Transcript cytotoxic drugs-students.ppt

Definition
Statistics
Carcenogenesis
Treatment
Principles
Cell cycle
Adverse effects
Classification
Individual drugs
What is Cancer?
U.S. - 500,000 deaths per
year.
2nd only to heart disease
as cause of mortality.
1 in 3 develop cancer.
50% die/survive.
17% cured by
chemotherapy.
Worldwide, more than 16
million new cancer cases
are diagnosed yearly and
10 million die of cancer.
Cancer cells manifest
four characteristics that
distinguish them from
normal cells:uncontrolled
proliferation
dedifferentiation and
loss of function
Invasiveness
metastasis.
1-Activation of protooncogenes to oncogenes:2-Inactivation of tumour
suppressor genes:-
How is Cancer treated?
a) surgery.
(b) radiation.
(c) chemotherapy.
1-Cytotoxic drugs:A-alkylating agents
B-antimetabolites.
C-Cytotoxic antibiotics.
D-plant derivatives.
2-Hormones:3-Enzymes:-e.g. L-Asparaginase.
1-compartment A
2-compartment B
3-compartment C
Class 1 agents (non cell cycle
specific)
eg. alkylating agents
Class 2 agents (cell
cycle spcific - phase
specific)
Reach a plateau in cell
killing with increasing
dosages
eg. hydroxyurea is toxic
to cells in S-phase.
Bleomycin is toxic to cells
in G2 and early M-phase.
Continuous infusion or
frequent small doses.
Class 3 agents (cell
cycle specific - nonphase specific)
Their dose response
curve follows first order
kinetics.
eg. anthracycline
antibiotics, chlorambucil,
cisplatin.
Administered in single
large doses
1. Complete eradication of tumor cells.
2. Drug kills a constant PROPORTION of tumor
cells rather than a constant NUMBER of cells
(first order kinetics).
The log kill hypothesis.
12
99.99% of 10 ,How many cells remain?
3. Tumors usually detected clinically late.
4. Adverse effects are decreased by giving
combinations of drugs.
5. Adjuvant therapy.
Bone marrow
toxicity
(myelosuppressi
on).
Loss of hair
(alopecia).
Damage to
gastrointestinal
epithelium
impaired wound
healing.
depression of
growth in children
teratogenicity.
Sterility
kidney damage
→urates.
Nausea and
vomiting.
Carcinogenic
RESISTANCE TO CHEMOTHERAPY

Decrease inward
transport
The use of monotherapy can lead
to the appearance of survivor cells
resistant to several other unrelated
6MP
cytotoxic agent i.e. MDR
Cyclophosphamide
Minimize incidence by using
combinations & if develops add
intracellular drug concentration
VERAPAMIL (a CCB) in adjuvance
Cytosine arabinoside
Cyclophosphamide to chemotherapeutics to inhibit PCisplatin
glycoprotein !!!
doxorubicin
vincristine
paclitaxel
atoposide
methotrexate
MDR
Reduced Folate
Carrier (RFC)
Folic a., THF,
Methotrexate
5-FU
Folate
Receptor
(FR-α)
Folic a., THFs
 inward transport
 Outward efflux
Effluxed Vincristine
Vincristine
Vincristine enters
A. Nitrogen mustards
Cyclophosphamide
B. Alkyl sulfonates
Busulfan
C. Nitrosoureas
1. Carmustine
2. Lomustine
Mechanism of action:-
It is inactive until
metabolised in the liver by
the P450 mixed function
oxidases.
It has a pronounced effect
on lymphocytes and can be
used as an
immunosuppressant.
Used in treatment of
lymphomas, ,
In Burkitt’s lymphoma,
myeloma,
chronic leukemias.
ADR:- nausea ,vomiting,
bone marrow depression
and haemorrhagic cystitis.
Haemorrhagic cystitis →
acrolein
ameliorated by ↑fluid
intake and
Mesna, sodium-2mercaptoethane
sulfonate,
e.g. lomustine and
carmustine ,
They are lipid soluble and
can, therefore, cross the
blood-brain barrier,
used against
tumours of the brain
and meninges.
depressive effect on
the bone marrow
that starts after 3
weeks.
