Granulocytes/RBCs) o How can we get around this? § Stimulation of Bone Marrow by Growth Factors → Promote blood cell production

  15. CHEMOTHERAPY DRUGS:CYTOTOXIC DRUGS Alkylating Agents: o Background Info: § (Note: Alkylating agents are Pro-Drugs → Activated to Highly- Reactive free-radical substances) § (Note: Liver cells have natural protection against alkylating agents since they possess Inactivating Enzymes However, Tumour cells tend to accumulate the toxic metabolites) o Phase: § Phase Non-Specific o Goal: § Disrupts DNA Replication (S-Phase) & Transcription (All Phases) in Rapidly-Dividing Cells o Classical Agents: § Cyclophosphamide – (Nitrogen Mustards) § Cisplatin – (Alkylation-like Drugs) § Nitrosureas

  16. CHEMOTHERAPY DRUGS:CYTOTOXIC DRUGS Indications: § Lymphomas (Hodgkin’s & Non-Hodgkin’s) § Chronic Lymphocytic Leukaemia § Ovarian/Breast/Testicular/Cervix/Bladder/Endometrial Cancers § (Also used as an immunosuppressant in Rheumatoid Arthritis) Mechanism of Action: § Forms Cross-Links Within/Between DNA Strands → Impairs Replication & Transcription:→ Forces Cell to ‘Cut Out’ & Repair these errors → Causes Strand-Breaks to occur→ Non-Homologous Joins (Highly Error- Prone) → Potentiates further errors →→APOPTOSIS § Certain tumours have mutated repair proteins, & are very sensitive to alkylating agents) Side Effects: § *Myelosuppression (& Immunosuppression) § GI Disturbances § (Rare: Leukaemia, Infertility)

  17. CHEMOTHERAPY DRUGS:Antimetabolites: Phase of action: § S-Phase Specific – (Ie: Impairs DNA Synthesis) § (Note: Also affects RNA Synthesis & therefore impedes Housekeeping functions too) Goal of therapy: § Provide cells with False Nuclear Substrates → Interferes with DNA Synthesis 3 Types: 1: Folate Antagonists: • Classical Agent: o Methotrexate • Mechanism of Action: o Inhibits Dihydrofolate-Reductase (A folate-dependent enzyme): § → Interferes with Purine Synthesis (Adenine & Guanine) § → Interferes with Thymidylate Synthesis (Thymine) o → Therefore interferes with DNA Synthesis • Indications: o Acute Lymphoblastic Leukaemic (Children) o Choriocarcinoma (Placental Cancer) o Lymphomas • Side Effects: o Myelosuppression (& Immunosuppression) o GI Disturbances

  18. CHEMOTHERAPY DRUGS:Antimetabolites: 3 Types: 2: Pyrimidine Analogues: • Classical Agent: o Fluorouracil • Mechanism of Action: o Inhibits Thymidylate Synthase: → Interferes with Thymidylate Synthesis (Thymine) o Is a Pyrimidine Analogue → Gives rise to Fraudulent Nucleotides: § Cytosine § Thymine • Indications: o Cancers of the GIT (Upper GI/Gastric/Colorectal) o Breast Cancer • Side Effects: o Myelosuppression (& Immunosuppression) o GI Disturbances

  19. CHEMOTHERAPY DRUGS:Antimetabolites: 3: Purine Analogues: • Classical Agents: o Mercaptopurine o Azathioprine (Metabolised to Mercaptopurine) o 6-Thioguanine • Mechanism of Action: o Is a Purine Analogue → Gives rise to Fraudulent Nucleotides: § Adenine § Guanine • Indications: o Leukaemias • Side Effects: o Myelosuppression (& Immunosuppression) o Hepatotoxicity

  20. CHEMOTHERAPY DRUGS:Cytotoxic Antibiotics Background: § Cytotoxic antibiotics are a widely used group that mainly produce their effects through direct action on DNA Phase of action: § S-Phase Specific – (Ie: Impairs DNA Synthesis) Goal of therapy: § Directly Damages DNA →Disrupts DNA Replication/Transcription & Produces Free Radicals Classical Agents: § Doxorubicin § Dactinomycin § Bleomycin § (Mitomycin-C)

  21. CHEMOTHERAPY DRUGS:Cytotoxic Antibiotics: Indications: § Doxorubicin–Acute Leukaemias, Hodgkin/non-Hodgkin Lymphomas, Breast/Ovarian Cancer § Dactinomycin – Paediatric Cancers, Rhabdomyosarcoma, Soft-Tissue Sarcomas, Uterine Cancer § Bleomycin – Germline Cancers Mechanism of Action: § Some insert themselves between pairs in DNA → Prevent/Disrupt Replication → Apoptosis § Some bind to RNA → Prevent/Disrupt protein Synthesis →Cell dies § Some Degrade DNA by Blocking Topoisomerase → Causes DNA Breaks & Inhibits Relegation → Apoptosis § Some Generate Free-Radicals → Directly destroy DNA →Apoptosis

  22. CHEMOTHERAPY DRUGS:Cytotoxic Antibiotics Side Effects: § Fever/Allergies/Rash § Myelosuppression § Hair Loss § GI Upset § (Bleomycin – Significant Cardiotoxocitity → Tachycardia, Arrhythmias, Hypotension, Pericardial Effusion, Congestive Heart Failure)

  23. CHEMOTHERAPY DRUGS: THE END THANK YOU VERY MUCH

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