Anti-cancer drugs Flashcards
Classification?
- Anti-metabolites drugs (Methotrexate, premetrexed, pralatrexate and 5-Fluorouracil)
- Anti-cancer antibiotics (Anthracyclines and Bleomycin)
- Alkylating agents.
(Cyclophosphamides, Ifosfamine and Nitrosoureas) - Anti-cancer drugs of plant origin (Vinca Alkaloids, topoisomerase 1 inhibitors, topoisomerase 2 inhibitors and Tanaxes).
- Cellular signalling modifiers.(Anti-angiogenic drugs, monoclonal antibodies and tyrosine kinase inhibitors).
Explain the pharmacology of Methotrexate, premetrexed and pralatrexate?
The general action of the anti-metabolite drugs is to prevent the synthesis of purines/pyramidines or to act as competitive agents in the process of their synthesis. They are specific for the S-phase of the cell growth, making them cell cycle specific.
MTX functions to inhibit the activation of folic acid (acts as antagonist) by inhibiting Dihydrofolate reductase which converts folic acid to its active form “Tetrahydrofolic acid”.
Premetrexed shares the same pharmacological actions as MTX, but has the additional function of inhibiting “Thymidine synthase”, preventing nucleotide synthesis.
Phk: Variable absorption at low dose, varied routes of administration (IV,IM and intrathecal as it does not cross BBB.) In the skin MTX may be hydroxylated at the 7th position to form “7-Hydroxymethotrexate”, which is a less soluble form that can cause “crystalluria”. Good hydration and alkylation of the urine is required to sustain dialysis and prevent kidney damage.
Therapeutic uses: Breast cancer, acute lymphocytic leukaemia, bladder cancer and carcinomas of the head and neck.
Adverse effects include “Haematological and GI toxicity”, which can be avoided by folic acid and B12 supplementation alongside the administration of the premetrexed and pralatrexate. Corticosteroid topical application before the administration of the anti-metabolites will prevent cutaneous reactions.
Explain the pharmacology of the anti-metabolite 5-FU?
5-FU is a “pyramidine analogue”. Its main function is to inhibit the interaction of “Deoxyuridylic acid” with “Thymidylic acid” to form the nucleotide thymine. This leads to a “Thymidine - less death” in the neoplastic cells. The drug acts in the s-phase of cell growth, making it cell cycle specific.
PhD: 5-FU itself cannot exert a anti-neoplastic effect. After passing through a carrier transport mediated system, intracelluarly it is converted into “5-fluoro-deoxyridine-monophosphate” which competes with “deoxyuridine monophosphate” to inhibit the “thymidylate synthase”. This results in a low thymidine production, leading to a “Thymidine less death”.
phK: 5-FU causes severe GI toxicity if administered orally, required IV administration or topical administration in the cases of skin cancer. It is metabolised in the liver into “Fluoro-β Alanine”, which is excreted in the urine.
Explain the pharmacology of the “Anti-cancer antibiotics” known as “Anthracyclines”.
Anthracyclines comprise of “Doxorubicin” and “Daunorubicin”. Doxorubicin is the hydroxylated analogue of the “Daunorubicin”. They function to induce cytotoxic effects in the neoplastic cells through the formation of “Doxorubicin derived free radicals” which leads to “lipid per oxidation” in tumour cells. (DNA cessation via oxidative processes).
phK: IV administration due to inactivation in the GIT after oral administration. Extensive distribution, plasma protein bound. Extensive hepatic metabolism and excretion in the biliary system.
The main adverse effect is “dose-dependent cytotoxicity”, which is thought to be the result of free radicals/lipid per oxidation.
Explain the pharmacology of the anti-cancer antibiotic “Bleomycin”.
Bleomycin causes oxidative DNA cessation by forming a complex with DNA and Fe2+. This is oxidised to DNA-Bleomycin-Fe3+, the liberated electrons from the oxidation reaction form “Superoxides” which attacks phophodiester bonds of the DNA.
phK: Varied methods of administration, most of the parent drug is lost in the urine.