Depresses the formation of granulocytes
and platelets in low dosage and red cells
in higher dosage.
No effect on lymphoid tissue or the
gastrointestinal tract.
It is used in chronic granulocytic
leukaemia.
Action is analogous to that of the alkylating
agents.
When it enters the cell, Cl- dissociates.
It causes intrastrand
& cross-linking.
Cisplatin is given by
slow intravenous
injection or infusion.
It is seriously nephrotoxic.
It has low myelotoxicity , very severe
nausea and vomiting.
ondansetron.
Tinnitus and hearing loss in the high
frequency range , peripheral neuropathies,
hyperuricaemia and anaphylactic reactions.
solid tumours of the testes and ovary.
Antimetabolites
Folate
Purine
Antagonists Analogues
Pyrimidine
Analogues
The main folate antagonist is methotrexate.
Folates are essential for the synthesis of
purine nucleotides and thymidylate.
Folates consist of three elements: a
pteridine ring, p-aminobenzoic acid
(PABA) and glutamic acid
Folates are actively taken up into cells.
In order to act as coenzymes, folates must
be reduced to tetrahydrofolate (FH4).
Methotrexate has a higher affinity for
dihydrofolate reductase than FH2;
It is actively taken up
into cells by the
transport system used
by folate and is
metabolised to
polyglutamate
derivatives, which are
retained in the cell for
weeks.
Clinical uses:-acute lymphoblastic
leukemias, Burkitt’s lymphoma, in adjuvant
therapy of breast carcinoma; in the
palliation of metastatic breast, head, neck,
cervical, and lung carcinomas
ADR:- depression of the bone marrow
,damage to the epithelium of the GIT,
pneumonitis.
At high-dose regimens → nephrotoxicity.
High-dose
regimens, must be
followed by
'rescue' with
leucovorin (a form
of FH4).
Fluorouracil:-an
analogue of uracil,
interferes with
DTMP synthesis .
It is converted into
a 'fraudulent'
nucleotide:
fluorodeoxyuridine
monophosphate
(FDUMP).
Fluorouracil is usually
given parenterally.
Clinical uses:combination regimens
in the treatment of
breast cancer, palliative
treatment of
gastrointestinal
adenocarcinomas.
ADR:- GIT epithelial
damage , myelotoxicity.
Cytosine arabinoside.
Cytarabine enters the
target cell and undergoes
phosphorylation
reactions to give the
cytosine arabinoside
trisphosphate→ ↓DNA
polymerase.
Clinical uses:-is used in the
chemotherapy of acute myelogenous
leukemia, it has been used
intrathecally in the treatment of
meningeal leukemias and lymphomas
as an alternative to methotrexate.
ADR:- GIT epithelial damage ,
myelotoxicity , nausea and vomiting.
The main anticancer purine analogues
include fludarabine, pentostatin , 6mercaptopurine.
Mercaptopurine is used in the
maintenance therapy of acute
lymphoblastic leukemia.
Fludarabine is metabolised to the
trisphosphate and inhibits DNA
synthesis by actions similar to
cytarabine .
Highly active in the treatment of
chronic lymphocytic leukemia.
It is myelosuppressive.
Pentostatin inhibits
adenosine
deaminase.
interfere with critical
pathways in purine
metabolism , on cell
proliferation.
Pentostatin is
effective in the
therapy of hairy cell
leukemia.
Antitumour antibiotics produce their effects
mainly by direct action on DNA.
A. Anthracyclines
Doxorubicin hydrochloride.
B. Dactinomycin.
C. Bleomycins
Doxorubicin
[anthracycline] has
several cytotoxic actions.
1-It binds to DNA and
inhibits both DNA and
RNA synthesis.
2-Its main cytotoxic action
is mediated through an
effect on topoisomerase
II (a DNA gyrase).
