Transcript Cytotoxic drugs I.pptx

Anti-neoplastic Drugs
Prof. Dr. Yieldez Bassiouni
Introduction
Normal cells…
•The division of normal cells is
precisely controlled. New cells
are only formed for growth or
to replace dead ones
•Balanced; cell birth=cell death
• Regulation: intracellular chemical
signals tell a cell when to start and
stop dividing
Cancer
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Cancer is one of the most common
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diseases in the developed world
1 in 4 deaths are due to cancer
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Cancer means uncontrolled growth of
cells coupled with malignant behavior:
invasion and metastasis
What causes cancer?
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Cancer arises as a result of:
 inactivation of tumor suppressor genes
 the activation of oncogenes (mutation of
the normal genes controlling cell division
and other processes)
Hereditary predisposition – Some families are
more susceptible to getting certain cancers (
cancer is not inherited)
The Development of Cancer
Within every nucleus of the human
body's 30 trillion cells exists DNA,
the substance that contains the
information needed to make and
control every cell within the body
DNA of a normal cell

This piece of DNA is an exact copy of the DNA from
which it came. When the parent cell divided to create
two cells, the cell's DNA also divided, creating two
identical copies of the original DNA
Mutation of DNA
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This section of DNA, one of the base pairs is different
from the original
So, this DNA has suffered a mutation, either through
mis-copying (when its parent cell divided), or through
the damaging effects of exposure to radiation or a
chemical carcinogen
Carcinogens
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Ionising radiation – X Rays, UV light
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Chemicals – tar from cigarettes
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Virus infection – papilloma virus can be
responsible for cervical cancer
Malignant cells…
Cancer cells have four characteristics that
distinguish them from normal cells:
 Grow more rapidly without control
 Irregular shape; loss of function
because of lack of capacity to
differentiate
 Invade surrounding cells
 The ability to metastasize
Benign and malignant growth
 Benign neoplasms remain localized, and freely moveable,
compress local tissue but do not invade
 Malignant neoplasms metastasize to distant tissues
through the lymph system and blood vessels. They also
have an irregular shape, invade local tissue
Main approaches to
deal with cancer
 Surgical

excision
Irradiation
 Anticancer
Drugs
 Immunotherapy
& Gene therapy
Chemotherapy
Chemotherapy: the treatment of
disease by chemical substances
 Adjuvant Chemotherapy: The use of
chemotherapy along with initial
surgery , irradiation can increase the
cure rate (i.e. in early stage breast
cancer)
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What are the uses & goals of
cancer chemotherapy
Primary therapy:
Treat tumors that cannot surgically excised :
e.g. leukemias & lymphomas
Adjuvant therapy:
In combination with surgery or radiation therapy
to treat solid tumors  prevent recurrence
Palliative therapy:
Inoperable solid tumors reduce size and retard
growth reduce symptoms caused by tumor
Major Classes of Anticancer Drugs
I. Cytoxic drugs
A. Alkylating agents
B. Antimetabolites
C. Plant alkaloids
D. Cytotoxic antibiotics
E. Miscellaneous agents
II. Hormones and hormones antagonists
III. Monoclonal antibodies
Cytotoxic Drugs
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are therapeutic agents active on
rapidly dividing cells intended for, but
not limited to, treatment of cancer
These drugs are known to be highly
toxic to cells, mainly through their
action on cell reproduction
Many drugs cause DNA damage 
initiates apoptosis "self programmed
cell death"
The Cell Cycle
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G0: resting state
G1: synthesis of
precursors, proteins
etc.. needed for
DNA synthesis
S: synthesis of DNA
G2: synthesis of
cellular components
required for mitosis
M: the cell divide
Classification of Cytotoxic
Drugs
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According to chemical structure
According to mechanisms of
anticancer action
According to the cell cycle or
