antineoplastic agents by rajarshi patel.ppsx

8/13/2019 Antineoplastic Agents by Rajarshi Patel.ppsx

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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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5

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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6

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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11


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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12


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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13

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.
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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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17

PART II

4. Mechanisms of action5. Side Effects

6. Drug Resistance

Pharmacology of Antineoplastic Agents


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18

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


E. Ifosfamide Same as above Germ cell cancer, cervicalcarcinoma, lung, Hodgkins

and non-Hodgkins

lymphoma, sarcomas


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



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d. Ethylenimines 1. Mechanism of

Action


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


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.


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

33


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


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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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)


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


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.

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 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 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

antineoplastic agents by rajarshi patel.ppsx

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