antineoplastic agents by rajarshi patel.ppsx
TRANSCRIPT
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Pharmacology of Antineoplastic Agents
1
Outline of Lecture Topics:
1. Background
2. Antineoplastic Agents: classification
a. Cell Cycle Specific (CCS) agentsb. Cell Cycle Non-Specific (CCNS) agents
c. Miscellaneous (e.g., antibodies) agents
4. Mechanisms of action
5. Side Effects
6. Drug Resistance
Rajarshi Patel, Ph.D.
Dept Oncology
+91-9033231942
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2
PART I
1. Background
2. Antineoplastic Agents
a. Cell Cycle Specific (CCS) agents
b. Cell Cycle Non-Specific (CCNS) agents
c. Miscellaneous (e.g., antibodies) agents
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Cancer
3
Definition:
Cancer* is a term used for diseases in which abnormal cells divide without
control and are able to invade other tissues. Cancer cells can spread to other
parts of the body through the blood and lymph systems, this process is calledmetastasis.
Categorized based on the functions/locations of the cells from which they
originate:
1. Carcinoma- skin or in tissues that line or cover internal organs. E.g.,
Epithelial cells. 80-90% reported cancer cases are carcinomas.
2. Sarcoma - bone, cartilage, fat, muscle, blood vessels, or other connective or
supportive tissue.
3. Leukemia- White blood cells and their precursor cells such as the bone
marrow cells, causes large numbers of abnormal blood cells to be produced
and enter the blood.
4. Lymphoma - cells of the immune system that affects lymphatic system.
5. Myeloma - B-cells that produce antibodies- spreads through lymphatic
system.
6. Central nervous system cancers - cancers that begin in the tissues of the
brain and spinal cord.
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Cancer Therapeutic Modalities (classical)
4
1. Surgery
2. Radiation
3. Chemotherapy
1/3 of patients without metastasis
Respond to surgery and radiation.
If diagnosed at early stage,
close to 50% cancer
could be cured.
50% patients will undergo chemotherapy,
to remove micrometastasis. However,
chemotherapy is able to cure only about 10-15%
of all cancer patients.
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New types of cancer treatment
Hormonal Treatments:These drugs are designed to prevent cancer cell growth by
preventing the cells from receiving signals necessary for their continued growthand division. E.g., Breast cancertamoxifen after surgery and radiation
Specific Inhibitors:Drugs targeting specific proteins and processes that are
limited primarily to cancer cells or that are much more prevalent in cancer cells.
Antibodies: The antibodies used in the treatment of cancer have been
manufactured for use as drugs. E.g., Herceptin, avastin
Biological Response Modifiers:The use of naturally occuring, normal proteins to
stimulate the body's own defenses against cancer. E.g., Abciximab, rituxmab
Vaccines:Stimulate the body's defenses against cancer. Vaccines usually contain
proteins found on or produced by cancer cells. By administering these proteins,
the treatment aims to increase the response of the body against the cancer
cells.
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Cancer Chemotherapy (Background)
A. Most of the recent progress using antineoplastic therapy is based on:
1. Development of new combination therapy of using existing drugs.
2. Better understanding of the mechanisms of antitumor activity.3. Development of chemotherpeutic approaches to destroying
micrometastases
4. Understanding the molecular mechanisms concerning the initiation of
tumor growth and metastasis.
5. Recognition of the heterogeneity of tumors
B. Recently developed principles which have helped guide the treatment of
neoplastic disease
1. A single clonogenic cell can produce enough progeny to kill the host.
2. Unless few malignant cells are present, host immune mechanisms do not
play a significant role in therapy of neoplastic disease.
3. A given therapy results in destruction of a constant percentage as
opposed to a constant number of cells, therefore, cell kill follows first order
kinetics.
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Cancer Chemotherapy
7
C. Malignancies which respond favorably to chemotherapy:
1. choriocarcinoma,
2. Acute leukemia,
3. Hodgkin's disease,
4. Burkitt's lymphoma,
5. Wilms' tumor,
6. Testicular carcinoma,
7. Ewing's sarcoma,
8. Retinoblastoma in children,
9. Diffuse histiocytic lymphoma and
10.Rhabdomyosarcoma.
D.Antineoplastic drugs are most effective against rapidly dividing
tumor cells.
