PCC2 Neoplastic Diseases - Chemotherapy

Chemotherapy Treatment of disease using chemical substances. Stages of the cell cycle - G0 - Resting phase where cells perform a pre-programmed role or specialised function. - It is not involved in the cell growth/division cycle - Cells in this phase are generally refractory to chemotherapy - Interphase encompasses G1, S and G2 = cell proteins and RNA are synthesised, including the enzymes required for synthesis of DNA Stages of the cell cycle - G1,S,G2 (Inter- - Synthesis (S) = cell produces a 2nd phase) copy of its DNA - G2 = DNA synthesis has stopped, but RNA and protein synthesis continue and where the microtubular precursors of the mitotic spindles are produced. Stages of the cell cycle - M (mitosis) When the cell divides after segregation of the DNA producing a copy (daughter) of the original cell. What happens to the cell after mitosis has been completed ? - Cell may enter the resting phase or - Start a new cycle of cell division 1. Having an effect only at a specific point in the cell cycle (e.g., only during mitosis) - Phase specific drugs Chemotherapy agents cell cycle classifi2. Having an effect anywhere in the cell cation cycle EXCEPT G0 - Phase non-specific drugs 3. Affecting cells at any point in the cell 1/9 cycle INCLUDING G0 - Cycle non-specific drugs The proportion of cells in the cycle and at rest. What is the growth fraction ? High growth fraction = more cells in the What does it mean for a tissue to have a cell cycle high growth fraction ? - They are more responsive or susceptible to chemotherapy. What does it mean for a tissue to have a Low growth fraction = fewer cells in the low growth fraction ? cell cycle. Chemotherapy is hypothesised to kill a constant proportion or percentage of cancer cells every time it is given. Log kill hypothesis - Necrotic centre - Outer layers - Hypoxic centre Describe the structure of the layers on a solid tumour ? Layers on a solid tumour - Necrotic cen- All the cells are dead or dying due to a tre lack of blood supply/nutrients. - Have invasive potential - Drugs can get to these cells because Layers on a solid tumour - Outer layers they have a good blood supply and source of nutrients including oxygen, so they can divide. - Blood/nutrient supply is not sufficient to allow growth but, sufficient to prevent cell death. - Cells are not exposed to chemotherapy 2/9 during initial treatment - When cells are exposed to chemotherLayers on a solid tumour - Hypoxic cenapy they may be resistant to the tre chemotherapy used previously (acquired resistance) = change in treatment may be required. The cancer cell numbers are below the What does it mean for cancer cells to be detectable level. 'in remission' ? - can be referred to 'disease free' - Alkylating and platinum based (platins) agents - Antimetabolites What groups can chemotherapy be clas- Plant alkaloids / topoisomerase insified into based on their MOA's and the hibitors type of drug they are derived from ? - Anthracyclines / antitumour antibiotics These are all Cytotoxic drugs - Cross-link DNA strands = results in breaks in the DNA strand that cannot be repaired and formation of DNA adducts. - Interferes with transcription and DNA Explain the pharmacology of Alkylating replication (S Phase) agents ? - There is a block at G2 = subsequential apoptotic cell death Examples of Alkylating agents - Platins ? - Carboplatin - Cisplatin - Oxaliplatin What 'platin' is the least renally toxic ? Carboplatin Cisplatin 3/9 - Platinum compound - Has low myelotoxicity Cisplatin MOA - Work similarly to anthracyclines = interacts directly with the nucleotide bases in the DNA of the cancer cell. Cisplatin side effects Severe nausea and vomiting - Consist of strong Pt-N bonded ligands and weaker Pt-LG links (LG represents a leaving group) - This enables the N atoms in the nucleotide bases to form strong N-Pt links with the accompanying loss of a chloride (Cl-) leaving group Describe the chemical structure of Platins ? - Leaving group in Carboplatin and Oxaliplatin = dicarboxylate anion (-OOC-X-COO-) - Platinum bonds to neighbouring bases in the DNA, preventing successful replication of the DNA molecule - Interferes with nucleoside (cytosine, uracil) inclusion in RNA or DNA or - Inhibiting enzymes involved in DNA synthesis (it is structurally similar to naturally occurring metabolites) Explain the pharmacology of Antimetabolites ? - Acts on the S phase Compete with or substitute for normal