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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
intranuclearXtranuclear
Radiotherapy
X-ray source
Radiotherapy sources
Biological effects
Rad is the unit of absorbed dose1 rad =100erg/g
Gy (Gray) 1 Gy = 100rads = joule/kg
Conformal radiotherapyAdvances in imaging techniquesE.g. Liver tumours
Time, Dose, Fractionation
Adjuvant radiotherapyBoron Neutron Capture Therapy
Adjuvant radiotherapyThermotherapy
MR-guided laser induced thermotherapy of osteiod osteoma
Adjuvant radiotherapyPhotodynamic therapy
Adjuvant radiotherapyBioreductive drug adjuvant therapy
Harmless prodrugUnder certain conditions is converted to a cytotoxic metabolite
E.g. AQ4N (alkylaminoanthraquinone N-oxide)
Harmless in oxic cellsConverted 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 derivativescyclophosphamide, chlorambucil, melphalan ethyleneimine derivatives thiotepanitrosoureas BCNU, CCNU alkyl sulphonates busulphan
3) Alkylating agents - examples
Cyclophosphamidetrade name: Cytoxan®
Metabolic activation of cyclophosphamide creates guanine adducts that block cell proliferationUsed 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