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E. The Main Goal of Antineoplastic Agents
IS to eliminate the cancer cells without affecting normal tissues (the concept of
differential sensitivity). In reality, all cytotoxic drugs affect normal tissues as
well as malignancies - aim for a favorabletherapeutic index (aka therapeutic
ratio).
Therapeutic Index =LD50-----
ED50
A therapeutic index is the lethal dose of a drug for 50% of the population (LD50
)
divided by the minimum effective dose for 50% of the population (ED50).
8
http://en.wikipedia.org/wiki/LD50http://en.wikipedia.org/wiki/LD50http://en.wikipedia.org/wiki/ED-50http://en.wikipedia.org/wiki/ED-50http://en.wikipedia.org/wiki/ED-50http://en.wikipedia.org/wiki/ED-50http://en.wikipedia.org/wiki/LD50http://en.wikipedia.org/wiki/LD50 -
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Infrequent scheduling of
treatment courses.
Prolongs survival but does not cure.
More intensive and
frequent treatment.
Kill rate > growth rate.
Untreated patients
F. The effects of tumor burden, scheduling, dosing, and initiation/duration of
treatment on patient survival.
Early surgical removal of the
primary tumor decreases the tumor
burden. Chemotherapy will remove
persistant secondary tumors.
9
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General rules of chemotherapy
Aggressive high-dose chemotherapyDose- limiting is toxicity towards normal cells
Cyclic regimens - repeated administrations with appropriate intervalsfor regeneration of normal cells (e.g., bone marrow cells)
Supportive therapy - to reduce toxicity
hematotoxicitybone marrow transplantation, hematopoieticgrowth factors
Specific antagonists: antifolate (methotrexate)folate(leucovorin)
MESNA - donor ofSH groups, decreased urotoxicity ofcyclophosphamide. Detoxifying agent.
dexrazoxane: chelates iron, reduced anthracycline cardiotoxicity
amifostine: reduces hematotoxicity, ototoxicity and neurotoxicityof alkylating agents
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General rules of chemotherapy
Combination of several drugs with different mechanisms of action,
different resistance mechanisms, different dose-limiting toxicities.
Adjuvant therapy: Additional cancer treatment given after the primarytreatment to lower the risk that the cancer will come back. Adjuvanttherapy may include chemotherapy, radiation therapy, hormone therapy,targeted therapy, or biological therapy.
Neoadjuvant therapy: Treatment given as a first step to shrink a tumor
before the main treatment, which is usually surgery, is given. Examples of
neoadjuvant therapy include chemotherapy, radiation therapy, and
hormone therapy. It is a type of induction therapy.
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General rules of chemotherapy
Supportive therapy:
-Antiemetics (5-HT3-antagonists)
-Antibiotic prophylaxis and therapy (febrile neutropenia)
-Prophylaxis of urate nephropathy (allopurinol)
-Enteral and parenteral nutrition
-Painanalgesic drugs
-Psychological support
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Alkylating agentsTopoisomeraseinhibitors Antimetabolites
Molecularlytargeted
busulfan dactinomycin cytarabine erlotinib
carboplatin daunomycin clofarabine imatinib
carmustine doxorubicin fludarabine sorafenib
cisplatin etoposide gemcitabine sunitinib
cyclophosphamide etoposide phosphate mercaptopurine tretinoin
dacarbazine idarubicin methotrexate Herceptin
ifosfamide irinotecan nelarabine Miscellaneous
lomustine liposomal daunomycin thioguanine arsenic trioxide
mechlorethamine liposomal doxorubicin Tubulin binders asparaginase
melphalan mitoxantrone docetaxel bleomycin
oxaliplatin teniposide ixabepilone dexamethasoneprocarbazine topotecan vinblastine hydroxyurea
temozolomide vincristine mitotane
thiotepa vinorelbine PEG-asparaginase
paclitaxel prednisone
Antineoplastic Agents
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Chemotherapy: classification based on the
mechanism of action
Antimetabolites:Drugs that interfere with the formation of key
biomolecules including nucleotides, the building blocks of DNA.
Genotoxic Drugs:Drugs that alkylate or intercalate the DNA causing theloss of its function.
Plant-derived inhibitorsof mitosis:These agents prevent proper celldivision by interfering with the cytoskeletal components that enable thecell to divide.
