1. Conventional cancer therapy These slides provide an overview of conventional therapies in cancer. These include surgery, radiotherapy, chemotherapy and adjuvant therapies. Dr. Momna Hejmadi, University of Bath N.B. Some images used in these slides are from the textbooks listed and are not covered under the Creative Commons license as yet This resource is Created by Dr. Momna Hejmadi, University of Bath, 2010, is licensed under the Creative Commons Attribution-Non-Commercial-Share Alike 2.0 UK: England & Wales License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/2.0/uk/http://creativecommons.org/licenses/by-nc-sa/2.0/uk/

2. Conventional cancer therapy Cancer detection & diagnosis SurgeryRadiotherapyChemotherapy Adjuvant therapies

3. 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

4. Tumour grading Microscopic examination - - likely behaviour - 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).

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

6. Cancer therapy - conventional Surgery Radiotherapy Chemotherapy Adjuvant therapies

7. Surgery Advantages:  quick & effective;  largest no of cures;  confirmation of excision Disadvantages:  no guarantee of complete removal;  critical normal tissues invasion  ineffective for metastasis.

8. Radiotherapy Radiotherapy sources Radioactive implants (brachytherapy)Radioactive implants (brachytherapy) External source (X-ray or gamma radiation)External source (X-ray or gamma radiation) X-ray source brachytherapy gamma source

9. Electromagnetic radiation intranuclear Xtranuclear

10. Biological effects Rad is the unit of absorbed dose 1 rad =100erg/g Gy (Gray) 1 Gy = 100rads = joule/kg

11. Conformal radiotherapy Stereotactic surgery combined with advanced imaging techniques  Increased radiation doses  Precise and focused delivery E.g. upto 60 Gy delivered in liver tumours ‘Gamma knife’ in brain tumours Time, Dose, Fractionation Currently hyperfractionation works best (multiple doses of 200cGy / day)

12. Adjuvant radiotherapy Boron Neutron Capture Therapy

13. Adjuvant radiotherapy Bioreductive drug adjuvant therapy Bioreductives: Harmless prodrugs which are converted to cytotoxic metabolites under certain conditions E.g. AQ4N (alkylaminoanthraquinone N-oxide) Harmless in oxic cells Converted into cytotoxic AQ4 in hypoxic cells combined with radiotherapy or chemotherapy RESISTANCE TO TUMOUR THERAPY AQ4N

14. Adjuvant radiotherapy Photodynamic therapy

15. Problems with radiotherapy Targets actively dividing cells Delivery limited by tissue tolerance limits Radiation-induced oedema leading to radiation necrosis Failure of complete remission Increased chances of metastasis

16. Chemotherapy Works by affecting DNA synthesis and function

17. 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

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

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

20. Classes of chemo agents Bacterial or fungal derivatives that affect cellular processes like DNA or protein synthesis 2) Antibiotics Topoisomerase inhibitors

21. 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

22. 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

23. 3) Alkylating agents - example Cisplatin / carboplatin forms covalent adducts at N-7 position of purines creating inter or intrastrand crosslinks that disrupt DNA synthesis and subsequent apoptosis. Effective against ovarian and testicular cancers Side effects - Nephrotoxicity but has minimal effects on the bone marrow - drug resistance Oxaliplatin Oxaliplatin (colorectal cancer) Satraplatin Satraplatin (oral administration; prostate cancer)

24. Nitrogen mustard derivatives cyclophosphamide, chlorambucil, melphalan ethyleneimine derivatives thiotepa nitrosoureas BCNU, CCNU alkyl sulphonates busulphan 3) Alkylating agents - examples

25. 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

26. Shortcomings of chemotherapy ToxicityToxicity –myelotoxic, nephrotoxic, increased risk of radiation-induced necrosis. Effective delivery - local variations in blood flowEffective delivery - local variations in blood flow Drug resistanceDrug resistance

27. Drug resistance Differences in chemosensitivity in cancer patients, leads to resistance during treatment. Mechanisms of drug resistance can be due to Decreased membrane transport (uptake) Overexpression of multidrug resistance genes Increased cytoplasmic detoxification Increased DNA repair Increased tolerance to DNA damage

28. References Chapter 16: Biology of Cancer by RA Weinberg AND/OR Cancer Biology by RJB King Chapter 13 AND/OR Scientific American (Sept 1996) special issue Optional reading