Transcript Slide 1

Antineoplastic drugs
Dr. Elayan, 2015.
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Cancer
a disease of cells characterized by the shift in the
control mechanism that govern cell proliferation and
differentiation.
Special Characteristics of Cancer Cells
•Uncontrolled Proliferation
•Dedifferentiation and loss of function
•Invasiveness (Spreading)
•Metastasis (spread of cancer from its primary site to
other places in the body
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Management of Cancer
Surgical
Radiation
Chemotherapy
If cancer has not spread, the best option is surgery and
cure. skin cancers, cancers of the lung, breast, and
colon.
If the tumor has spread to local lymph nodes only, these
can also be removed.
• If surgery cannot remove all of the cancer, the options
for treatment include radiation, chemotherapy, or
both. Some cancers require a combination of surgery,
radiation, and chemotherapy.
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Chemotherapy
• It is the treatment of disease by chemicals
especially by killing micro-organisms or cancerous
cells.
• In popular usage, it refers to antineoplastic drugs
used to treat cancer or the combination of these
drugs into a regimen.
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Types of Therapies:
• Adjuvant:
Additional treatment after the primary treatment to
lower the risk that the cancer will come back.
• Neo-Adjuvant therapy :
Treatment as a first step to shrink a tumor before
the main treatment.
• Concurrent therapy:
When two or more therapies are given together,
such as chemotherapy and radiation.
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Cell Cycle
• G0 : A resting phase.
• G1 : Cells increase
in size.
• S : DNA replication occurs.
• G2 : Gap between DNA synthesis and mitosis,
the cell will continue to grow.
• M : Cell growth stops ,and cellular energy is
focused on division into two daughter cells.
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Principles of cancer chemotherapy
1.Goal of treatment:
• The ultimate goal of chemotherapy is cure. i.e.
long term disease free survival.
• If cure is not attainable, then the goal becomes
palliation i.e. alleviation of symptoms and avoidance
of life-threatening toxicity.
• The neoplastic cell burden is initially reduced either
by surgery and /or radiation followed by
chemotherapy or combination therapy.
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Principles of cancer chemotherapy, con...
2. Indications for treatment:
• Chemotherapy is indicated when neoplasms are
disseminated (Spread over a large area)and are not
cured by surgery.
• Chemotherapy is also used as a supplemental
treatment to attack micro metastasis following
surgery and radiation treatment.
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Principles of cancer chemotherapy con…
3. Tumor susceptibility and growth cycle:
• Rapidly dividing cells are generally more sensitive
to anti cancer drugs.
The fraction of tumor cells that are in replicative stage
of their cycle are most susceptible.
• Non proliferating cells (those are in Go phase)
usually survive the toxic effects of many of these
agents.
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Principles of cancer chemotherapy con..
4. Cell cycle specificity of drugs:
• The normal and tumor cells
differ in the number of cells that are
in various stages of the cycle.
• Chemotherapeutic agents that are
effective only against replicating cells
are called cell cycle specific (CCS) drugs.
• Others are said to be cell cycle non specific
(CCNS) drugs.
• The non specific drugs have more toxicity in cycling
cells and are useful against tumors that have low
percentage of replicating cells.
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Principles of cancer chemotherapy con..
CCS – effective against hematological malignancies and
in solid tumors with large growth fraction.
CCNS drugs – solid tumors with low growth fraction solid
tumors
CCS drugs are given after a course of CCNS
5. Tumor growth rate:
• The growth rate of most solid tumors is initially rapid,
but decreases as tumor size increases, because of
unavailability of nutrients and oxygen.
• Reducing the tumor burden through surgery or radiation
promotes the remaining cells growth into active
proliferation and increases their susceptibility to
chemotherapeutic agents.
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Principles of cancer chemotherapy con..
6. Treatment regimens and scheduling:
•Drugs are administered on the bases of body surface
area.
•Destruction of cancer cell follows first order kinetics ,
i.e. a given dose destroys constant fraction of cells.
(Log kill)
Visible tumor = 1g or 10⁹cells.
Each cycle of therapy kills less than 99% of the cells, so
multiple cycles are necessary to kill all tumor cells.
Magnitude of a tumor cell kill is a logarithmic function:
4 log kill means reduction from 10¹² to 10⁸
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Log kill
if treatment leads to a 99.999-percent kill, then 0.001
percent of cells would remain.
