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