Download Pharmacology 21b – Cytotoxic Drugs

Pharmacology 21b - Cytotoxic Drugs
Anil Chopra
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To be able to define the term ‘Cancer.’
To be able to describe the characteristics of cancer cells.
To be familiar with the molecular basis of chemotherapy.
To be able to discuss the potential targets for chemotherapy.
To be able to identify the major classes of anticancer drugs and describe their
mechanisms of action.
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Cancer = a disease in which there is uncontrolled multiplication and spread within
the body of abnormal forms of the body’s own cells
Normal cells are turned into cancer cells via a series of complex genetic mutations
Neoplasia = new growth
Neoplasm which expresses uncontrolled proliferation only = benign
Neoplasm which expresses uncontrolled proliferation, invasiveness and
metastases = malignant
Cancer is usually far advanced before the diagnosis is made – generally more than
2cm and near the surface
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Cytotoxic drugs are drugs that modify the growth of cells and tissues. They are used in:
 Anti-cancer agents
o To eradicate disease
o Induce a remission
o Control symptoms
 Control of immune responses in organ transplantation
 Management of autoimmune disease
Drug Aims
 They tend to be anti-Proliferative and so do not affect the ability to invade or
metastasise
 Are commonly used in combination – 2-6 drugs to increase effectiveness and
reduce resistance
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Will affect all rapidly dividing tissues – hence side effects (e.g. bone marrow, GI
epithelium, hair)
The aim of chemotherapy is to eliminate/ block proliferation of neoplastic cells
and inhibit their invasion and metastatic potential.
Elimination of cells is achieved using very toxic chemicals that target rapidly
proliferating cells.
Blocking the proliferation of cells is aimed at stalling tumour growth and
encouraging apoptosis and immunosurveillance (removal of abnormal cells by the
immune system).
Cancer cell have their own particular phenotypes:
 Disregard of signals to stop proliferating.
 Disregard of signals to differentiate.
 Capacity for sustained proliferation.
 Evasion of apoptosis.
 Ability to invade.
 Ability to promote angiogenesis
Neoplasia: new growth
Benign: uncontrolled proliferation only
Malignant: uncontrolled proliferation with the potential to invade and metastasise.
Cancers are difficult to treat because they are very similar to normal cells, need to be
entirely eradicated to be gone and are normally diagnosed when they are very
advanced. Tumour cells can be:
 Dividing (sensitive to anticancer treatment)
 No longer able to divide (not a problem)
 Resting in G0 phase (insensitive to anticancer treatment and could start dividing
again after chemotherapy).
Cytotoxic Drugs
- Antiproliferative
- Do not affect invasiveness
- Used as combinations
- Affect rapidly dividing normal cells as well as tumours.
Alkylating Agents
Names
Nitrogen mustards: cyclophosphamide, melphalan, chloirambucil
Methotrexate
DHFR
Usage
DHFR
Mode of Action
They contain a carbonium ion which
covalently bonds with nucleophiles. Their
main target is guanine as it is the most
electron rich (also adenine and cytosine) and
interfere with transcription and replication
by causing inter or intra chain cross-links.
FH4(glu)n
F(glu)n
FH2(glu)n
FH4(glu)n +
1-carbon unit
Thymidylate
synthetase
O
CH3
HN
O
O
DTMP
DUMP
Fluorouracil
HN
O
F
N
HN
N
R
R
O
O
N
R
Antimetabolites
Names
Methotrexate, fluorouracil, azathioprine
Usage – Anti-cancer. Chemotherapy.
Mode of action
They block pathways in DNA synthesis, either as folate antagonists (methotrexate)
interfering with synthesis of thymidilate; pyrimidine analogues (fluorouracil) interfere
with 2’-deoxythymidylate synthesis or purine analogues (Azathioprine) which inhibits
purine synthesis.
Cytotoxic antibiotics
Names
Actinomycin , Doxorubicin, Bleomycin
Usage – Anti-cancer. Chemotherapy.
Mode of Action
These work by directly interacting with DNA. Actinomycin D intercalates DNA and
interferes with topoisomerase II. Doxorubicin inhibits DNA and RNA synthesis.
Bleomycins are metal-chelating glycopeptide antibiotics that degrade DNA.
Mitotic inhibitors (Plant derivatives)
Names
Podophyllotoxins: etoposide
Vinva alkaloids: vincristine
Usage – Anti-cancer. Chemotherapy.
Mode of Action
Etoposide inhibit DNA synthesis by causing cell cycle block at G2. The vinca
alkaloids e.g. vincristine, act by binding to tubulin and inhibiting polymerisation into
microtubules which therefore inhibits spindle formation at prophase of mitosis.
Miscellaneous agents
Usage – Anti-cancer. Chemotherapy.
Name - Hyroxyurea,
Mode of Action
Hydroxyurea inhibits ribonucleotide reductase (essential for DNA synthesis).
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Name - cisplatin
Mode of Action - Cisplatin interacts with DNA causing guanine intrastrand crosslinks.
Name - Procarbazine
Mode of Action - Procarbazine inhibits DNA and RNA synthesis and interferes with
mitosis at interphase, it is activated by cytochrome P450 and monoamine oxidase to
alkylate DNA.
Hormones
Names
Generally Gonadotrophin releaseing hormone analogues such as goserelin. Also
prednisolone, fosfestrol, Tamoxifen.
Usage
Used in chemotherapy but not cytotoxic.
Mode of Action
Can inhibit tumours in hormone-sensitive tissues.
GENERAL SIDE EFFECTS
 Myelotoxicity.
 Impaired wound healing.
 Depression of growth (children)
 Sterility.
 Teratogenicity.
 Loss of hair.
 Nausea and vomiting
Affect rapidly dividing cells by inhibiting division; affect slowly dividing cells by
inducing mutations which can induce secondary tumours.
Immunopharmcology
Cytotoxic drugs can also be
used as immunosuppressants
at much lower doses than
used to treat cancer. These
can be used in the prevention
of transplant rejection. At
these lower doses they have a
relatively selective action on
lymphocytes. Principally the
anti-metabolites
(methotrexazte, azathioprine)
are used with the alkylating
agents (cyclophosphamide)