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Introduction 03
Ch 21. Anticancer agents
Angiogenesis
 As a tumour grows, its cancerous cells require a steady supply of
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amino acids, nucleic acid bases, carbohydrates, oxygen, and growth
factors  bloody supply
hypoxia :depletion of oxygen, in the center of the tumour.
Hypoxia-inducible factors, HIF-1  upregulate gene  release
growth factors; vascular endothelial growth factor (VEGF), fibroblast
growth factor (FGF-2).
 leading to the branching and extension of existing capillaries.
Angiogenesis.
Normally, angiogenesis helps in the repair of the injured tissues and
controlled by angiogenesis inhibitors, angiostatin, thrombospondin.
Angiogenesis
 Metastasis
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increased availability of blood vessels.
Interleukin-6; released from newly developing endothelial cells.
Blood vessel arising from angiogenesis -- abnormal
Disorganized, dilated, and leaky structure.
Integrin, on the surface: absent from mature vessels, protect the new
cells from apoptosis.
Matrix metalloproteinases (MMPs) : Before angiogenesis can begin,
the basement membrane round the blood vessels has to be broken
down by MMPs.
Angiogenesis
Metastasis
increased availability of blood vessels.
Interleukin-6; released from newly developing endothelial cells.
Blood vessel arising from angiogenesis -- abnormal
Disorganized, dilated, and leaky structure.
Integrin, on the surface: absent from mature vessels, protect the new
cells from apoptosis.
 Matrix metalloproteinases (MMPs) : Before angiogenesis can begin,
the basement membrane round the blood vessels has to be broken
down by MMPs.
 Angiogenesis inhibitors: generally safer and less toxic than
traditional chemotherapeutic agents.
 Normalization of abnormal blood vessels help anticancer agents
reach tumour more effectively  tumour becomes starved.
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Angiogenesis
 Cells in the center of the tumour are starved of oxygen and nutrients
  stop growing and become dormant.
  anticancer drugs do not work. (most anticancer drugs act best on
actively dividing cells)
  After stop of anticancer therapy, dormant cells start multiplying.
 Hypoxic of condition in tumour center  glycolysis  acidic
byproducts  exporting acidic protons into the extracellular space
 tumour is more acidic than normal tissue.
Tissue invasion and metastasis
 Benign tumours grow and remain in localized site without fatal result.
 Malignant cancers are life threatening; break away from the
primary tumour, invade a blood vessel or a lymphatic vessel, travel
through the circulation, set up tumours elsewhere in the body.
 Cell adhesion molecules (e.g., E-cadherin) : a molecular signature on
their surface which identifies whether they are in the correct part of
the body or not.
 Integrin : a transmembrane receptor that is the bridge for cell-cell
and cell-extracellular matrix (ECM) interactions. anchoring process.
  If a normal cell becomes detached, it stops growing and
apoptosis is triggered.
  This prevents cells from one part of the body straying to other
parts of the body.
Tissue invasion and metastasis
 Cell adhesion molecules are missing in metastasized in cancer cells,
allowing them to break away from the primary tumour.
 It is thought that oncogene in metastasized tumour cells send false
messages back to the nucleus implying that the cell is still attached.
 It is noticeable that most cancers derived from epithelial cells.
 Epithelial cells grow on a basement membrane, barriers to the
movement of the cells.
 Moving cells : cancer cells and whit blood cells; contain matrix
metalloproteinase; hydrolyses the proteins composing the barrier.
Tissue invasion and metastasis
 Once a cancer cell breaks through the basement barrier, it has break
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down a similar barrier surrounding the blood vessel in order to enter
the blood supply.
 spread round the body.
 finally adhere to the blood vessels.
 break out by the opposite process in order to reach new tissue.
 fewer than 1 in 10000 cells succeed in setting up a secondary
tumour.
 metastasis.
From starting in most tissues, finally lung.
From starting in intestines, finally liver.
Treatment of cancer
 There are three traditional approaches to the treatment of cancer;
Surgery, Radiotherapy, Chemotherapy.
 Chemotherapy; normally used alongside surgery and radiotherapy.
 Combination therapy; the simultaneous use of various anticancer
drugs with different mechanisms of action. ; increase efficiency of
action, decreased toxicity, and evasion of drug resistance.
Treatment of cancer
 Identifying unique targets of cancer cells is not easy.
 Cancer cells are normally growing faster than normal cells. They
accumulate nutrients, synthetic building blocks, and drugs more
quickly.
 Traditional anticancer drug: severe side effect; weakening of the
immune response and a decreased resistance to infection 
secondary infection.
  impaired wound healing, loss of hair, damage to the epithelium of
the gastrointestinal tract, depression of growth in children, sterility,
teratogenicity, nausea, and kidney damage.
Treatment of cancer
 Most traditional anticancer drugs: disrupting the function of DNA.
 Molecular targeted therapeutics : highly selective agents which
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target specific molecular targets that are abnormal or
overexpressed in the cancer cells.
Imatinib (Glivec) ; kinase inhibitor.
Antibodies, gene therapy.
Knowledge of the cell cycle; some drugs are more effective during
one part of the cell cycle than another.
Micortubule : M-phase, DNA: S-phase.
Cisplatin : alkylating agents.
Treatment of cancer
 A better understanding of the molecular mechanisms behind specific
cancers is yielding better and more specific treatments.
 Early detection of cancer is very important.
 Personalized medicine; the genetic analysis of tumours in individual
patients allows the early detection and identification of cancer, as
well as identifying the best treatment.
 Genetic finger printing.
 Reducing cancer : smoking, drinking, vs high-fibre food, fruit,
vegetables.
 Dithiolthiones, Genistein, Epigallocatechin gallate.
Resistance
 Intrinsic resistance : the tumours shows little responseto an anticancer
agent from the very start ; slow growth rate, poor uptake of the drug,
the biochemical /genetic properties of the cell.
 The cells in the center of the tumour may be in the resting state and
be intrinsically resistant as a result.
 Tumour stem cells : ingerently resistant to current anticancer agents
 re-emergence of certain tumours after successful initial treatment.
Resistance
 Acquired resistance : When a tumour is initially susceptible to a drug,
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but becomes resistant.
The presence of a mixture of drug-sensitive and drug-resistant cells
within the tumour.
The drug wipes out the drug-sensitive cells but this only serves to
select out and enrich the drug-resistant cells.
The survival of even one such cell can lead to failure of the
treatment.
Genetically, cancer cells are unstable, and to induce mutations.
Resistance
 Acquired resistance.
 Decreased uptake of drugs.
 Inhibitions of drug activation.
 Efflux : expelled from the cells.
 ABC transporters : ATP-binding cassette transporters : It normally
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expels toxins from normal cells.
Mutation can result in increased expression of this kind of proteins.
P-glycoprotein.
Multidrug resistance (MDR) : cells acquiring resistance to the vinca
alkaloid are also resistant to dactinomycin (actinomycin D) and
anthracyclines.
Verapamil, ciclosporin A, quinine : Inhibitors for P-glycoprotein.