cancer drugs.docx

Key features of disease Cancer characterised by uncontrolled multiplication and spread of abnormal cells. In 2016, cancer research UK predicted that half of people born after 1960 would be diagnosed with some form of cancer. Responsible for 30% of deaths. Lung, bowel, breast and prostate most common...

Key features of disease Cancer characterised by uncontrolled multiplication and spread of abnormal cells. In 2016, cancer research UK predicted that half of people born after 1960 would be diagnosed with some form of cancer. Responsible for 30% of deaths. Lung, bowel, breast and prostate most common forms. Tends to be a disease of old age as mutations accumulate. How is a cancer cell formed? Normal cell becomes cancer cell following one or more mutations. Mutations can be random, inherited, acquired through carcinogens e.g. pollution, tobacco, asbestos, UV radiation. Can be caused by epigenetic factors Genetic changes Protooncogenes which are involved in cell division, apoptosis and differentiation become converted by viruses or carcinogens to become oncogenes which induce malignant changes in cells. Tumour suppressor genes become inactivated. Loss of function of these genes becomes key to carcinogenesis. Properties of cancer cells Hallmarks of cancer: Uncontrolled proliferation De-differentiation and loss of function Invasiveness Metastasis From lecture: Abnormal growth with self-sufficient growth signalling and insensitivity to anti-growth signals Immortalisation – normal cells divide 60 times before apoptosis and cancer cells exceed this. Invasion and metastasis – travel to nearby tissues Evasion of apoptosis Sustained angiogenesis – cancer cells need glucose to fuel rapid growth therefore need increased blood supply. They release angiogenic factors to increase vascularisation. DNA instability – increased rate of mutation Tumour promoting inflammation and avoiding immune destruction General principles of treatment: Three main approaches to treatment: Drug treatment – Chemotherapy and immunotherapy, biologicals Surgical excision Irradiation Chemotherapy: Induce cell cytotoxicity. Drugs inhibit cell division (anti-proliferative) Cancer chemotherapy can only target cells within a tumour that are still continuously diving which may form as little as 5% of solid tumours. Cancer treatments generally non-specific as they only target one aspect of cancer cells – cell division. They do not have an inhibitory effect on invasiveness, loss of differentiation of tendency to metastasise. Generally act in S phase. Intention is to distrupt DNA replication and damage DNA in order to induce apoptosis. As target is cell division drugs affect rapidly dividing cells which can include normal tissue such as hair and blood cells. Cytotoxicity proportional to total drug exposure. Effectvieness of anti-proliferative chemotherapy linked to rate of cell division. Resistance can be primary or acquired and accumulates as treatment continues. Due to Darwinian evolution. Resistance cells survive and reproduce, leading there to eventually be regrowth of a resistant tumour. General side effects: Lots of side effects of chemotherapy as drugs are not specific to cancer cells. bone marrow toxicity (myelosuppression) with decreased leukocyte production and thus decreased resistance to infection; impaired wound healing ; loss of hair (alopecia); damage to GI epithelium (including oral mucous membranes); depression of growth in children; sterility ; teratogenicity ; carcinogenicity – because many cytotoxic drugs are mutagens. tissue necrosis if it leaks into surrounding tissue during IV infusions. Rapid cell destruction also entails extensive purine catabolism, and urates may precipitate in the renal tubules and cause kidney damage. Finally, in addition to specific toxic effects associated with individual drugs, virtually all cytotoxic drugs produce severe nausea and vomiting, an ‘inbuilt deterrent’ now thankfully largely overcome by modern antiemetic drug prophylaxis. Types of chemotherapy and combination of treatments Curative – cure the cancer by killing all cancerous cells Adjuvant – given in combination with other treatments to cure cancer or prevent it coming back. Given after surgery or radiation. Neoadjucant – given in combination but before surgery/radiotherapy to shrink tumour Palliative – non-curative used for prolonging life and reducing symptoms Maintenance – to keep cancer away after patient has gone into remission. Regimens of more than one drug used because: There is improved cell cytotoxicity Heterogenous tumour cell populations are killed It reduces the development of resistance Monotherapies have been shown to be ineffective in clinical trials Drug treatments Drug class and example Mechanisms of action Side effects Other points Alkylating agents - cyclophosphamide Addition of alkyl groups to nucleotide bases in DNA. Forms covalent cross links between nucleotide bases after formation of a carbonium ion. This disrupts the normal structure of the DNA molecule so it interferes with functions such as replication and transcription. Consequence: cell cycle is disrupted therefore leads to apoptosis of cancer cells See general Treats blood cancers. Given oral or IV. Generally used in combination as it is less specific. Inactive until it’s metabolised in the liver by p450. Platinum compounds – cisplatin, carboplatin oxaliplatin Similar to above. Platinum based ages become activated in aqueous environment of cells, causes DNA crosslinking though covalent bonding to nitrogenous bases. TOXIC. Nephrotoxic therefore needs hydration and diuresis. SEVERE N+V Used for germ cell, testes, bladder, ovary, head and neck and other difficult to treat cancers. Antimetabolites – includes folic acid antagonists (methotrexate), purine antagonists (thioguanine, pentostatin, mercaptopurine) and pyrimidine antagonists. Interfere with normal cellular processes by mimicking essential structures within the cell. Affect de-novo synthesis of nucleic acid precursors. Methotrexate – antifolate analogue Inhibits thymidine and purine biosynthesis by inhibiting dihydrofolate reductase (converts precursors of purines. 