This document discusses anti-neoplastic agents used to treat cancer. It begins by introducing malignant disease and cancer treatment options such as surgery, radiotherapy, chemotherapy, immunotherapy and gene therapy. It then categorizes anti-cancer drugs according to their chemical structure, mechanism of action, and cell cycle specificity. Examples of major drug classes discussed include alkylating agents, platinum compounds, antimetabolites, and plant extracts. Common mechanisms of action and adverse effects are also summarized for several representative drugs.

1. Anti-neoplastic Agent
Dr. Naga Prashant Koppuravuri,
M.Pharm, Ph.D, FAGE.,
Assistant Professor,
Department of Pharmaceutical Chemistry

2. Introduction
• Malignant disease accounts for a high proportion
of deaths in industrialised countries.
• The treatment with anticancer drug is to give
palliation, induce remission and if possible,
cure.

3. Introduction
 Cancer occurs after normal cells have been
transformed into neoplastic cells through alteration of
their genetic material and the abnormal expression of
certain genes.
 Neoplastic
abnormalities
cells
and
usually exhibit
of their
chromosomal
differentiated
the loss
properties. These changes lead
the
to uncontrolled cell
division and many result in invasion of previously
unaffected organs a process called metastasis.

5. Treatment options of cancer:
 Surgery: before 1955
 Radiotherapy: 1955~1965
 Chemotherapy: after 1965
 Immunotherapy and Gene therapy

6. According to chemical structure and

resource of the drug;
According to biochemistry mechanisms of

anticancer action;
According to the cycle or phase specificity

of the drug

7.  According to chemical structure and
resource
Alkylating
of the drug:
Agents, Antimetabolite,
Antibiotics, Plant Extracts，Hormones，
ImmunotherapyRadiotherapeutic Agents,
Cytoprotective Agents, Antineoplastic
Platinum Compounds

8.  According to biochemistry mechanisms of
anticancer action:
Block nucleic acid biosynthesis
Directly influence the structure and function
of DNA
Interfere
Interfere
Influence
transcription and block RNA synthesis
protein synthesis and function
hormone homeostasis

9. According
specificity
to the cycle or phase
of the drug:
Cell cycle specific agents (CCSA)
Cell cycle nonspecific agents (CCNSA)

10. The cycle of cell replication includes:
G1（ Gap1, period
before S） phase
S（ DNA synthesis）
phase
G2（ Gap2,period
after S） phase
M（ Mitosis） phase

11. The Basic Concept of
Cell Generation Cycle
The G1 phase is the period when newly created cell is
remains in the G1 phase
born. The period
depends upon the
cell).Cells can be
state.
of time the cell
type of cell (tumor cell or normal
born in proliferated or non-proliferated
If the cell is a proliferating cell,it will move quickly to
or synthesis phase. In this period, DNA replicates and
two copies of DNA are present in the cell.
The next phase is G2 phase and cells are prepared for
final cell cycle M phase or Mitosis.
There are two major control points in cell cycle, G1/S
phase, the cell replicates and G2 / M phase, the cell
divides.
G1 / S phase is important in understanding cancer and
cancer treatment.
S

12.  Tumor cells can be classified as proliferating
cells and
 The ratio
non-proliferating
of proliferating
cells.
cells in the whole
(GF).
tumor tissue is called growth fraction
Proliferating cell group
GF＝
Total tumor cell group

13.  The faster the tumor cells proliferate, the bigger
the GF is and the higher the sensitivity of tumor
to a drug is.
 Generally, in the early stage, the GF of a tumor
is bigger and the effect of a drug on the tumor is
better
CCNSA：drugs that are active throughout the cell
cycle.
CCSA: drugs that act during a specific phase of
the cell cycle.