3-Doxorubicin
interacts with
molecular oxygen ,
producing superoxide
ions and hydrogen
peroxide , which
cause single strand
breaks in DNA.
4-Binds cell
membrane
• Doxorubicin can
cause cumulative,
dose-related
cardiac damage,
leading to
dysrhythmias and
heart failure.
Extravasation → local
necrosis.
Marked hair loss
Clinical uses:- carcinomas
of the breast, ovary,
endometrium, bladder, and
thyroid ,it is included in
several combination
regimens for lymphomas
and Hodgkin’s disease.
Dexrazoxane is a
cardioprotective agent
used to protect the heart
against the cardiotoxic side
effects of doxorubicin
Dactinomycin intercalates
in the minor groove of DNA
between adjacent
guanosine-cytosine pairs,
interfering with the
movement of RNA
polymerase along the
gene and thus preventing
transcription.
has a similar
action to the
anthracyclines on
topoisomerase II.
Clinical uses:gestational
choriocarcinoma,
testicular tumors,
lymphomas,
melanomas, and
sarcomas.
ADR:- NVD,
myelosuppression,
immunosuppression
,elevated liver
function tests,
hepatitis,
extravasation
→necrosis.
The bleomycins are a
group of metalchelating
glycopeptide
antibiotics that
degrade preformed
DNA, causing chain
fragmentation and
release of free
bases.
Bleomycin is most effective in the G2
phase of the cell cycle and mitosis, also
active against non-dividing cells
causes little myelosuppression.
Clinical uses:- advanced testicular
carcinomas, Hodgkin’s and non-Hodgkin’s
lymphomas.
Its most serious toxic
effect is pulmonary
fibrosis.
Allergic reactions .
mucocutaneous
reactions and may
develop hyperpyrexia.
A. Vinca alkaloids
1. Vincristine
2. Vinblastine
B. Epipodophyllotoxins
1. Etoposide
2. Teniposide
C. Taxanes: paclitaxel
Vincristine, Vinblastine
The vinca alkaloids bind avidly to tubulin.
Extensively bound to
tissues.
Biliary excretion.
Vincristine is a component
of the combination for acute
lymphoblastic leukemia,
Hodgkin’s disease
The periwinkle plant
Vinblastine → testicular carcinomas ,
Hodgkin’s disease, breast cancer, and
renal cell carcinoma.
Neurological toxicity → vincristine.
Bone marrow toxicity → vinblastine.
tissue necrosis if extravasated.
Etoposide ,
semisynthetic
derivative of
podophyllotoxin →
roots of the
American
mandrake, or May
apple.
Podophyllum
complexes with topoisomerase II, which
results in a single-strand breakage of
DNA.
Lethal to cells in the S- and G2phases of the cell cycle.
useful against testicular and ovarian germ
cell cancers, lymphomas, and acute
myelogenous and lymphoblastic leukemia.
ADR:- mild nausea, alopecia, allergic
reaction, phlebitis at the injection site, and
bone marrow toxicity.
Paclitaxel → bark
of the Pacific yew
tree.
Promotes the
assembly of
filaments and
preventing their
depolymerization.
Large volume of
distribution, highly
metabolized in the liver.
Used in carcinomas of
the breast, ovary, lung,
head, and neck.
+ cisplatin → ovarian
and lung carcinomas
+doxorubicin → breast
cancer.
ADR:- myelosupression,
alopecia, numbness &
tingling sensation
Tumours derived from hormone-sensitive
tissues may be hormone dependent.
Glucocorticoids
→↓ lymphocyte
proliferation, used
in leukaemias and
lymphomas.
→↓ intracranial
pressure.
Estrogens, fosfestrol (a pro-drug→
prostatic tumours.
Estrogens → recruit resting mammary
cancer cells (i.e. cells in compartment B).
• Anti-estrogens :• Tamoxifen → hormonedependent breast cancer.
• Chemopreventive in
women at high risk for
breast cancer.
• Endometrial cancer
• Tamoxifen is
cardioprotective.
Given orally , well
absorbed,
maximum plasma
levels 4-6h.