This is defined as a five-log kill .
At this point, the patient will become asymptomatic, and
the patient is in remission
For most bacterial infections, a five-log (100,000-fold)
reduction in the number of microorganisms results in a
cure, because the immune system can destroy the rest.
However, tumor cells are not as readily eliminated, and
additional treatment is required to totally eradicate the
leukemic cell population.
• Combine drug therapy is more successful than single
drug treatment.
• •In combine therapy the drugs must have different
toxicities & different mechanisms of action.
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Principles of cancer chemotherapy con…
Effects of various treatments on the cancer
cell burden:
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Clinical Considerations
• 1. Early intensive start to the treatment is helpful
• 2. Complete remission is the goal of chemotherapy
• 3. Combined chemotherapy is useful - Drug regimens
or effective designing of number of cycles can reduce
large tumour burden and delayed emergence of
resistance
• 4. Combined chemotherapy can be curative when
applied to minute residual tumour cell population after
surgery or radiation
• 5. Treatment must continue past the time when cancer
cells can be detected using conventional techniques
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Toxicities
Bone marrow depression – limits treatment
Buccal mucosa erosion – due to high epithelial
turnover (stomatitis, bleeding gums)
GIT: Diarrhea, shedding of mucosa, hemorrhage
Nausea, vomiting – CTZ direct stimulation
Skin: alopecia
Gonads: oligospermia, impotence, amenorrhea
and infertility
Lymphoreticular system: Lymphocytopenia and
inhibition of lymphocyte function – loss of host
defense mechanism – susceptibility to infections
Carcinogenicity
Teratogenicity and Hyperuricemia
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Anticancer Drugs
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Alkylating Agents
Nitrogen Mustards
Nitrosoureas
Alkyl sulfonate
Platinum complexes
• Mechlorethamine
• Cyclophosphamide
• Ifosfamide
• Carmustine
• Lomustine
• Busulfan
• Cisplatin
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• Carboplatin
Alkylating Agents
Mechanism of Action:
- Nitrogen mustards inhibit cell reproduction by binding
irreversibly with the nucleic acids (DNA)
- After alkylation, DNA is unable to replicate and therefore can
no longer synthesize proteins and other essential cell
metabolites
- Consequently, cell reproduction is inhibited and the cell
eventually dies from the inability to maintain its metabolic
functions.
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Nitrogen Mustards
Mechlorethamine: (MUSTARGEN)
Unstable, given IV immediately after being made up
Part of MOPP (Mechlorethamine – oncovine-prednisolone
and procarbazine) in Hodgekin`s lymphoma .
Toxicity:
• Severe Vomiting
• bone marrow toxicity
(myelo and immunosuppression)
• tissue damage with extravasation
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Ifosphamide
longer half life & greater activity than
cyclophosphamide
Given IV with MESNA (2-mercaptoethane
sulfonate).
Converted by liver cytochrome P450 to active &
toxic metabolites.
Toxicity: N&V, neurotoxicity (confusion),
nephrotoxicity, hemorrhagic cystitis or hematuria
(prevented by concurrent MESNA), cardiac toxicity
with high dose, bone marrow toxicity
used mainly in testicular tumor
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Alkylating agents
Nitrosoureas
Inhibits DNA, RNA and protein synthesis
lipid soluble (cross blood-brain barrier)
Carmustine (BCNU) :
IV infusion over 1-2hrs
Lomustine (CCNU) : taken orally
Effective against brain tumors and also
in Hodgkin's lymphoma
Toxicity:
profound delayed and cumulative bone marrow
depression, N&V, pulmonary fibrosis (6 months after
therapy to 15 years after), renal damage, reversible
liver damage and leukemia.
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Alkylating agents
Alkyl sulfonates
Busulfan
Well absorbed orally;
plasma half-life 2-3hrs
Active against Chronic Myeloid Leukemia
Toxicity:
N&V, bone marrow depression (stem
cells), pulmonary infiltrates and fibrosis.
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Platinum complexes
Cisplatin
Cisplatin is the cornerstone drug in the modern
management of head and neck cancer
Mechanism:
Covalent crosslinks
with GG base pairs
(bends DNA)
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Platinum complexes: Cisplatin
Pharmacology:
IV, not effective orally; most (90%) bound to plasma
proteins.
concentrates in liver, kidney, intestine and ovary;
excreted in urine.
