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 Methotrexate, 5-fluorouracil, cytosine arabinoside, 6- mercaptopurine Analogues of normal metabolites Function in 3 ways Substitution Competition for catalytic site Competition for regulatory site 1) Antimetabolites:

antimetabolites serine hydroxymethyltransferase (SHMT) thymidylate synthase (TS) dihydrofolate reductase (DHFR)

methotrexate choriocarcinoma Folic acid antagonist Dihydrofolate reductase Reduced synthesis of A & G Cytotoxicity reversed by leucovorin

Classes of chemo agents Bacterial or fungal derivatives that affect cellular processes like DNA or protein synthesis 2) Antibiotics 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 substitute alkyl groups for H atoms forming DNA adducts 2 functional groups which can form inter / intra strand crosslinks in DNA 3) Alkylating agents

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. 3) Alkylating agents - examples 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 Vinca alkaloids like vincristine, vinblastine & paclitaxel, prevent tubulin polymerisation resulting in mitotic arrest 4) Plant alkaloids 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