Plant-derived topoisomerase inhibitors: Topoisomerases unwind or
religate DNA during replication.
Other Chemotherapy Agents:These agents inhibit cell division bymechanisms that are not covered in the categories listed above.
http://localhost/var/www/apps/conversion/Plocha/Dokumenty/index.cfm?page=429http://localhost/var/www/apps/conversion/Plocha/Dokumenty/index.cfm?page=482http://localhost/var/www/apps/conversion/Plocha/Dokumenty/index.cfm?page=520http://localhost/var/www/apps/conversion/Plocha/Dokumenty/index.cfm?page=1285http://localhost/var/www/apps/conversion/Plocha/Dokumenty/index.cfm?page=1285http://localhost/var/www/apps/conversion/Plocha/Dokumenty/index.cfm?page=520http://localhost/var/www/apps/conversion/Plocha/Dokumenty/index.cfm?page=482http://localhost/var/www/apps/conversion/Plocha/Dokumenty/index.cfm?page=429 -
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G0= resting phase
G1= pre-replicative phase
G2= post-replicative phaseS = DNA synthesis
M = mitosis or cell division
M
S
G G2 1 Hydrocortisone
Vincristine,Vinblastine
G0
CyclophosphamideBleomycinActinomycin D
Actinomycin D5-FluorouracilCytosine arabinosideMethotrexate
6-Mercaptopurine6-Thioguanine
Purine antagonistsMethotrexateCyclophosphamide5-Fluorouracil
Cytosine arabinosideDaunomycin
Paclitaxel, Docetaxel
resting
Cell cycle specificity of Anti-Neoplastic Agents
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PART II
4. Mechanisms of action5. Side Effects
6. Drug Resistance
Pharmacology of Antineoplastic Agents
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DNA
RNA
Protein
tubulin
Purines andPyrimidines
Asparaginase
Tubulin binders
Alkylating agentsTopoisomerase Inh.
Antimetabolites
Chemotherapy: Mechanisms of Action
1
M j Cli i ll U f l Alk l ti A tCancer Chemotherapy
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Major Clinically Useful Alkylating Agents
19
Bis(mechloroethyl)amines Nitrosoureas Aziridines
Cancer Chemotherapy
Chapter 55. B.G. Katzung
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H2N
O
N
N
HN
N
HO
O
OP
O
NH2
O
N
NNH
N
OO
P
OH
O
N
R
Crosslinking: Joining two or more molecules by a covalent bond. This can either
occur in the same strand (intrastrand crosslink) or in the opposite strands of the
DNA (interstrand crosslink). Crosslinks also occur between DNA and protein.
DNA replication is blocked by crosslinks, which causes replication arrest andcell death if the crosslink is not repaired.
An Example of DNA Crosslinking
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Alkylating Agents (Covalent DNA binding drugs)
1. The first class of chemotherapy
agents used.2. They stop tumour growth bycross-linking guaninenucleobasesin DNAdouble-helixstrands - directly attacking DNA.
3. This makes the strands unable touncoil and separate.
4. As this is necessary in DNAreplication, the cells can no longerdivide.
5. Cell-cycle nonspecific effect6. Alkylating agents are alsomutagenic and carcinogenic
AT
C G
CG
GAT
G C
http://localhost/var/www/wiki/Guaninehttp://localhost/var/www/wiki/Nucleobasehttp://localhost/var/www/wiki/DNAhttp://localhost/var/www/wiki/DNAhttp://localhost/var/www/wiki/Nucleobasehttp://localhost/var/www/wiki/Guanine -
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E.g., Mechlorethamine (Nitrogen Mustards)
22Cancer Chemotherapy
Dr.Rajarshi N. Patel
C l h h id
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Cyclophosphamide
Cyclophosphamideis an alkylating agent. It is a widely used as
a DNA crosslinking and cytotoxic chemotherapeutic agent.
It is given orally as well as intravenously with efficacy.
It is inactive in parent form, and must be activated to cytotoxic
form by liver CYT450 liver microsomaal system to 4-Hydroxycyclophamide and Aldophosphamide.
4-Hydroxycyclophamide and Aldophosphamide are delivered to
the dividing normal and tumor cells.
Aldophosphamide is converted into acroleinand
phosphoramidemustard.