Adverse effects: Pulmonary toxicity is the main adverse effect which begins as “rales/coughing” which can progress into a pulmonary fibrosis. Bleomycin inactivating enzyme is high in concentration in the liver/spleen but is in low concentrations within the lungs and skin, which accounts for toxic effects of Bleomycin at these sites.
Explain the pharmacology of the “Alkylating agents” (Cyclophophamide/ifosfamide)
Alkylating agents exert cytotoxic effects by alkylating DNA.
The cyclophosphamide is metabolised into the active compounds “phosphoramide mustard” and “acrolein”. DNA’s interaction with phosphoramide mustard is thought to be the main cytotxic step for the cyclophosphamindes.
phK: Cyclophosphamine is administered orally/IV and ifosfamine is administered via IV. Cyclophosphamide is metabolised in the liver into active and inactive compounds. Ifosfamide is metabolised in the liver. Both drugs renally excreted.
Adverse effects: “Hemorrhagic cystitis” is a unique toxicity which can lead to the development of a bladder fibrosis. It is thought that the toxic metabolites of Ifosfamine and “acrolein” metabolite of cyclophophamide in the urine is thought to cause the toxicity.
Explain the pharmacology of the Alkylating agent “Nitrosoureas” .
There are 2 types of Nitrosoureas “Carmustine” and “Iomustine”. Their key ability to penetrate the CNS makes them a good option for the treatment of brain tumours.
They are alkylating agents and therefore they functoion to alkylate the DNA which lead to inhibition of DNA synthesis, RNA action and eventually synthesis of protein synthesis.
phK: Carmustine has IV administration, Iomustine is administered orally. High distribution due to CNS penetration, renal excretion.
Explain anti-cancer drugs of plant origin?
- Vinca alkaloids and their derivatives - affect the equilibrium between the polymerised and depolymerised forms of the microtubules, thereby causing cytotoxicity. Block mitosis in metaphase (M phase. ADR’s include: Phlebitis or cellulitis, Nausea, vomiting, diarrhoea, and alopecia, myelosuppressant.
- Topoisomerase-1 inhibitors (Camptothecins) – inhibit topoisomerase 1, S-phase specific. ADR’s : nausea, vomiting, alopecia.
- Topoisomerase-2 inhibitors (Podophyllotoxins) - Major target is topoisomerase II. They cause breaks in the DNA inside the cancer cells and prevent them from further dividing and multiplying, leading to death of the neoplastic cells. ADR’s : Vomiting & alopecia, Bone marrow suppression.
- Taxanes - They bind reversibly to the β2-tubulin (ESSENTIAL FOR CELL TRANSPORT AND DIVISION). they promote stabilisation of the microtubules rather than destruction. The overly stable microtubules formed are nonfunctional. This results in death of the cell. ADR’s : Hypersensitivity. Peripheral neuropathy.
Explain the pharmacology of the “Cellular signalling modifiers” ?
- Anti-angiogenic drugs - attaches to and stops vascular endothelial growth factor from stimulating the formation of new blood vessels // epidermal growth factor receptor on the surface of cancer cells and interfering with their growth. Used in the treatment of metastatic colorectal cancer. ADR’s : hypertension, stomatitis, and diarrhoea.
- Monoclonal antibodies – “Trastuzumab” Specifically targets the extracellular domain of the transmembrane human epidermal growth factor receptor protein 2 (HER2) that has intrinsic tyrosine kinase activity. Trastuzumab binds to HER2 sites in breast cancer tissue and inhibits the proliferation of cells that over express the HER2 protein, thereby decreasing the number of cells in the S phase in that tumour. “Rituximab” is a monoclonal antibody directed against the CD20 antigen which is found on the surfaces of normal and malignant B lymphocytes. ADR’s: hypotension, bronchospasm, angio-odema.
- Tyrosine kinase inhibitors - signal transduction inhibitor, used specifically to inhibit tumour tyrosine kinase activity. Used for the treatment of chronic myeloid leukaemia in blast crisis, as well as GI stromal tumour. ADR’s: Fluid retention and oedema. Hepatotoxicity.
