Cancer Detection and Diagnosis Early Cancer May Not Have Any symptoms Pap Test Mammograms Blood tests Prostate-specific antigen (PSA) Carcinoembryonic antigen (CEA) Fecal Occult Blood Test (FOBT) TISSUE BIOPSY

Tumour grading Microscopic examination - - likely behavior - responsiveness to treatment. "grade" a low number grade (grade I or II) refers to cancers with fewer cell abnormalities than those with higher numbers (grade III, IV).

Tumour Staging 1.How large is the tumour, and how far has it invaded into surrounding tissues? 2. Have cancer cells spread to regional lymph nodes? 3. Has the cancer spread (metastasized) to other regions of the body?

Cancer is a multi- step process

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 osteoid 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

References 1) Mol & Cell Biol of cancer by Knowles and Selby Chapters 23,24,25 AND/OR 2) Cancer Biology by RJB King Chapter 13 AND/OR 3) Scientific American (Sept 1996) special issue