They crosslink DNAs resulting in inhibition of DNA synthesis
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Cyclophosphamide Metabolism
Inactive
C l h h id
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Cyclophosphamide
Clinical Applications:
1. Breast Cancer
2. Ovarian Cancer
3. Non-Hodgkins Lymphoma4. Chronic Lymphocytic Leukemia (CLL)
5. Soft tissue sarcoma
6. Neuroblastoma
7. Wilms tumor
8. Rhabdomyosarcoma
C l h h id
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Cyclophosphamide
Major Side effects
1. Nausea and vomiting
2. Decrease in PBL count
3. Depression of blood cell counts4. Bleeding
5. Alopecia (hair loss)
6. Skin pigmentation
7. Pulmonary fibrosis
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Ifosphamide
Mechanisms of Action
Similar to cyclophosphamideApplication
1. Germ cell cancer,
2. Cervical carcinoma,3. Lung cancer
4. Hodgkins and non-Hodgkins lymphoma
5. Sarcomas
Major Side Effects
Similar to cyclophosphamide
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1. Mechanism of
Action
2. Clinical application 3. Route 4. Side effects
a. Nitrogen Mustards
A. Mechlorethamine DNA cross-links,resulting in
inhibition of DNA
synthesis and
function
Hodgkins and non-Hodgkins lymphoma
Must be givenOrally
Nausea and vomiting,decrease in
PBL count, BM depression,
bleeding, alopecia, skin
pigmentation, pulmonary
fibrosis
B. Cyclophosphamide Same as above Breast, ovarian, CLL, soft
tissue sarcoma, WT,neuroblastoma
Orally and I.V. Same as above
C. Chlorambucil Same as above Chronic lymphocytic
leukemia
Orally effective Same as above
D. Melphalan Same as above Multiple myeloma, breast,
ovarian
Orally effective Same as above
E. Ifosfamide Same as above Germ cell cancer, cervicalcarcinoma, lung, Hodgkins
and non-Hodgkins
lymphoma, sarcomas
Orally effective Same as above
A. Alkylating agents
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1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
b. Alkyl Sulfonates
A. Busulfan Atypical alkylating agent. Chronic granulocytic
leukemia
Orally effective Bone marrow depression,
pulmonary fibrosis, and
hyperuricemia
c. Nitrosoureas 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
A. Carmustine DNA damage, it can
cross blood-brain barrier
Hodgkins and non-
Hodgkins lymphoma, brain
tumors, G.I. carcinoma
Given I.V. must be
given slowly.
Bone marrow depression,
CNS depression, renal
toxicity
B.Lomustine Lomustine alkylates and
crosslinks DNA, thereby
inhibiting DNA and RNA
synthesis. Also
carbamoylates DNA and
proteins, resulting in
inhibition of DNA and RNAsynthesis and disruption of
RNA processing. Lomustine
is lipophilic and crosses the
blood-brain barrier
Hodgkins and non-
Hodgkins lymphoma,
malignant melanoma and
epidermoid carcinoma of
lung
Orally effective Nausea and vomiting,
Nephrotoxicity, nerve
dysfunction
C.Streptozotocin DNA damage pancreatic cancer Given I.V. Nausea and vomiting,
nephrotoxicity, liver toxicity
A. Alkylating agents
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d. Ethylenimines 1. Mechanism of
Action
2. Clinical application 3. Route 4. Side effects
A. Triethylene
thiophosphoramide
(Thio-TEPA)
DNA damage,
Cytochrome
P450
Bladder cancer Given I.V. Nausea and vomiting,
fatigue
B.Hexamethylmelamine
(HMM)
DNA damage Advanced ovarian tumor Given orally after
food
Nausea and vomiting, low
blood counts, diarrhea
d. Triazenes 1. Mechanism of
Action
2. Clinical application 3. Route 4. Side effects
A. Dacarbazine (DTIC) Blocks, DNA, RNA and
protein synthesis
Malignant Melanoma,
Hodgkins and non-
Hodgkins lymphoma
Given I.V. Bone marrow depression,
hepatotoxicity, neurotoxicity,
bleeding, bruising, blood
clots, sore mouths.
A. Alkylating agents
Summary
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Summary
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Tubulin Binding Agents
a
Polymerization
tubulin
Depolymerization
e.g., Vincristine,
Vinblastine, Vindesine
Vinorelbine: Inhibition
of mitotic spindle
formation by binding to
tubulin.