phase specificity of the drug
Classification of Cytotoxic
Drugs
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According to chemical structure
and resource of the drug:
Alkylating Agents, Antimetabolites,
Antibiotics, Plant Extracts
Classification of Cytotoxic
Drugs
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According to their effect on
the cell cycle:
Cell cycle nonspecific drugs
(CCNS)
 Cell cycle specific drugs (CCS)
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Cell cycle specific drugs
Cell cycle-Specific Drugs (CCS):
 Exert their action during a specific
phase of the cell cycle
 Effective for high growth malignancies
& Hematological malignancy
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S Phase Specific Drug: Antimetabolites
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M Phase Specific Drug: Vinca Alkaloids
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G2 Phase Specific Drug: Bleomycin
Cell cycle
Non-specific drugs
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Cell Cycle Nonspecific drugs (CCNS)
Act on cancer cells when they r
traversing cell cycle and when they r
resting
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Alkylating agents
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Platinum Compounds
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Antibiotics
Toxicity of Cytotoxic Drugs
 Can affect normal cells undergoing
rapid proliferation
Buccal mucosa & GIT
Bone
marrow
Hair cells
Gonads
Common Toxicity of Cytotoxics
GI Mucosa: Nausea, vomiting,
stomatitis,oral ulceration,
dysphagia and diarrhea
Bone Marrow suppression, anemia,
leukopenia, infection
Hair: alopecia
Gonadal Cells: Oligospermia and
infertility in men. Menstrual
irregularities and premature
menopause in women
Common Toxicity of Cytotoxics
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In certain circumstances, may be
carcinogenic (e.g. some alkylating
agents)
If there is rapid cell destruction with
extensive purine catabolism, urates
may precipitate in the renal tubules
causing kidney damage
All cytotoxic drugs produce severe
nausea and vomiting
I. Alkylating Agents &
Related Compounds
 Alkylating
agents used in cancer
chemotherapy include a diverse
group of chemicals that have in
common the capacity to
contribute alkyl groups to DNA
(alkylation of DNA)
 Alkylating
agents are CCNS,
proliferating cells are more
sensitive to the drugs
 Alkylating
agents are used in
combination with other agents to
treat lymphatic and solid tumors
 Alkylating agents are mutagenic,
and carcinogenic (may lead to
acute leukemia)
 Resistance may occur during
treatment with alkylating agents
Major classes of alkylating agents
Nitrogen mustards
Cyclophosphamide
Chlorambucil
Alkyl sulfonates
Busulfan
Nitrosoureas
Carmustine
Lomustine
Streptozocin
Related agents
Platinium compounds; Cisplatin
Thiazines; Dacarbazine
MOA of alkylating agent
Cross
Intrastrand
Guanine base of DNA is main target for alkylation
Alkylating agents
form covalent bonds
between alkyl groups of the
drug and N-7 of guanine
bases of DNA
Intrastrand and cross linking
of DNA
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This stops replication of
DNA (Inhibit cell division)
DNA is unable to
replicate
1.Nitrogen mustards
Nitrogen mustards are related
to the 'mustard gas' used
during the First World War
1. Cyclophosphamide
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Cyclophosphamide is the most commonly used
alkylating agent
Cyclophosphamide is a prodrug, well absorbed
orally
It is usually given orally or by IV injection but
may also be given IM
Activated by the liver microsomal cytochrome
P 450 to cytotoxic metabolites; phosphoramide
mustard and acrolein
Reaction of phosphoramide mustard with DNA is
the cytotoxic step
Causes myelosuppression (especially lymphocytes)
Clinical uses of
Cyclophoshamide
Hodgkin disease &
other lymphomas
Ovarian cancer
Breast Cancer
Lung cancer
(CMF) Cyclophoshamide,
methotrexate & fluorouracil
Clinical uses of
Cyclophoshamide
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Cyclophosphamide is a potent immunosuppressant drug used in:
(a) control of organ rejection after
transplantation
(b) disorders associated with altered
immune reactivity such as
intractable rheumatoid arthritis
Common adverse effects of
Cyclophosphamide
Alopecia, Nausea & Vomiting, diarrhea
Amenorrhea, testicular atrophy & sterility.