metabolites: - Folate antagonists = e.g., methotrexate - Purine analogues = e.g., mercaptopurine 4/9 - Pyrimidine analogues = e.g., 5-Fluorouracil e.g., Vincristine - A plant alkaloid Used to treat: - Leukaemia - Multiple myelomas - Lymphomas - Solid tumours Vinca-alkaloid - Block formation of the mitotic spindle - Prevents assembly of tubulin dimers and cell division Vinca-alkaloids MOA Intravenously How are Vinca alkaloids administered ? - Can be fatal if administered intrathecally - Irinotecan - Topotecan Examples of topoisomerase I inhibitors ? MOA of Topoisomerase I inhibitors ? - Inhibit topoisomerase I - Prevent the supercoiling of the DNA, needed to allow the DNA to fit the available space 5/9 - Inhibits topoisomerase II - Cause irreversible double-strand breaks in DNA MOA of Etoposide What molecule is the Anthracyclines structure based on ? Anthraquinone 1. Intercalation = drugs inserts itself between the base pairs of the DNA preventing replication or the production of Explain the pharmacology of AnthracymRNA clines / anti-tumour antibiotics ? 2. Bind to DNA = causing single or double strand breaks by forming free radicals - An anthracycline Daunorubicin Describe the chemical structure of Daunorubicin ? - Flat, plate like molecules - Neatly slide between the strands of DNA, bind strongly to each strand - This delays the DNA replication process Varies depending on the exact number What does the log P and binding ability of H-bond donor and acceptor groups of anthracyclines depend on ? present in the molecule. Depletes asparagine (amino acid required by some cancer cells) Asparaginase MOA - They are cytokine = act as immunomodulators 6/9 How can Interferons be used in cancer - They are antiproliferative + have anti-tuchemotherapy treatment ? mour activity Hormones - Glucocorticoids They are lympholytic = commonly used for leukaemias and lymphomas. Hormones - Tamoxifen MOA Blocks oestrogen from binding to receptors of oestrogen sensitive breast cancer Hormones - GnRH analogues MOA e.g., Goserelin - inhibit the release of pituitary LH and FSH = reduces testosterone levels in men / oestradiol levels in women Hormones - Aromatase inhibitors MOA Block oestrogen production from non-adrenal gland sources. MOA of Monoclonal antibodies used in cancer chemotherapy treatment ? Selectively bind to receptors overexpressed on tumour cells inhibiting their proliferation. Cell proliferation An increase in the number of cells as a result of cell growth and cell division. What are the 2 main adjunctive drugs used in cancer chemotherapy treatment ? - Folinic acid = e.g., leucovorin - Mesna (sodium-2-mercapoethane) - Fluorouracil - Methotrexate What chemotherapy drugs is Folinic acid often used in combination with ? - To enhance the anticancer effects with fluorouracil Why is Folinic acid used as an adjunctive - To help prevent or lessen side effects with methotrexate drug ? 7/9 Fluorouracil when given alone = stays in the body for only a short time Given in combination with Folinic acid: - Folinic acid enhances the binding of fluorouracil to an enzyme inside the cancer Explain why Folinic acid is given in com- cell bination with Fluorouracil ? - Fluorouracil stays in the cancer cell longer and exerts its anti-cancer effect on the cells - Severity of side effects are increased when used in combination - Methotrexate competes with folic acid in cancers cells = folic acid deficiency in cells leads to cell death Explain why Folinic acid is given in combination with Methotrexate ? - Methotrexate also affects normal cells causing side effects = low white, red, platelet blood count/ hair loss/ mouth sores/ difficulty swallowing/ diarrhoea/ liver, lung, nerves and kidney damage Using Folinic acid: - Reverses the effects - Folinic acid provides a source of the active form of folic acid for the body's cells - Administered 24hrs after methotrexate is given = gives it a chance to exert it anti-cancer effects Capecitabine Prodrug of Fluorouracil 8/9 Alkylating agents: - Ifosfamide - Cyclophosphamide They are oxazaphosphorine agents What chemotherapy drugs is mesna used in combination with ? What is the issue associated with the use It may produce haemorrhagic cystitis as of Ifosfamide and Cyclophosphamide ? a dose limiting toxicity. - Both are pro-drugs How are Ifosfamide and Cyclophos- Undergo metabolic activation via liver phamide converted to their active/inacP-450 microsomes to both active and intive metabolites ? active metabolites 9/9