BB20023/BB20110: DNA and disease
Cancer therapy I: Conventional therapies
Surgery:
Advantages: quick & effective; largest no of cures; confirmation of excision
Disadvantages: no guarantee of complete removal; critical normal tissues invasion & most important
ineffective for metastasis.
Radiotherapy
Primary curative modality in ~ 30% of patients
technological innovations has led to improved & expanded applications including radium, high vacuum
tubes, linear accelerators, transistors, imaging techniques
Advantages: quicker recovery by healthy tissues, preservation of anatomical structures surrounding tumour
maintaining function eg uterine cervix, prostate
Disadvantages: failure of complete remission, metastasis (whole body radiation). Radiation dose required
depends on tumour type & number of tumour clonogens, does not avoid adverse effects in normal tissue.
Conformal radiotherapy
Uses advances in imaging, computers & treatment planning. CAT, MRI
e.g. liver tumours -25Gy usually deleterious
but 60Gy can be done with conformal
radiotherapy
time, dose & fractionation: Small dose
fractions produces relatively less damage to
late responding than early responding
tissues.
Adjuvant therapies
boron neutron capture therapy (BNCT): Based on the nuclear reaction that occurs when boron-10, a
stable isotope, is irradiated with low-energy thermal neutrons to yield alpha particles and recoiling lithium-7
nuclei. For BNCT to be successful, a large number of B-10 atoms must be localized on or preferably within
neoplastic cells, and a sufficient number of thermal neutrons must be absorbed by the B-10 atoms to sustain
a lethal B-10 (n, alpha) lithium-7 reaction. Used to treat high-grade gliomas and metastatic brain tumors.
Thermotherapy: the use of hyperthermia (38-45oC) in conjuction with radiation or chemotherapy. Used to
treat head & neck, cervical tumours
Photodynamic therapy (PDT): PDT involves the localization of a
photosensitizer in the target tissue prior to illumination using an appropriate
wavelength. Cytotoxic agents generated upon illumination trigger a cascade
of biochemical responses that inactivate cancer cells either directly or
through the induction of vascular stasis. These treatments are better
tolerated as they destroy diseased tissue while leaving normal tissue intact.
(Nature Reviews Cancer 3; 380-387 (2003) photodynamic therapy for
cancer D E.J.G.J. Dolmans, D Fukumura, R K. Jain)
Chemotherapy
Chemotherapy is an important line of defense against hematological malignancies and aggressive forms of
solid tumor. Most chemotherapeutic drugs require systemic administration and
work by affecting DNA synthesis & function. They can be broadly categorised
into
Antimetabolites: Compounds that are analogues of normal metabolites that
inhibit nucleic acid synthesis. Function in 3 ways; either by substitution,
competing for a regulatory site or competing for a catalytic site. E.g.
methotrexate: A folic acid analogue that competitively inhibits dihydrofolate
reductase (DHFR), the enzyme essential for nucleic acid synthesis. It’s the
only drug used to treat choriocarcinoma.
5-fluorouracil: Uracil derivative that is incorporated into RNA. Used to treat
breast and stomach cancer.
Cytosine arabinoside (Ara-C): cytosine analogue that inhibits DNA polymerase . Effective against
leukaemias.
MV Hejmadi, 2004-05
BB20023/BB20110: DNA and disease
2) Antibiotics
Bacterial or fungal derivatives that affect cellular processes like DNA or protein synthesis. E.g.
Doxorubicin: 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.
Others include daunomycin anthracycline antibiotics, Actinomycin D ( dactinomycin), Bleomycin sulphate,
Mitomycin C
3) alkylating agents substitute alkyl groups for H atoms forming adducts with DNA
bases resulting in impaired DNA synthesis. They have 2 functional groups, each of
which can form inter or intrastrand crosslinks. Examples include
nitrogen mustard derivatives like cyclophosphamide, chlorambucil, melphalan
ethyleneimine derivatives e.g. thiotepa
nitrosoureas e.g. BCNU, CCNU
alkyl sulphonates e.g. busulphan
cyclophosphamide: 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.
cisplatin (cis-Dichlorodiammineplatinum): 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.
4) Plant alkaloids: Vinca alkaloids like vincristine, vinblastine & paclitaxel, prevent
tubulin polymerisation resulting in mitotic arrest. Taxol (a terpene from yew trees)
causes a similar effect by preventing tubulin depolymerisation. Used against testicular
and ovarian cancers and leukaemias.
N.B.
Drug Resistance: Although inappropriate treatment can result in the selection of more resistant and
aggressive cells, cancer patients are often treated with a standard regimen protocol without considering
individual differences in chemosensitivity; this invariably 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
1) direct inhibition of steroid synthesis : E.g. using
either LHRH superagonists or aromatase
inhibitors in breast cancer
2) 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
Reading list
1) Cancer Biology by RJB King Chapter 13
2) Scientific American (Sept 1996) special issue
3) The Lancet (1997) vol 349, suppl II pgs 1-3
Optional Reading:
Drug sensitivity and resistance genes in cancer chemotherapy: a chemogenomics approach by Huang Y,
Sadee W (APR 15 2003) DRUG DISCOVERY TODAY 8 (8): 356-363
MV Hejmadi, 2004-05