Toxicity:
N&V, diarrhea, hypersensitivity reactions (rashes),
renal damage (reduced with hydration), ototoxicity
with high frequency hearing loss and tinnitus,
peripheral sensory neuropathy (paresthesia and
loss of proprioception), bone marrow depression.
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Antimetabolites
Structurally related to normal compounds that exist
within the cell.
Folate antagonist:
Methotrexate (Mtx).
Purine antagonist:
6-Mercaptopurine (6-MP)
Azathioprine.
Pyrimidine antagonist: 5-Fluorouracil (5-FU)
Effects are in S-phase
(cell-cycle specific).
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Folate antagonist:
Methotrexate
Mechanism of action:
Folic acid is an essential dietary factor.
It is converted to tetrahydrofolate cofactors essential for the
synthesis of precursors of DNA (thymidylate and purines)
and RNA (purines).
Methotrexate inhibits the enzyme dihydrofolate reductase
(DHFR) causing partial depletion of the tetrahydrofolate
cofactors required for synthesis of thymidylate and purines.
In addition, methotrexate is converted to a series of
polyglutamates (MTX-PGs) in both normal and tumor cells
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and inhibits the thymidylate synthase (TS).
Methotrexate Cont..
Therapeutic uses:
MTX is effective against
acute lymphocytic leukemia,
Choriocarcinoma (Choriocarcinoma of the placenta during
pregnancy)
Burkitt lymphoma in children (a type of non-Hodgkin's
lymphoma)
breast cancer
head and neck carcinomas.
low-dose MTX is effective against certain
inflammatory diseases, such as severe psoriasis,
rheumatoid arthritis and Crohn disease.
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Routes of administration: Oral, IM, IV, intrathecal.
MTX may cause crystalluria
. Adverse effects:
MTX causes stomatitis, myelosuppression,
erythematic, rash, urticaria, and alopecia.
• Most frequent toxicities: N, vomiting, and diarrhea.
• Adverse effects can reversed by leucovorin.
Long-term use of MTX may lead to liver cirrhosis.
Neurologic toxicities: subacute meningeal irritation,
stiff neck, headache, and fever. Rarely, seizures,
encephalopathy or paraplegia.
• Contraindications: pregnancy.
alopecia
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Purine antagonist:
6-Mercaptopurine
Mechanism of action:
6-MP inhibit the conversion of inosine monophosphate to
adenine and guanine nucleotides that are building blocks
for RNA and DNA.
6-MP converted to 6-MPribose phosphate (6-thioinosinic
acid, or TIMP)
TIMP inhibits the first step of de novo purine-ring
biosynthesis.
TIMP is converted to thioguanine monophosphate (TGMP),
which can be incorporated into RNA. The deoxyribonucleotide analogs that are also formed are
incorporated into DNA.
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This results in nonfunctional RNA and DNA.
Purine antagonist: 6-Mercaptopurine
Pharmacokinetics:
Oral administration, well distributed except for the
cerebrospinal fluid.
Metabolized in the liver. The parent drug and its
metabolites are excreted by the kidney.
Adverse effects:
Bone marrow depression is the principal toxicity.
Side effects also include anorexia, nausea,
vomiting, and diarrhea.
Hepatotoxicity in the form of jaundice has been
reported in about one third of adult patients.
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Pyrimidine antagonist:
5-Fluorouracil (5-FU).
Mechanism:
Converted in to 5-fluoro2deoxyuridine
monophosphate
(5-FdUMP),which inhibits
thymidylate synthase and blocks the conversion of
deoxyuridilic acid to deoxythymidylic acid.
5-FU incorporated into RNA, interferes with RNA synthesis
and causing cytotoxic effect.
5-FU produces its effect in the S phase of the cell cycle. 32
Uses:
Pyrimidine antagonist: 5-Fluorouracil
Treatment of slowly growing solid tumors (colorectal,
breast, ovarian, pancreatic, and gastric carcinomas).
Leucovorin (Folinic acid ) enhances the effect of 5-FU by
inhibiting thymidylate synthase. Folinic acid is used in
combination with 5-FU in treating colon cancer.
