a brief pahrmacology of antineoplastic agent

1. ANTINEOPLASTIC AGENT
Prepared by
Sagar shrestha
6th sem. B pharm
Hope Intl college

2. Cancer
• Cancer is a disease in which there is uncontrolled multiplication and
spread within the body of abnormal forms of body’s own cells.
Characteristics of tumour cells
1. Uncontrolled proliferation
2. Dedifferetiation and loss of function
3. Invasiveness
4. Metastasis

3. Types of tumours
1. Benign tumours
There are slow growing and donot invade other parts of body
They can be removed by surgery and doesnot lead to death
They are indicated by suffix “oma”
2. Malignant tumours
These are fast growing and invade other body parts
These cannot be removed by surgery as there is no clear demarcation between
normal and tumour cells and may lead to death
Of mesenchymal origin------ indicated as sarcoma
Of epithelial orgin-------------indicated as carcinoma

4. Genesis of cancer
• A normal cell turns into cancer call because of following reasons
1. Mutation in its DNA that may be inherited or acquired
2. One or more genetic changes
a. activation of protooncogens to oncogens
b. Inactivation of tumour suppressor genes
3. Epigenetic factors
a. Hormonal action
b. Co-carcinogens
c. Tumour promoting effects like smoking, excess alcohol consumption,
circumcision, betelnut etc.

5. Carcinogenic agents
1. Chemical agents:
a. Initiator eg: aromatic amines, polygenic aromatic hydrocarbons (in
smoking),azodyes, naturally occurring substances like betel nuts etc
b. Promoter: eg: phenolic compounds, phenobarbital, artificial sweeteners
like saccharin and cyclamate
2. Physical agents: radiation, mechanical injury for tissue
3. Hormonal agents: eg oestrogen--- endometrial cancer
anabolic steroids--- liver cancer
4. Biological agents eg: stones in gall bladder and urinary tract-----cancer
Viral infections (herpes virus)

6. Treatment
• There are 3 main approaches for treatment of established cancer
1. surgical excision
2. Irradiation
3. Chemotherapy

7. Cell cycle

8. Drugs used in cancer chemotherapy
• Based on cell cycle
1. Phase specific agents
These act on specific phase of cell cycle
G1 : vinblastine
S: methotrexate, cytarabine, thioguanine,mercaptopurine, doxorubicin
G2 ; bleomycin etoposide
M : vincristine, vinblastine, paclitaxel

9. 2. Cell cycle specific agents
• These act specifically at all stages of cell cycle but do not have effect
on cells out of cycle
• Eg alkylating agents, doxorubicin, dactinomycin and cisplatin
3. Cell cycle non specific agents:
These act on cells which are either present or absent in cycle
Eg: bleomycin and nitrosourea

10. 1. Cytotoxic drugs
a) Alkylating agents eg: Cyclophosphamide, chlorambucil, busulphan, uracil
mustard
b) Antimetabolites eg: mercaptopurine, flurouracil, methotrexate, azothioprine
c) Plant derivatives eg: vincristine, vinblastine, taxol, cisplastin, mitotane,
tamoxifen, interferon alpha
d) Antibiotics eg: doxorubicin, mitomycin
2. Hormones
Mitotane, Tamoxifen,
Immunotherapy: Interferon alpha 2a and 2b.
Miscellaneous
1. cisplastin, carboplastin, hydroxyurea, procrbazine, l-asparaginase etc
Classification

11. Cytotoxic drugs
a. Alkylating agents
Alkylating agents have cytotoxic and radiomimetic(like ionizing
radiation) actions
Most of them are cell cycle non-specific which act on dividing as well as
resting cells
They can interfere not only with transcription but also with replication
when some parts of the DNA are unpaired and more susceptiblevto
alkylation, i.e. during the S-phase, resulting in a block at G2 and
subsequent cell death.