14.  Cell Cycle Nonspecific Agents (CCNSA)
drugs
cycle
that are active throughout the cell
Alkylating Agents
Platinum Compounds
Antibiotics




15.  Cell Cycle Specific Agents (CCSA)
drugs that act during a specific phase of
the cell cycle
S Phase Specific Drug:
Antimetabolites, Topoisomerase Inhibitors
M Phase Specific Drug:
Vinca Alkaloids, Taxanes
G2 Phase Specific Drug:
Bleomycin

17.  Block nucleic acid (DNA, RNA) biosynthesis
 Directly destroy DNA and inhibit DNA
reproduction
 Interfere
 Interfere
 Influence
transcription and block RNA synthesis
protein synthesis and function
hormone homeostasis

18.  Alkylating Agent: mechlorethamine,
cyclophosphamide and
 Platinum: cis-platinium
thiotepa
 Antibiotic: bleomycin and mitomycin C
 Topoismerase inhibitor: camptothecine and
podophyllotoxin

19.  One of the frightening developments of World
War I was the introduction of chemical warfare.
These compounds were known as the nitrogen
mustard gases. The nitrogen mustards were
observed to inhibit cell growth, especially of bone
marrow. Shortly after the war, these compounds
were investigated and shown to inhibit the growth
of cancer cells.

20. Alkylating Agents
Alkylating agents were one of the earliest classes of drugs
used to treat cancer, beginning in the 1940’s.
The biggest weakness of most cancer cells is
very sensitive to DNA damage.
that they are
Alkylating agents work by reacting with the proteins that
double helix
bond together to form the very delicate
structure of a DNA molecule, adding an alkyl group to some
or all of them. This prevents the proteins from linking up
as they should, causing breakage of the DNA strands and
eventually, the death of the cancer cell.

21. Alkylating Agents
This phenomenon is essentially a mutation
the cancer cell’s ability to multiply.
that takes away
While there are many different classes of alkylating
agents, they all work by this same chemical mechanism.
Alkylating agents are highly electrophilic compounds which
react with nucleophiles to form a strong covalent bond.
It acts by transfer of alkyl group to biologically important
constituents such as amino, sulfhydryl or phosphate group
whose function is then impaired.

22. Alkylating Agents
Alkylating agents are known to react
RNA and protein
with DNA,
They act by alkylating N - 7 position of guanine
in DNA, which results in the formation of
apurinic site. The alkylating agent
most effective in G1 or S phase.
appears to be
H+ Y+
nu – H + alkyl - Y alkyl – nu + +
Alkylating
agent
Nucleophileof
biopolymer

23. Alkylating Agents
The five major categories of alkylating agents are
Nitrogen Mustards & aziridine mediated alkylators
Nitrosoureas
DNA Methylators
Organo Platinum Complexes
Miscellaneous DNA Alkylators

24. Nitrogen Mustards & aziridine mediated alkylators

26. Nitrosoureas

27. DNA Methylators

28. Organo Platinum Complexes

30. Miscellaneous DNA Alkylators

31. Resistance to
causes:
alkylating agents has several
 Membrane transport may be decreased.
 The drug may be bound by glutathione (GSH)
via GSH-S-transferase or metallothioneins
in the cytoplasm and inactivated.
 The drug
species.
may be metabolized to inactive

32.  Myelosuppression is the dose-limiting
adverse effect for alkylating agents.
 Nausea and vomiting are as common as
teratogenesis and gonadal atrophy,
although in the latter cases these are
variable, according to the drug, its
schedule, and route of administration.
 Treatment also carries a major risk of
leukemogenesis and carcinogenesis.

33. O
O
H2O
P
(ClCH2 CH2)2N
HN
2-[Bis (2-chloroethyl) amino] tetrahydro - 2H -1,3,2- oxazo -
phosphorin -2- oxide monohydrate
Use: It is used against multiple myeloma, chronic lymphocytic
leukemia and acute leukemia of children

34. Cisplatin:
Mechanism of Action:
 Cisplatin binds to guanine in DNA and RNA,
and the interaction is stabilized by
mechanism
hydrogen bonding. The molecular
of action is unwinding and shortening of the
DNA helix.

35. Cisplatin:
Indications:
 Cisplatin has efficacy against a wide range of
neoplasms. It is given intravenously as a first-
line drug for testicular, ovarian, and bladder
cancer, and it is also useful in the treatment of
melanoma and a number of other soild tumors.
 Cisplatin produces relatively little
myelosuppressio but can cause severe nausea,
vomiting and nephrotoxicity.
Adverse Effect:

36. Carboplatin:
Indication:
 Carboplatin has a similar spectrum of
activity, but it is approved only as a
second-line drug for ovarian cancer.

