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Pharmacokinetics and principles of action and chemotherapeutic drugs
1,2. Outline the major classes of anti-cancer drugs. Describe, using examples, the mode of
action of the major classes of anticancer drugs: antimetabolites, intercalating agents,
antimitotics etc.
Cancer treatment may involve surgery, radiotherapy and chemotherapy. Anti-cancer drugs target processes
associated with increased cell growth:
 Metabolic activity
 DNA synthesis
 RNA synthesis
 Protein synthesis
There are 5 categories of anti-cancer drugs. These include alkylating agents, natural products, antimetabolites,
synthetic chemicals and molecular targeted drugs.
Classifications of Drugs
DRUG
CLASS
ALKYLATING
AGENTS
DRUG
TARGET
TRANSPORT
APPLICATION
Diffusion
Nitrogen mustard
DNA
(N-7 DNA guanine
crosslinks)
Hodgkin’s disease
(First treatment of
lymphomas &
leukaemia’s however
not drug of choice now.
Still used in developing
countries.)
Chronic lymphocytic
leukaemia (CLL)
Multiple myeloma,
ovarian
Chlorambucil
DNA
Diffusion
Melphalan
DNA
Transporter
Cyclophosphamide
DNA
Diffusion
Common/widely
used
Busulfan
DNA
Diffusion
DNA
(cross-links
through O-6G)
Diffusion
Nitrosoureas
Use to be main drug of
choice for CML, (may
still have uses as is
relatively low cost).
Useful as lipid soluble
and able to penetrate
BBB. Besides cancer
treatment of CNS,
limited application.
Dihydrofolate
reductase
Thymidylate
synthase
DNA & RNA
Folate transporter
Diffusion/Transport
6-thioguanine
6-mercaptopurine
DNA
DNA
Diffusion/Transport
?
Doxorubicin
/Adriamycin
(anthracycline
antibiotic)
Daunorubicin
(anthracycline
antibiotic)
Actinomycin D
DNA
Diffusion
(BCNU)
Methotrexate
ANTIMETABOLITES
NATURAL
PRODUCTS
5-Fluorouracil
Cytosine
arabinoside
DNA
Inhibits
Transport
Diffusion
Non-Hodgkin’s
Lymphoma, Leukaemia.
MODE OF ACTION
The addition of an alkyl group
to DNA. This prevents
transcription and replication.
Guanine bases are especially
susceptible.
Some cause cross-linking of
DNA, impairing DNA replication
and therefore results in
apoptosis. The main alkylating
agent in cyclophosphamide.
Block or disrupt DNA synthesis by
mimicking or competing with an
intracellular metabolite. These
include folate antagonists,
pyrimidine analogues and purine
analogues.
Solid tumours
Acute Leukaemia
These cytotoxic antibiotics affect
DNA directly either by inhibiting
synthesis, interfering with
topoisomerase II, DNA
fragmentation and intercalation.
Older anticancer drug,
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transcription
NATURAL
PRODUCTS
CONT.
Bleomycin
(antibiotic)
Mytomycin C
(antibiotic)
Vinblastine
Vincristine
(plant derivative)
Taxol/Paclitaxel
(plant derivative)
Etoposide/VP16
(plant derivative)
may be used in
combination variety of
cancers.
The plant derivatives (eg
Vincristine) binds to tubulin
inhibiting spindle formation. Thus
inhibiting DNA synthesis.
DNA
DNA
Tubulin (prevent
polymerisation)
Diffusion
Testicular cancer
Diffusion
Childhood leukaemia
Diffusion
Topoisomerase II
Diffusion
DNA
Diffusion
Cis-platinum
SYNTHETIC
CHEMICALS
Carboplatin
Oxaliplatin
(less ototoxicity &
nephrotoxicity than
cis-platinum &
carboplatin)
Small-cell lung cancer,
testicular cancer,
lymphomas
Cisplatin/carboplatin:
variety- sarcomas,
some carcinomas (small
cell lung cancer, ovarian
cancer), lymphomas &
germ cell tumors.
These drugs can easily
result in renal damage,
thus pt needs to drink 
H2O prior and post
therapy.
Oxaliplatin use in colon
cancer
Binds to the N7 of guanine in DNA
forming inter- and intra- DNA
strand crosslinks
3. Outline differences between anticancer treatments and ‘typical’ drug therapy.
Anti-cancer therapies target rapidly dividing cells. All cells (normal and neoplastic) progress through the cell
cycle. Cells spend a different percentage of time in each portion of the cell cycle. The percentages indicated in
the figure below are typical for a neoplastic cell. However, the duration of both Go and G1 can vary greatly.
The majority of cancer drugs used are cytotoxic and exert their effects and by inducing an apoptotic cell
pathway. Anti-cancer drugs can either act at a specific part of the cell cycle, cell cycle specific drugs (CCS), or at
any stage of the cell cycle, cell cycle non-specific drugs (CCNS). Depending on the specific growth factors of a
neoplastic cell will determine which phase the cell spends most time in. For example, drugs that act during a
specific portion of the cell cycle (CCS drugs) will be least effective at treating cancers that have low growth
factors. This is because most of the cells would be in the phase G0.
Cell-cycle specific: Target a specific stage of the cell cycle. For example, plant alkaloids target phases G2-M
whereas antimetabolites target DNA synthesis during the S phase, therefore only proliferating cells undergo
apoptosis.
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Cell cycle non-specific: Act on cells in any stage of the cycle. (Eg alkylating agents, some natural products). The
CCNS drugs act at any phase of the cell cycle including G0. Therefore both proliferating and non-proliferating
cells may undergo apoptosis.
Non-specific: Effective against actively dividing cells not in the Go phase.
Resistance to cancer chemotherapeutic drugs is a major limitation to treatment. Cancers vary in their drug
sensitivity. Primary resistance occurs when some inherent characteristic of the neoplastic cells prevent the drugs
from having any affect on the neoplastic cells. Acquired resistance occurs when the cancer cells become
resistant during treatment and fail to do not turn on the pathway to undergo apoptosis. Acquired resistance is
commonly seen in breast and ovarian cancers. Even more problematic is when a cancer becomes multidrug
resistant. This occurs when tumour cells become cross-resistant to a wide range of chemically dissimilar agents
after exposure.
Cancer cells have the ability to become resistant to different drugs and are believed to be due to similar
mechanisms. Either through altered P-glycoprotein, enzymatic deactivation, decreased drug permeability,
altered binding sites and alternative metabolic pathways they develop.
Drug resistance may be why chemotherapy can be rather ineffective.
4. Describe the log cell kill hypothesis as it applies the use of cytotoxic drugs.
FRACTION CELL HYPOTHESIS
The cell kill hypothesis proposed that actions of cytotoxic drugs follow first order kinetics; a given dose kills a
constant PROPORTION of a tumour cell population, rather than a constant NUMBER of cells.
Each time the chemotherapy dose is repeated, the same proportion of cells is killed. Therefore it is possible to
achieve a cure after repeated doses of chemotherapy, with short breaks in between.
An example:
3 LOG KILL. 1 LOG REGROWTH PRINCIPLE- In a tumour with 1010 cells, a cycle of chemotherapy will result in 103
(3 log kill) cells dying and 107 cells remaining. Hence repeated cycles (with short breaks in-between) are required
to eradicate remaining and re-growing cells. Without continuous treatment, the remaining cells may grow, reforming the malignant tumour.
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