12. Mechanism of action
Alkylating agents
Produce highly reactive carbonium ion immediately
Transfer alkyl group to cellular macromolecules by forming covalent bonds
Alkylation results in cross linking,chain scission or abnormal base pairing
Decrease Cell division /cell death

13. Name MOA Indication ADR
Mechlorethamine Undergoes intramolecular cyclization
losing chlorine ion and forms reactive
metabolite that interact with DNA
Hodgkins disease and other
lymphoma
Also for solid tumours (breast
cancer, prostate cancer)
Nausea ,vomiting,
Anemia, severe bone marrow
depression
Chlorambucil ‘’ In lymphatic leukemia,
Hodgkins disease
As immunosuppressive agent
Skin rashes, pulmonary
fibrosis(rare), hyperuricemia,
seizures
Busfulan ‘’ In chronic granulocytic
leukemia
Mucosistis, skin rash,
pulmonary fibrosis,
hepatotoxicity
Cyclophosphamide
and isosfamide
Transform into active metabolite
aldophosphamide in liver that exerts
cytotoxic action
To treat chronic lymphatic,
leukemia, lymphoma and solid
tumours
Also as an immunosupressive
Hemorrhagic cystitis, alopecia,
amenorrhea, secondary
malignancies
(allopurinol Phenobarbiton
and rifampicin )

14. Antimetabolites
• Antimetabolites are structurally related to normal components of
DNA or of co enzymes involved in nucleic acid synthesis
• They generally interfere with availability of purine or pyrimidine
nucleotide precursor by inhibiting their synthesis or by competing
with them in DNA or RNA synthesis. Their maximal cytotoxic effects
are in S-phase
1. Folate antagonists eg: Methotrexate
2. Purine analog eg: mercaptopurine, azothioprine
3. Pyrimidine analog eg: flurouracil

15. 1. Folic acid analogues
Name MOA Indication ADR
Methotrexate inhibits dihydrofolate
reductase and by blocking
conversion of dihydrofolic
acid to tetrahydrofolic acid.
In combination with other
drugs,is effective against
acute lymphocytic
leukemia,breast cancer,
bladder cancer and head
and neck carcinoma
As a single agent against
certain inflammatory
disease such as psoriasis ,
rheumatoid arthritis
Used in non small cell lung
cancer
Stomatitis, rash alopecia,
in high dose cause
neurotoxicity
(pregnancy,hypersensitivity
,lactation

16. MOA
Diet or intestinal flora
Folate
Folate
Dihydrofolate
reductase
FH2 FH4
N5,N10 methylene FH4
dTMP
dUMP
METHOTREXATE
methotrexate
Deoxythymidylic acid methionine
------------------------------ ---------------------------------- --------------------------- -------------------- ------------- -------------------
Target
cell

17. Uses
In acute lymphatic leukaemia
Choriocarcinoma and other malignancies
Also used for treatment for rheumatoid arthritis, psoriasis
As immunosuppressant
Adverse effects
Depression of bone marrow
Damage to gastrointestinal epithelium
Pneumonitis, nephrotoxicity, pulmonary toxicity
Neurological toxicity

18. 2. Purine antagonists
6-mercaptopurine(6MP) and 6- thioguanine (6-TG)
These are highly effective antineoplastic drugs
6 mercaptopurine
6- thio- inosinic acid
(thio IMP)
IMP
AMP
XMP

19. 2. Purine analogues/antagonist
Name MOA Indication ADR
Mercaptopurine Converted in the body to
corresponding mono
ribonucleotide which inhibits the
conversion of mononucleotide to
adenine guanine nucleotides
Acute leukaemia
Chorcarcinoma
Solid tumours
Acute lymphoblastic
leukemia
Nausea vomiting and
diarrhea
Bone marrow depression
hepatotoxicity
Azothioprine inhibit synthesis of DNA, RNA, and
proteins. It may also interfere with
cellular metabolism and inhibit
mitosis. Its mechanism of action is
likely due to incorporation of
thiopurine analogues into the DNA
structure, causing chain
termination and cytotoxicity.
severe rheumatoid
arthritis not responded to
other medications (e.g.,
nonsteroidal anti-
inflammatory
drugs/NSAIDs such as
ibuprofen)..
Hyperuricemia,
bonemarrow depression