ADR:-Menopausal
symptoms, fluid
retention ,edema,
thromboembolic
events,
Anti-androgens,
flutamide and
cyproterone,
are used in
prostate
tumours.
L-asparaginase →
Escherichia coli
and Erwinia
carotovora.
Hydolizes Lasparagine to
aspartic acid and
ammonia.
Tumor cells
sensitive to Lasparaginase are
deficient in the
enzyme
asparagine
synthetase.
Remains primarily
in the
intravascular
space.
Little appears in the CSF.
Used for acute lymphoblastic leukemia &
certain types of lymphoma.
ADR:-may produce hypersensitivity
reactions, urticarial skin rashes and severe
anaphylactic reactions, pancreatitis .
Lacks toxicity to bone marrow,
gastrointestinal tract, and hair follicles.
TREATMENT MODALITIES
ANTINEOPLASTIC AGENTS
3. IMMUNOTHERAPY
Surgery
Radiotherapy
Chemotherapy 
Hormonal therapy 
Immunotherapy 
Biological therapy
Rational of immunotherapy is to activate host defenses to act indirectly to
mediate anti-tumour effects or directly to modulate tumor differentiation
Interleukin-2  induces &/or expands cytolytic T cells against tumors
 in metastatic malignant melanoma & renal cell carcinoma
Interferon-a 2b  activates macrophage phagocytic & T cell
cytotolytic activities  in hairy cell leukemia, refractory chronic myeloid
leukaemia, advanced malignant melanoma & follicular lymphoma.
Immunostimulatory drugs as; Thalidomide  refractory malignant
myeloma & Levamisol  adjunctive in colon cancer
TREATMENT MODALITIES
ANTINEOPLASTIC AGENTS
4. BIOLOGCAL THERAPY
Surgery
Radiotherapy
Chemotherapy 
Hormonal therapy 
Immunotherapy 
Biological therapy
MOLECULARLY TARGETED AGENTS
Developed to target specific
molecules or cellular processes
on or within the malignant cell.
By Recombinant
Technology
MOA
Biological Therapy
By Non-Recombinant
Technology
Molecular
Biological Therapy
MOA
The mice or hamsters are immunized by the
needed molecular target
Lymphocytes producing antibodies are fused
with “immortal” human B-lymphocytes
The immortal hybrid can be cloned to
produce HUMANIZED ANTIBODIES against
a single target antigen
Rituximab  against CD20 expressed on lymphocytes in b cell
lymphoma & chronic lymphocytic leukemia
Bevacizumab  against Vascular Endothelium GFR so aborts
angiogenesis to suppress metastasis specially in colorectal &
lung cancer / induce shrinkage of breast & renal cancer
Cetuximab  Epidermal GFR in many carcinomas as breast,
lung, colon,…..
Trastuzumab  HER2/ neu ( a special EGFR) expressed on 30% of
breast cancer cells  in metastatic breast cancer
Molecular Therapy
Imatinib (Gleevec, Glivec)  inhibits cytoplasmic TK signaling
BCR-ABL present in myeloid leukemia & platelet derived
GF in stromal tumors  chronic myeloid leukemia (CML) &
gastro-intestinal stromal tumors
Erlotinib (Tarcevac)  inhibits TK linked to EGFR  non-small
cell lung cancer
Bortezomib (Velcade) 
Proteosome Inhibitor 
inhibit degradation of IkB
inhibit NFkB
refractory multiple myeloma
Mechanism of action: TKIs
EGFR
TKIs
Erlotinib  Molecular 
–ve TK phosphorylation
Inhibits TK
activity
Phosphorylation
 Proliferation
P
P
Akt
BCL-2 BAX
Tumor Survival
Cetuximab  MOA 
prevents EGF binding
No Signalling
 Invasion
MAPK
 Metastasis
 Angiogenesis
M
 Apoptosis
 Sensitivity to
chemotherapy
 Adhesion
G1
G2 S
Tumor Proliferation
Apoptosis
G1 arrest