5-fluorouracil (5FU) – pyrimidine antagonist. Binds to thymidylate synthetase – inhibits DNA synthesis. Overall: prevents nucleic acid synthesis, resulting in cell death Methotrexate – depression of bone marrow and damage to GI epithelium. nephotoxic Act in S phase. Methotrexate – choriocarcinoma, acute lympocytic anaemia. 5FU - solid tumours of breast, ovary, oesophagus, colon, skin. Topoisomerase inhibitors Top1 – Irinotecan Top2 - Etopside Normal function of topoisomerase: Relax DNA conformation to allow replication, transcription and translation through ligation. Top1 cuts single strand and allows other strand to pass through to open it up, Top 2 cuts through both strands and allows whole strand to pass through – quickly relaxes supercoiling. Irinotecan – stabilises DNA-toposiomerase I complex, preventing continuation of normal DNA replication. Leads to apoptosis. Etopside – stabilises top II DNA complex. N+V, diarrhoea, myelosuppression, hair loss. Fewer unwanted effects than other anticancer drugs. Irinotecan – IV and for colon, lung, cervix. Etoposide plant derived and given either orally or IV, is used in treatment of Kaposi’s sarcoma, Ewing's sarcoma, lung cancer, testicular cancer, lymphoma, nonlymphocytic leukemia, and glioblastoma multiforme. DNA binding agents – Anthracyclines – doxorubicin, daunorubicin, epirubucin. They were originally designed as antibiotics Direct action on DNA – intercalate between DNA strands which inhibits DNA repair – leads to fragmentation and aopoptosis. Inhibits DNA and RNA synthesis. Stabilises structure after cut with topoisomerase II. Alopecia, N+V, cardiotoxicity, leukopenia (low WBCC), stomatitis (mucous membrane inflammation). Local necrosis by doxorubicin Administered IV. Breast, ovarian, gastric, lung, lymphomas. Microtubular inhibitors: vinka alkaloids – vincristine, vinblastine Prevent microtubule assembly by binding to beta tubulin and inhibiting polymerisation into microtubules, therefore prevents formation of mitotic spindle. Off-target effects = inhibition of cellular functions that require microtubules e.g. phagocytosis, chemotaxis, axonal transport. Neurotoxic – mainly causes paraesthesisa, abdo pain, weakness Administered IV vinblastine – testicular and Hodgkin’s disease. Vincristine – breast cancer, lymphoma. Leukaemia. Microtubular inhibitors: taxanes – paclitaxel, docetaxel Bind to beta tubulin and antagonises depolymerisation of microtubules -halts mitosis by ‘freezing’ it. Bone marrow suppression, cumulative neurotoxicity Blocked in G2/M phase. Given Iv due to poor solubility. Hypersensitivity, needs pre-treatment with antihistamines or corticosteroids. Small molecule inhibitors: tyrosine kinase inhibitors – imatinib, dastinib, erlotnib, sunitnib Receptor tyrosine kinase binds to ATP and transfers phosphates to tyrosine residues, which act as docking sites for other downstream signalling proteins. Common cancer mutation: mutation in receptor tyrosine kinase which leads to constitutive phosphorylation and signalling. SMIs such as imatinib bind to ATP binding site intracellularly and on cell membrane and prevent continuation of downstream signalling pathways. GI symptoms, fatigue, headaches, rashes Chronic myeloid leukaemia and gastro intestinal stromal tumours not susceptible to surgery. Given orally. Resistance is a problem due to common mutation in kinase gene in which case other TK inhibitors such as dasatinib can be used. Endocrine therapy for breast cancer: Aromatose inhibitors – Anastrozole, letrozole Selective estrogen receptor modulators - tamoxifen Selective estrogen receptor downregulators - fulvestrant Some breast cancers express oestrogen receptors which grow in response to oestrogen binding due to upregulation of genes e.g. growth factors. Therefore, reduction of oestrogen is a therapeutic priority in these cases (60-80%) Aromatose inhibitors – inhibit aromatose – responsible for conversion of testosterone to oestrodiol therefore reduces production of oestrogen. SERMS – antagonise oestrogen receptor – competitive antagonist. SERDs – full antagonist and can cause degradation of ER. Bind ER causing immobilization and instability of the ER-SERD complex and facilitate ER degradation by the ubiquitin-proteasome pathway. Similar to unwanted symptoms in menopause – hair thinning and loss, low energy, dry skin, vaginal dryness, pain and polyps, hot flushes and sweats. Tamoxifen – oral anti-oestrogenic in breast cells. Partial agonist in endometrium, bone and CV system. Cardioprotective effects (extra beneficial in women over 50) as it protects LDL against oxidative damage.