Bone marrow depression
Carcinogenesis may appear years after
therapy (acute leukemia)
Adverse effects of
Cyclophosphamide
Characteristic toxicity: Hemorrhagic cystitis
It is due to toxic metabolite “acrolein”
in urine
chemical irritation &
fibrosis of the bladder
Prevented by: Proper hydration + IV of
mercaptoethane sulfonate “MESNA”
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Sterile hemorrhagic cystitis due to
chemical irritation produced by
reactive metabolites of
cyclophosphamide (acrolein) in urine
can be ameliorated by increasing fluid
intake and administering compounds
that are sulphydryl donors, e.g.
Sodium 2-mercaptoethane sulfonate
(MESNA)
MESNA neutralizes the toxin acrolein,
forming a non-toxic compound
2. Chlorambucil
 An
alkylating agent used in
treatment of chronic lymphocytic
leukemia
 Chlorambucil causes BM
depression ( anemia,
neutropenia, thrombocytopenia)
GIT upset
Chlorambucil is mutagenic
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3. Melphalan
Used for treatment of multiple
myeloma (collections of abnormal plasma
cells accumulate in BM , interfere with
the production of normal blood cells)
Common side effects include: N,V and
oral ulceration.
BM suppression, including
WBC &
increased risk of infection and
platelet count causing increased risk of
bleeding
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2-Alkyl sulfonates
Busulfan
Busulfan
The main pharmacological action of
busulfan is myelosuppression,
depressing the formation of
granulocytes and platelets in low
dosage and red cells in higher dosage
 Therapeutic uses:
 Busulfan is the drug of choice in
chronic granulocytic leukemia
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Busulfan
Adverse effects:
 Myelosuppression
 N & V and diarrhea
 Carcinogenic
Characteristic toxicity:
1. Pulmonary fibrosis
2. Skin pigmentation
3. Adrenal insufficiency
3-Nitrosoureas
Carmustine
Lomustine
Streptozocin
Carmustine and Lomustine
Use: Treatment of tumors of brain & meninges
High lipid solubility
cross the BBB
 They have a severe
cumulative depressive
effect on the BM that
starts 3-6 weeks
after initiation of
treatment
 Weekly monitoring of
platelets and WBCs
Streptozocin
 Uses: Treatment of insulinoma
 in medical research to produce
an animal model for Type 1 diabetes
Toxic to the β
cells of
pancreas
can reduce the tumor
size and reduce
hypoglycemia due
to
insulin secretion
by insulinomas)
Platinum complexes
Cisplatin
Carboplatin
Oxaliplatin
Cisplatin
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Cisplatin is contains a central platinum atom
surrounded by two chlorine atoms and two
ammonia groups
It causes intrastrand, cross-linking of
adjacent guanine molecules
It is seriously nephrotoxic. Nephrotoxicity is
a dose-limiting side effect.
Creatinine clearance (a measure of renal
function)
Strict regimens of hydration and diuresis
must be initiated
Used for solid tumors: breast, ovarian, testicular,
lung, bladder cancers
Cisplatin
Carboplatin
1. Severe N/V
2. Dose-related
nephrotoxicity (Rx
hydration, mannitol)
3. Neurotoxic; peripheral
neuritis + Ototoxicity
4. Hypersensitivity
reactions
5. It has low
myelotoxicity
1. Much less N/V
2. Much less nephrotoxicity
3. Less risk of peripheral
neuropathy , ototoxicity
4. It is more myelotoxic
Oxaliplatin
A
new member of this class
with better pharmacological
profile
Used in the treatment of
colorectal cancer
Dacarbazine
 Belong to Thiazines
 Is a prodrug, activated in the liver, and
the resulting compound is cleaved in the
target cell to release an alkylating
derivative
 Treatment of melanomas
Common adverse effects:
 Severe nausea & vomiting
 Myelotoxicity
 Hepatotoxicity
Resistance to alkylating
agents
 Increased DNA repair
 Decreased permeability of
the drug
 Increased conjugation with
thiols (trapping agents)
Essays
Use
of nanoparticles in detection and
treatment of skin cancers
 Resistance to cancer chemotherapy:
Mechanisms & Solutions
 Antifungal Drugs in treatment of skin
diseases
Thank you