Transcript ppt lecture
Cancer therapy - conventional Surgery Radiotherapy Chemotherapy Adjuvant therapies Surgery Advantages: quick & effective; largest no of cures; confirmation of excision Disadvantages: no guarantee of complete removal; critical normal tissues invasion ineffective for metastasis. Electromagnetic radiation intranuclear Xtranuclear Radiotherapy X-ray source Radiotherapy sources Biological effects Rad is the unit of absorbed dose 1 rad =100erg/g Gy (Gray) 1 Gy = 100rads = joule/kg Conformal radiotherapy Advances in imaging techniques E.g. Liver tumours Time, Dose, Fractionation Adjuvant radiotherapy Boron Neutron Capture Therapy Adjuvant radiotherapy Thermotherapy MR-guided laser induced thermotherapy of osteiod osteoma Adjuvant radiotherapy Photodynamic therapy Adjuvant radiotherapy Bioreductive drug adjuvant therapy Harmless prodrug Under certain conditions is converted to a cytotoxic metabolite E.g. AQ4N (alkylaminoanthraquinone N-oxide) Harmless in oxic cells Converted into cytotoxic AQ4 in hypoxic cells combined with radiotherapy or chemotherapy Chemotherapy Works by affecting DNA synthesis and function Classes of chemo agents 1) Antimetabolites: Methotrexate, 5-fluorouracil, cytosine arabinoside, 6mercaptopurine Analogues of normal metabolites Function in 3 ways Substitution Competition for catalytic site Competition for regulatory site antimetabolites serine hydroxymethyltransferase (SHMT) thymidylate synthase (TS) dihydrofolate reductase (DHFR) methotrexate Folic acid antagonist Dihydrofolate reductase Reduced synthesis of A & G Cytotoxicity reversed by leucovorin choriocarcinoma Classes of chemo agents 2) Antibiotics Bacterial or fungal derivatives that affect cellular processes like DNA or protein synthesis Topoisomerase inhibitors Doxorubicin (Adriamycin) Fungal anthracycline that has multiple effects 1) it intercalates within the DNA 2) causes single and double strand breaks and 3) inhibits topoisomerase II. Used against leukaemias, breast, lung and ovarian cancer Classes of chemo agents 3) Alkylating agents substitute alkyl groups for H atoms forming DNA adducts 2 functional groups which can form inter / intra strand crosslinks in DNA 3) Alkylating agents - examples Nitrogen mustard derivatives cyclophosphamide, chlorambucil, melphalan ethyleneimine derivatives thiotepa nitrosoureas BCNU, CCNU alkyl sulphonates busulphan 3) Alkylating agents - examples Cyclophosphamide trade name: Cytoxan® Metabolic activation of cyclophosphamide creates guanine adducts that block cell proliferation Used in combination with methotrexate and 5-FU against several cancers including breast, colon, ovarian and lung cancers. Cisplatin forms adducts at N-7 position of purines creating inter or intrastrand crosslinks that disrupt DNA synthesis. Effective against ovarian and testicular cancers and has minimal effects on the bone marrow Classes of chemo agents 4) Plant alkaloids Vinca alkaloids like vincristine, vinblastine & paclitaxel, prevent tubulin polymerisation resulting in mitotic arrest Taxol (a terpene from yew trees) causes a similar effect by preventing tubulin depolymerisation. Used against testicular and ovarian cancers and leukaemias Drug resistance individual differences in chemosensitivity in cancer patients leads to accruing resistance during treatment. Several genetic factors influence the chemosensitivity of cancer cells, including genes involved in drug uptake and secretion, drug metabolism, DNA repair and apoptosis Hormone therapy Hormone sensitive cancers (Breast cancer in females and prostate cancer in males) are susceptible to deprivation of the corresponding mitogenic hormone. E.g. Treatment of involves either direct inhibition of steroid synthesis : E.g. using either LHRH superagonists or aromatase inhibitors in breast cancer blocking their effects at the target cell level through the receptors: Steroid receptor antagonists block receptor activity. E.g. tamoxifen is an oestrogen receptor antagonist. Problems with hormone therapy include sexual dysfunction (e.g.ovulation), secondary cancers etc