M-phase of the cell
cycle.
e.g., Paclitexal: binds
to tubulin, promotes
microtubule formation
and retards
disassembly; results in
mitotic arrest.Paclitexal (taxol)
Vincristine
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B. Natural Products
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1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
A. Vincristine Cytotoxic: Inhibition of
mitotic spindle formation
by binding to tubulin.
M-phase of the cell cycle.
Metastatic testicular cancer,
Hodgkins and non-Hodgkins
lymphoma, Kaposis sarcoma,
breast carcinoma,
chriocarcinoma, neuroblastoma
I.V. Bone marrow depression,
epithelial ulceration, GI
disturbances, neurotoxicity
B.Vinblastine Methylates DNA and
inhibits DNA synthesis and
function
Hodgkins and non-Hodgkins
lymphoma, brain tumors, breast
carcinoma, chriocarcinoma,
neuroblastoma
I.V. Nausea and vomiting,
neurotoxicity, thrombocytosis,
hyperuricemia.
1. Antimitotic Drugs
1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
Paclitaxel (Taxol) Cytotoxic: binds to tubulin,
promotes microtubule
formation and retards
disassembly; mitotic arrest
results
Melanoma and carcinoma of
ovary and breast
I.V. Myelodepression and
neuropathy
2. Antimitotic Drugs
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1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
A. Etoposide Binds to and inhibits
Topoisomerase II and its
function. Fragmentation of
DNA leading to cell death,
apoptosis.
Testicular cancer, small-cell
lung carcinoma, Hodgkin
lymphoma, carcinoma of
breast, Kaposis sarcoma
associated with AIDS
I.V. Myelosuppression, alopecia
B. Teniposide Same as above Refractory acute lymphocytic
leukemia
I.V. Myelosuppression,
3. Epipodophyllotoxins (These are CCS)
Accumulation of
single- or double-
strand DNA breaks,
the inhibition of
DNA replication and
transcription, and
apoptotic cell
death.
Etoposide acts
primarily in the
G2 and S
phases of the
cell cycle
Act on Topoisomerase II
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35Cancer ChemotherapyDr.Rajarshi Patel
4. Antibiotics (CCS)
1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
a. Dactinomycin
(ACTINOMYCIN D)
It binds to DNA and inhibits
RNA synthesis, impaired
mRNA production, and
protein synthesis
Rhabdomyosarcoma and Wilm's
tumor in children;
choriocarcinoma (used with
methotrexate
I.V. Bone marrow depression, nausea
and vomiting, alopecia,
GI disturbances, and ulcerations of
oral mucosa
b. Daunorubicin
(CERUBIDIN)
Doxorubicin
(ADRIAMYCIN)
inhibit DNA and RNA
synthesis
Acute lymphocytic/granulocytic
leukemias; treatment of
choice in nonlymphoblastic
leukemia in adults when
given with cytarabine
I.V. Side effects: bone marrow
depression, GI disturbances and
cardiac toxicity (can be prevented
by dexrazoxane)
inhibit DNA and RNA
synthesis
Acute leukemia, Hodgkin's
disease, non Hodgkin's
lymphomas (BACOP regimen), CA
of breast & ovary,
small cell CA of lung, sarcomas,
best available agent
for metastatic thyroid CA
I.V. Cardiac toxicity, Doxorubicin
mainly affects the heart muscles,
leading to tiredness or breathing
trouble when climbing stairs or
walking, swelling of the feet .
c. Bleomycin
(BLENOXANE)
fragment DNA chains and
inhibit repair
Germ cell tumors of testes and
ovary, e.g., testicular
carcinoma (can be curative when
used with vinblastine & cisplatin),
squamous cell carcinoma
Given I.V.
or I.M.
Mucosocutaneous reactions and
pulmonary fibrosis; bone
marrow depression much less than
other antineoplastics
Inhibit DNA and RNA syntheses
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5. Enzymes: L-asparaginase
1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
L-asparaginase Hydrolyzes L-asparagine (to
L-aspartic acid) an essential
amino acid to many
leukemic cells
Acute lymphocytic leukemia,
induction of remission in acute
lymphoblastic leukemia when
combined with vincristine,
prednisone, and anthracyclines
I.V. or
I.M.