20. 3 pyrimidine antagonist
• 5-fluoro-uracil
• It is analog of uracil(pyrimidine)

21. MOA
5-FU FdUMP
Thymidilate synthetase
dUMP Thymidine monophosphate
DNA synthesis (selective failure)

22. Uses
In solid treatment of breast, colon, urinary bladder, liver etc
Also effective in treating superficial basal cell carcinomas by topical
application
ADR
GI disturbances
Ulcer in GI tract
Bone marrow depression
Anorexia

23. Plant derivatives
Microtubule inhibitors
The mitotic spindle consists of chromatin and a system of microtubules
composed of protein tubulin.
The mitotic spindle is essential for equal partitioning of DNA into two
daughter cells when mitotic cell division takes place.
Several plant derived substances act on this mechanism by disrupting
the process. They are
Vinca alkaloids: eg: vincristine, vinblastine
Taxanes eg: paclitaxel, docetaxel

24. MOA

25. Uses:
In lymphosarcoma, hodgkins disease
Testicular timours, lung cancer
Bladder carcinoma, wilms tumour
ADR
Nausea, vomiting, diarrhea
Myelosuppresive activity
Alopecia
Muscle weakness
Anaphylatic reaction and hypotension

26. Antibiotics
1. Doxorubicin and daunorubicin
These antibiotics bind to DNA and inhibit both DNA and RNA synthesis
MOA
They produce breaks in DNA strands by activating topoisomerase –II
and generating semiquinone free radicals which reduce molecular
oxygen to superoxide ions and hydrogen peroxide that cause single
strand scission of DNA

28. USES
Treatment of sarcoma
Lung cancer, breast cancer
Acute lukaemia, lymphoma
ADR
Cardiotoxicity
Bone marrow depression
Stomatitis
GI disturbances
Alopecia

29. Hormones
• General MOA of natural steroid hormones

30. Tamoxifen
It stands under hormonr antagonist. It is highly metabolized by liver and slowly
eliminated in stools.
MOA
It binds to the estrogen receptors and breast cancer can be treated by independent
of estrogen blockde. Its action is not related to any specific phase of the cycle. It
delays the growth of metaphase. It is less toxic than other anticancer drugs.

31. Indication
Metastatic carcinoma of breast, endometrial carcinoma
It is used as palliative treatment of advanced breast cancer
Dose:
10-20 mg BD.
Drug interaction:
Cocurrent administration of estrogen decreases effectiveness of tamoxifen

32. MITOTANE
Mechanism of Action:
Mitotane is an adrenal cytotoxic agent, although it can cause adrenal inhibition, apparently without
cellular destruction.
It modifies the peripheral metabolism of steroids as well as directly suppressing the adrenal cortex.
Mitotane also alters the extra-adrenal metabolism of cortisol in man; leading to a reduction in
measurable 17-hydroxy corticosteroids, even though plasma levels of corticosteroids do not fall.
The drug apparently causes increased formation of 6-β-hydroxycortisol.

33. Indications:
Mitotane is indicated in the treatment of inoperable adrenal cortical
carcinoma of both functional and nonfunctional types.

34. Cisplatin
It is a heavy metal platinum co-ordination complex containing a central atom of
platinum surrounded by two entities each of chloride ions and two ammonia
molecule in cis geometry. It is mainly excreted by the kidneys.
MOA
It inhibits both DNA and RNA synthesis by producing cross linkage of parent DNA
strands. Protein and RNA synthesis are also inhibited to a lesser extent. Is
antineoplastic actions are non cell-cycle specific
Indication
Metaststic testicular and ovarian carcinoma
Head, neck, cervical and lung cancer

35. Dose: 15-20 mg/m2 IV daily for 5 days every 3-4 weeks
ADR:
Seizure,anaemia, leucopenia
Drug interaction
Aminoglycosides,antibiotics, furosemide may produce nephrotoxicity and
ototoxicity effect of cisplastin
Contraindication: pregnancy, lactation, hypersensitivity

36. Interferon alpha 2a and 2b
Interferons (IFNs) are a group of signaling proteins made and released by host cells in response to the
presence of pathogens, such as viruses, bacteria, parasites, or tumor cells.

