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22 Cards in this Set

  • Front
  • Back
What is cancer?
Cancer is an uncontrolled mutliplication and spread of abnormal cells

Cancer is synonymous with "malignant neoplasm" or "malignant tumour"

Commonest cancers include lung, colon, breat and prostate (make up 40% of total)
What are the properties of cancer cells?
- Uncontrolled proliferation
- Loss of differentiation and function
- Invasiveness of surrounding tissues
- Ability to spread to distant sites via blood or lymphatics ("metastasise")
Is cancer detectable from the onset?
No. Cancer is undetectable for a substantial time.
How does cancer arise?
Cancer involves DNA mutations, hereditary or acquired.

May get:
- activation of proto-oncogenes to oncogenes and/or
- Inactivation of tumour suppressor genes
What can be affected in a cancer cell?
Cancer cells can have changes in one or more of the following:
- growth factors, their receptors or related parthways
- cell cycle transducers (e.g. cyclins)
- apoptosis (programmed cell death)
- expression of telomerase (an enzyme that protects telomers on the ends of chromosomes and that may confer immortality on a cell)
- ability to stimulate local blood vessel formation (angiogenesis)
What approaches are there to the treatment of cancer?
Anticancer drugs

Some cancer are more amenable to anticancer drugs than others
What are the principles of cancer chemotherapy?
Chemotherapy has its greatest chance when applied aggressively against small, high growth rate tumours.

As there are no invitro tests to determine the best drug, drugs are chosen on the basis of previous success against that cancer

Appropriate combinations of drugs with different mechanisms of action and toxicities are best.

Therapy should be intermittent so that normal, dividing cells have a chance to recover.
What are some examples of anticancer drugs?
Cytotoxic drugs - generally toxic to all rapidly growing cells

Hormones or hormone antagonists - in hormone sensitive cancers e.g. tamoxifen in breast cancer

Monoclonal antibodies - directed against cancer cells

Agents that enhance the host's defensive response to cancer (e.g. interferon gamma)

Stimulators of cell differention (e.g. tretinoin in leukemia)

Inhibitors of cell signalling pathways (e.g. imatinib)
How do cytotoxic drugs work?
Inhibit cell division e.g. by affecting availability of DNA, RNA or their precursors

Purine & pyrimidine synthesis --> Ribonucleotides --> Deoxyribonucleotides --> DNA --> RNA --> protein

- generally kill a constant fraction, not a constant number of cells
- can slow the progression of cells through the cell cycle, and can be most active during a particular phase or phases of this cycle.
- are not selectively toxic toward cancer cells
What are the adverse effects of cytotoxic drugs?
Inhibit rapidly dividing cells e.g. in gut, hair follicles and bone marrow

Therefore often get: nausea, vomiting & loss of appetite; hair loss; bone marrow suppression

These effects are generally reversible after cessation of treatment

Some drugs have other specific adverse effects e.g. doxorubicin is toxic to the heart & vincristine is toxic to nerves and muscles
What types of cytotoxic drugs are there?
Anitmetabolites - inhibit formation or polymerisation of deoxynucleic acids needed for DNA synthesis (e.g. inhibit purine or pyrimidine synthesis)

Alkalating agents - cause DNA or DNA-protein cross linking

Antibiotics - e.g. cause DNA strand breaks or bind to DNA to block unwinding of helix

Mitotic inhibitors - bind to tubulin and inhibit function of microtubules.
Give examples of antimetabolites (cytotoxic drug).
Methotrexate - related to folic acid, and blocks its synthesis via action on dihydrofolate reductase, resulting in inhibition or purine synthesis

Azathioprin - converted to 6-mercaptopurine, a purine analogue that inhibits DNA synthesis

Both drugs also used as immunosuppressants.
Give examples of Alkylating agents (cytotoxic drug).
Bind covalently with DNA especially during synthesis

Resulting DNA damage triggers apoptosis

Examples include:
- cyclophosphamide (can cause bladder damage)
- cisplatin (related to alkylating agents (can be nephrotoxic), contains platinum
Give examples of Antibiotics (cytotoxic drug).
They interact with DNA, disrupting its function (e.g. by causing strand breaks, or by binding to prevent unwinding of helix)

They are often cell-cycle specific

Examples include:
- doxorubicin (cardiotoxic)
- procarbazine (used in Hodgkin's disease)
Give examples of mitotic(microtubule inhibitors) (cytotoxic drug).
Examples include:
Vinca alkaloids, e.g. vincristine (can cause nerve toxicity and muscle weakness). Bind to tubulin & prevent microtubule and spindle formation in dividing cells.

Taxanes e.g. paclitaxel (can also be toxic to nerves). Bind to microtubules and inhibit thier function.
Give examples of hormones (cytotoxic drug).
Glucocorticoids - inhibit lymphocyte proliferation and may be used in leukaemias or lymphomas. They also help reduce raised intracranial pressure

Gonadotrophin-releasing hormone analogues - can inhibit gonadotrophin release and are sometimes useful in hormone-dependent breast or prostate cancer.
Give examples of hormone antagonists (cytotoxic drug).
Examples include:

Tamoxifen (oestrogen receptor modulator)and Anastrozole (oestrogen synthesis inhibitor) - useful in oestrogen-dependent breast cancer

Flutamide (anti-androgen) useful in prostate cancer
Give examples of Monoclonal antibodies (cytotoxic drug).
Examples include:
- MAb to CD20 on B lymphocytes, used against B cell lymphomas e.g. rituximab (Rituxan)
- MAb to human epidermal growth factor receptor 2, useful in HER2 +ve breast cancers, e.g. trastuzumab (Herceptin)
- MAb to vascular endothelial growth factor (inhibits angiogenesis), useful in colorectal cancer, e.g. bevacizumab (Avastin)

Adverse effects of MAbs include hypotension, fecer and hypersensitivity reactions

Generally very expensive
Interferon-gamma and interleukin-2 can help enhance the body's response against cancer cells

Tretinoin can induce differentiation in leukemic cells

Imatinib inhibits a cytolasmic kinase thought to be a unique factor in the pathogenesis of chronic myeloid leukemia.
Why are anticancer drugs used in combination?
Two or more drugs are often used ot treat cancer because:
- increases the proportion of cells killed
- decreases toxicity
- kills cells in tumours that contain heterogenous populations of cancer cells
- reduces the chance of development of drug resistance
How can resistance to anticancer drugs come about?
Resistance to anticancer drugs may be primary or acquired:
- reduced uptake of drug into cell
- inactivation of drug
- increased utilisation by cancer cells of metabolic pathways not affected by the drug
- rapid repair of drug-induced lesions.
What are possible future strategies for using anti-cancer drugs?
- More monoclonal antibodies
- More angiogenesis inhibitors
- More agents that affect cell signalling
- Telomerase inhibitors
- Agents targeting p53 (a gene important in allowing DNA repair, and that is mutated in >50% camcers)
- Antisense oligonucleotides or siRNA (small interfering RNAs)