Nausea and vomiting, Poor
appetite, Stomach cramping,
Mouth sores, Pancreatitis. Less
common: blood clotting
MTX
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C. Antimetabolites
Reduced
Folate
Carrier
protein
MTX
Kills cells
during
S-phase
(Folic acid analog)
polyglutamates
Are selectively
retained
In tumor cells.
Folic acid is a growth factor that provides single
carbons to the precursors used to form the
nucleotides used in the synthesis of DNA and
RNA. To function as a cofactor folate must bereduced by DHFR to THF.
* *
* **
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1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
1.
Methot
rexate
inhibits formation
of FH4
(tetrahydrofolate)
from folic
acid by inhibiting
the enzyme
dihydrofolate
reductase (DHFR);since FH4 transfers
methyl groups
essential to DNA
synthesis and
hence DNAsynthesis blocked.
Choriocarcinoma,
acute
lymphoblastic
leukemia
(children),
osteogenic
sarcoma, Burkitt's
and other non-Hodgkins
lymphomas, cancer
of breast, ovary,
bladder, head &
neck
Orally
effecti
ve as
well
as
given
I.V.
bone marrow
depression,
intestinal lesions
and interference
with
embryogenesis.
Drug interaction:
aspirin andsulfonamides
displace
methotrexate
from plasma
proteins.
C. Antimetabolites
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1. Mechanism of
Action
2. Clinical application 3. Route 4. Side effects
2 Pyrimidine Analogs:
Cytosine Arabinoside
inhibits DNA
synthesis
most effective agent for induction of
remission in acute myelocytic
leukemia; also used for induction of
remission acute lymphoblastic leukemia,
non-Hodgkin's lymphomas; usually used in
combination chemotherapy
Orally
effective
bone marrow
depression
1. Mechanism of
Action
2. Clinical application 3. Route 4. Side effects
2 Purine analogs:
6-Mercaptopurine (6-MP) and Thioguanine
Blocks DNA synthesis
by inhibitingconversion of
IMP to AMPS and to
XMP as well as
blocking conversion
of AMP to
ADP; also blocks first
step in purine
synthesis.
Feedback inhibitionblocks DNA synthesis
by inhibiting
conversion of IMP to
XMP as well as GMP
to GDP; also blocks
first step in purine
synthesis by
feedback inhibition
most effective agent for induction of
remission in acute myelocyticleukemia; also used for induction of
remission acute lymphoblastic leukemia,
non-Hodgkin's lymphomas; usually used in
combination chemotherapy
Orally
effective
bone marrow
depression,
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6. Drug Resistance
One of the fundamental issue in cancer chemotherapy is the development
of cellular drug resistance. It means, tumor cells are no longer respond to
chemotherapeutic agents. For example, melanoma, renal cell cancer,brain cancer often become resistant to chemo.
A few known reasons:
1. Mutation in p53 tumor suppressor gene occurs in 50% of all tumors.
This leads to resistance to radiation therapy and wide range of
chemotherapy.
2. Defects or loss in mismatch repair (MMR) enzyme family. E.g., colon
cancer no longer respond to fluoropyrimidines, the thiopurines, and
cisplatins.
3. Increased expression of multidrug resistance MDR1 gene which
encodes P-glycoprotein resulting in enhanced drug efflux and reduced
intracellular accumulation. Drugs such as athracyclines, vinca
alkaloids, taxanes, campothecins, even antibody such as imatinib.
Summary
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Summary1. The main goal of anti-neoplastic drug is to eliminate the cancer cells
without affecting normal tissues.
2. Log-Kill Hypothesis states that a given therapy kills a percentage of
cells, rather then a constant number, therefore, it follows first orderkinetics.Aim for a favorable therapeutic index.
3. Early diagnosis is the key.
4. Combination therapy and adjuvant chemotherapy are effective for small
tumor burden.
5. Two major classes of antineoplastic agents are:
a. Cell Cycle Specific and
b. Cell Cycle Non-Specific agents
5. Because chemotherapeutic agents target not only tumor cells, but also
affect normal dividing cells including bone marrow, hematopoietic, and
GI epithelium. Know what the side effects are.
6. Drug resistance is often associated with loss of p53 function, DNA
i t h i t d i d MDR1 i