37. Interferon alfa-2a
Interferon alfa-2a, recombinant, is a sterile protein product for use by injection.
It is manufactured by recombinant DNA technology. Interferon alfa-2a,
recombinant is a highly purified protein containing 165 amino acids.
Interferon alfa 2b
An antiviral drug originally discovered in the laboratory of Charles Weissmann at
the University of Zurich.

38. Pharmacokinetics:
Interferons are well absorbed after intramuscular or subcutaneous
injections.
Interferons undergo glomerular filtration and are degraded during
reabsorption, but liver metabolism is minimal.

39. Indications:
Interferon alfa-2a is indicated for the treatment of chronic hepatitis C and
hairy cell leukemia in patients 18 years of age or older.
In addition, it is indicated for chronic phase, Philadelphia chromosome (Ph)
positive Chronic Myelogenous Leukemia (CML) patients who are minimally
pretreated within 1 year of diagnosis.

40. Interferon alfa 2b
It has been used for a wide range of indications, including viral infections and
cancers.
This drug is approved around the world for the treatment of chronic hepatitis C,
chronic hepatitis B, hairy cell leukemia, chronic myelogenous leukemia, multiple
myeloma, follicular lymphoma, carcinoid tumor, and malignant melanoma.

41. Mechanism of Action:
Interferons secreted from producing cells interact with surface receptors on other
cells, at which site they exert their effects.
Bound interferons are neither internalized nor degraded.
The α and β interferons compete with each other for binding and, therefore,
presumably bind at the same receptor or in close proximity; the β interferons bind
at different receptors.
As a consequence of the binding of interferon, a series of complex intracellular
reactions take place.
These include synthesis of enzymes, suppression of cell proliferation, activation of
macrophages, and increased cytotoxicity of lymphocytes.
However, the exact mechanism by which the interferons are cytotoxic is unknown.

42. Miscellaneous
sn Drugs MOA ADR USES
1 Hydroxy urea Blocks conversion of ribonucleotides
to deoxyribonucleotides by inhibiting
enzyme ribonucleoside phosphate
reductase
Myelosuppression
GI disturbances
Alopecia
stomatitis
Chronic
granulocytic
Leukemia
Polycythemia
Thrombocytosis
Some solid
tumours
2. Procarbazine Inhibits DNA, RNA and protein
synthesis
Vomiting
Leucopenia
Thrombocytopeni
a
Dermatitis
In hodgkins
disease
Lung cancer

43. 3. L- asparaginase Depletes asparagine from host
thus depriving malignant cells
from asparagine
Hypersensitivity
Decrease in clotting
factors
Pancreatitis
Seizures, coma
In childhood acute
lymphocyticlukemia
In reticulum cell
sarcoma
4. Cisplastin By intrastrand crossing of DNA
resulting in denaturation of
DNA chain
Nausea
Vomiting
Renal damage
Tinnitus
Hearing loss
In metastatic testicular
and ovarian cancer
In solid tumours

45. General toxicity of cytotoxic drugs
1. Bone marrow depression
Depression of bone marrow results in granulocytopenia,
agranulocytosis, thrombocytopenia, aplastic anaemia etc
2. Lymphoreticular toxicity
Lymphocytopenia and inhibition of lymphocyte function results in
suppression of cell mediated as well as humoral immunity
3. Oral cavity
It may produce stomatitis, trauma in gums and oral mucosa, bleeding
gums, xerostomia etc

46. 5. skin : alopecia,dermatitis
6. gonads : impotence in male, inhibition of ovulation and amenorrhea
in female
7. Foetus: abortion, foetal death, teratogenesis
8. carcinogenicity: secondary cancers like lukemias, lymphomas etc
9. hyperuricaemia: gout and urate stone in urinary tract

47. THANK YOU