Cancer Chemotherapy Lecture (PHTH1011 2023) PDF

Cancer Chemotherapy Lecture by: Zolia Nelson (Ms.) Course: PHTH1011 2023 Objectives At the end of this lecture, students should have an understanding of: ⚫ Cancer and its development ⚫ Drugs used in cancer chemotherapy. Cancer/ Malignant tumours/ Neoplasms The development of abnormal cells within...

Cancer Chemotherapy Lecture by: Zolia Nelson (Ms.) Course: PHTH1011 2023 Objectives At the end of this lecture, students should have an understanding of: ⚫ Cancer and its development ⚫ Drugs used in cancer chemotherapy. Cancer/ Malignant tumours/ Neoplasms The development of abnormal cells within the body due to mutations in the DNA of normal cells. ⚫ Characterized by uncontrolled proliferation and spread of the abnormal cells. ⚫ Normal cells generally live for a given time and then die. ⚫ Apoptosis plays a major role in cancer development. ⚫ Apoptosis ⚫ Programmed cell death Role: ⚫ Facilitates proper development ⚫ Destroys cells that would affect the integrity of an organism if allowed to proliferate. In apoptosis, both extrinsic and intrinsic signals play a role in initiating the process. Apoptosis and Cancer ⚫ Mutations in genes and pathways that regulate apoptosis can promote the development of cancer cells. ⚫ Example, p53 ⚫ Cancerous cells lack the components that instruct them to stop dividing and to die. Types of Tumour Malignant Benign Uncontrolled proliferation Uncontrolled proliferation Non-invasive vs Very Invasive No regrowth De-differentiation Do not metastasize Metastasize Causes of Cancer Mutations in genes that facilitates normal physiological function. These occur due to factors such as: ⚫ Errors during cell division ⚫ Harmful substances in the environment ⚫ Hereditary The risk of cancer development increases with increased age. Causes of Cancer Carcinogens that stimulates cell proliferation Referred to as tumour promotors. E.g. Estrogen – excess levels increases the risk of developing endometrial cancer. Cancer causing viruses E.g. Epstein-Barr virus, human papilloma virus and hepatitis B virus. Principles of Cancer Chemotherapy ⚫ Aims at producing total tumour cell kill, with the elimination of all neoplastic cells. ⚫ Early treatment is critical because the greater the tumour burden, the more difficult it is to treat the disease. Principles of Cancer Chemotherapy ⚫ Achievement of a therapeutic effect often involves drugs that have a narrow therapeutic index (TI); it may require combinations of several drugs with different mechanism of action, etc. ⚫ A therapeutic effect is usually achieved by killing actively growing cells, which are most sensitive to this class of agent. Cancer Chemotherapy ⚫ Vinca alkaloids ⚫ Folate antagonist – Methotrexate ⚫ Alkylating agent → Nitrogen mustards & Nitrosoureas Vinca alkaloids Vincristine, vinblastine, vindesine, vinrosidine Derived from the periwinkle plant (Catharantus roseus) Mechanism of Action Effects occurs during mitosis of the cell cycle. Binds to β-tubulin and prevents its ability to polymerize with α-tubulin into microtubules. ⚫ Prevents spindle formation in the dividing cells ⚫ Mitotic arrest at metaphase ⚫ Interference with chromosome segregation Administered intravenously (IV) Liver metabolism and biliary excretion Toxicity Alopecia generally occurs with all drugs from this class. Cellulitis may also occur. Nausea and bone marrow depression Vincristine Acute lymphocytic leukemia (ALL), Hodgkin lymphoma, non-Hodgkin lymphomas, Wilms' tumor, neuroblastoma. Metabolized in the liver by CYP450 3A4 Excretion 80% of an injected dose of vincristine sulfate is excreted via feces. 10 - 20% is excreted via urine. Vincristine PPB – 75% Half-life – Triphasic 5 minutes, 2 hr and 85 hr Adverse effects Mild myelosuppresive activity, neurotoxic, paraesthesias, abdominal pain and weakness Vinblastine Breast cancer, testicular cancer, neuroblastoma, Hodgkin's and non-Hodgkins lymphoma. Half-life – Triphasic 35 min, 53 min and 19 hrs PPB – 98-99% Metabolized in the liver by CYP450 3A4 to form Desacetylvinblastine. Biliary excretion. Toxicity – Leukopenia, reversible hair loss, neurotoxic (less neurotoxic than vincristine). Folate Antagonist Role of folate in the DNA synthesis Folate are required for the synthesis of purine nucleotides and thymidylate. Both precursors are essential for DNA synthesis and cell division. Folate is converted to tetrahydrofolate (FH4 ) in 2 steps. This conversion is catalyzed by the dihydrofolate reductase. DHFR Folate → FH2 → FH4 FH4 donates methyl group FH2 is generated DUMP DTMP Thymidylate synthase Methotrexate Folate antagonist – well known antimetabolite Mechanism of Action Inhibits the enzyme dihydrofolate reductase (DHFR) which prevents the formation of FH4. This action leads to indirect inhibition of DNA synthesis. Methotrexate has a higher affinity for DHFR than FH2 Methotrexate DHFR reduced Folate → FH2 → FH4 FH4 donates methyl group FH2 is generated DUMP DTMP Thymidylate synthase ⚫ Administered : Orally, Intravenously, intramuscularly, intrathecally. ⚫ Low lipid solubility ⚫ Metabolized to polyglutamate derivatives – retained for weeks or month in the cell. ⚫ Cellular uptake occurs via folate transport system. ⚫ Excreted mainly in the urine. 8.7-26% of an intravenous dose in the bile. Toxicity GIT epithelial damage and GIT disturbances, cirrhosis of the liver. Myelosuppressive, producing severe leukopenia, bone marrow aplasia, and thrombocytopenia. Skin rash, alopecia. ⚫ “Folinic acid (leucovorin) rescue technique” Indication Childhood acute lymphoblastic leukemia, Burkitt’s lymphoma and other non-Hodgkin lymphomas, lung carcinoma, and head and neck carcinomas Alkylating agent All alkylating agents target N-7 of guanine. Binds covalently to DNA. Binding to N-7 of guanine leads to abnormal base pairing, depurination (followed by DNA chain scission), ring cleavage, and DNA strand crosslinks. Eventual death of cell. Alkylating Agent - Nitrogen mustards ⚫ Cyclophosphamide, bendramustine, estramustine (chlorambucil + estrogen) Mechanism of action Cross-links DNA leading to defective DNA and abnormal function. ⚫ Cyclophosphamide Metabolized in the liver by CYP3A4 to the active form. Forms 4-hydroxycyclophosphamide, which in turn is nonenzymatically cleaved to aldophosphamide. The aldophosphamide cleaves to Phosphoramide mustard which is the cytotoxic metabolite produced from cyclophosphamide. The metabolite Acrolein causes haemorrhagic cystitis. Administered orally and intravenously Half-life – 4-7 hrs Adverse effects Bone marrow depression, hemorrhagic cystitis, nausea and vomiting. Indications: Malignant lymphomas, leukemias, multiple myeloma, breast and ovarian carcinoma, and small cell lung cancer. Applied in combination therapy. Alkylating Agent - Nitrosoureas ⚫ Lomustine, carmustine, semustine, streptozotocin Mechanism of action Forms inter-strand cross links in DNA leading to defective DNA and abnormal function. Metabolized in the liver. ⚫ Able to cross the blood-brain barrier. Hence are used in brain tumours and meninges. ⚫ Lymphoma and multiple myloma Adverse effect Bone marrow depression