Pharmacokinetics:
Because of its severe toxicity to the GI tract, 5-FU is given IV or, in
the case of skin cancer, topically.
Adverse effects:
Nausea, vomiting, diarrhea, and alopecia, severe ulceration of the
oral and GI mucosa, bone marrow depression.
5-FU causes “hand-foot syndrome” is seen after extended
infusions (reddening, swelling,
numbness and skin peeling on
palms of the hands and the feet )
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Antineoplastic Antibiotics:
Doxorubicin
Mechanism of action:
Blocks synthesis of DNA and RNA; DNA strands scission – by
affecting topoisomerase II. Free oxygen radical generation
Clinical uses:
Breast carcinoma, Ovarian carcinoma, Testicular
carcinoma Thyroid carcinoma, Lung carcinoma
Given by rapid IV infusion, distributes widely except to CNS.
Toxicity:
N&V, severe local tissue damage with extravasation, diarrhea,
fever, transient ECG changes, ventricular arrhythmia,
cardiotoxicity, anaphylactoid reactions and bone marrow
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depression.
Microtubule Inhibitors:
Vinca alkaloids: Vincristine, Vinblastine.
Plant alkaloids
now produced
synthetically.
Mechanism:
Antimicrotubule (Mitotic spindle). Binds to tubulin, inhibits
tubulin polymerization into microtubules which are a major
component of the mitotic spindle.
Given by IV infusion to treat various types of leukemia.
Vincristine is occasionally used as an immunosuppressant.
The main side effects are:
peripheral neuropathy, hyponatremia, constipation and hair
loss.
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Hormonal Agents
Glucocorticoids
Prednisone
Direct antitumor effects are related to their
lympholytic properties.
Glucocorticoids can inhibit mitosis, RNA synthesis,
and protein synthesis in sensitive lymphocytes.
Considered cell-cycle nonspecific .
Resistance to a given glucocorticoid may develop
rapidly and typically extends to other
glucocorticoids.
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Tamoxifen
Mechanism:
Competitive inhibitor of estradiol binding the
estrogen receptor.
Pharmacology:
oral; metabolized in liver to active metabolites.
Trans 4-hydroxytamoxifen (25-100 more potent
than tamoxifen)
Therapeutic Use:
Estrogen-dependent breast cancer
Toxicity:
N&V, hot flashes, transient increase in bone or
tumor pain when cancer has metastasized
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Aromatase inhibitors (AIs)
Exemestane, Letrozole
Aramatose is the enzyme that synthesizes
estrogen.
AIs work by inhibiting the action of the enzyme
aramatase which converts androgen into
estrogen.
AIs are used in the treatment of breast & overran
cancers in postmenopausal women.
As breast tissue is stimulated by estrogens,
decreasing their production suppresses
recurrence of the breast tumor tissue.
.
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Tyrosine- kinase inhibitors (TKI)
Imatinib & Geftinib
Tyrosine kinases are enzymes responsible for the
activation of many proteins by signal
transduction cascades.
Effective anti-tumor agents and anti- leukemic
agents.
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Tyrosine- kinase inhibitors (TKI)
Imatinib
used in the treatment of multiple cancers, e.g. Philadelphia
chromosome- positive (Ph+) chronic myelogenous
leukemia (CML).
tyrosine kinase enzymes are turned on and off as needed.
In Ph-positive CML cells, one tyrosine kinase enzyme, BCRAbl, is stuck on the "on" position, and keeps adding
phosphate groups causing abnormal cell proliferation.
It is present in 95% of patients with (CML).
Imatinib blocks this BCR- Abl enzyme, and stops it from
adding phosphate groups. As a result, these cells stop
growing, and die.
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Monoclonal antibodies
Trastuzumab, Rituximab, Ibritumomab
Directed at specific targets and often have fewer adverse
effects.
• Designed to recognize and find specific abnormal proteins
on cancer cells.
• Each monoclonal antibody recognizes one particular
protein.
Three types of monoclonal A-bodies:
1. Trigger the immune system to attack and kill cancer
cells. E.g. Rituximab
2. Stop cancer cells from taking up proteins E.g.
Trastuzumab
3. Carry cancer drugs directly to cancer cells These are
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called conjugated MABs. E.g. Ibritumomab