37. Antimetabolites:
• Folic Acid
reductase
• Pyrimidine
Antagonist: inhibit dihydrofolate
(methotrexate)
Antagonist: inhibit thymidylate
synthetase (fluorouracil) ; inhibit DNA
polymerase (cytarabine)
• Purine Antagonist: inhibit interconversion of
purine nucleotide (mercaptopurine)
• Ribonucleoside Diphosphate Reductase
Antagonist:
(hydroxyurea)

38. In the 1950's a biochemical difference in metabolism
related to the amino acid asparagine was found. Normal cells
cells
they
apparently can synthesize asparagine while leukemia
cannot. If leukemia cells are deprived of asparagine,
will eventually die If the enzyme L-asparaginase is given to
humans, various types of leukemias can be controlled. Tumor
cells, more specifically lymphatic tumor cells,
with
an
require huge
amounts
malignant
destroys
of asparagines to keep up
is
their rapid,
growth.
asparagine
L-asparaginase enzyme that
are
external to the cell. Normal cells
able to make all the asparagine they need internally whereas
tumor cells become depleted rapidly and die.
 Bind with DNA to block RNA production. doxorubicin

39. General Characteristics：
 Antimetabolites are S phase-specific
drugs that are structural analogues of
essential metabolites and that interfere
with DNA synthesis.
 Myelosuppression is the dose-limiting
toxicity for all drugs in this class.

41.  Folic acid Antagonists: MTX
 Purine Antagonists: 6MP
6TG
 Pyrimidine Antagonists： 5FU
araC
HU

42. Methotrexate （ MTX）
Mechanism of Action：
 The structures of MTX and folic acid are
similar. MTX is actively transported into
mammalian cells and inhibits dihydrofolate
reductase, the enzyme that normally converts
dietary folate to the tetrahydrofolate form
required for thymidine and purine synthesis.

43. Methotrexate （ MTX）
Indications：
 MTX is used in the treatment of
choriocarinoma, a trophoblastic tumor, was the
first demonstration of curative chemotherapy.
 It is especially effective for treating
lymphocytic leukemia and for treating
meningeal metastases of a wide range
acute
the
of tumors.

44. Methotrexate （ MTX
）
Adverse Effects：
 MTX is myelosuppressive, producing severe
leukopenia, bone marrow aplasia, and
thrombocytopenia.
 This agent may produce severe gastrointestinal
disturbances.
 Renal toxicity may occur because of precipitation
(crystalluria) of the 7-OH metabolite of MTX.

45. 6-Mercapapurine（ 6-MP）
The drugs are believed to act similarly to inhibit
purine base synthesis, although their exact
mechanisms of action are still uncertain.
Indications:
 Mercaptopurine is used primarily for the
maintenance of remission in patients with acute
lymphocytic leukemia and is given in combination
MTX for this purpose.
Adverse Effects:
with
 Well tolerate.
 Myelosuppression is generally mild with
thioguanine.Long-term mercaptopurine use may cause
hepatotoxicity.

46. 5-Fluorouracil (5-FU)
Mechanism of Action：
 Fluorouracil is an analogue of thymine
methyl group is replaced by a fluorine
two active metabolites: 5-FdUMP and
in which the
atom. It has
5-FdUTP. 5-
FdUMP inhibits thymidylate synthetases and
the synthesis of thymidine, a major building
DNA. 5-FdUTP is incorporated into RNA by
prevents
block of
RNA
polymerase and interferes with RNA function.

47. 5-Fluorouracil (5-FU)
Indications：
 Fluorouracil is exclusively used to treat
solid tumors, especially breast, colorectal,
and gastric tumors and
and
squamous cell
neck.
tumors of the head

48. 5-Fluorouracil (5-FU)
Adverse Effects：
 Fluorouracil may cause nausea and vomiting,
myelosuppression, and oral and gastrointestinal
ulceration. Nausea and vomitting are usually mild.
 With fluorouracil, myelosuppression is more
problematic after bolus injections, whereas
mucosal damage is dose-limiting with continuous
infusions.

49. Cytarabine
Indications：
 Cytarabine has a narrow clinical spectrum and is
primarily used in combination with daunorubicin or
thioguanine for the treatment of acute
nonlymphocytic leukemia.
 High doses of cytarabine can damage the liver,
heart, and other organs.
Adverse Effects:

50. Pyrimidine antagonists:

51. Purine antagonists:

52. Folate antagonists:

53. DNA polymerase and chain elongation inhibitors:

55. Miscellaneous antimetabolites:

56. A. Fluorouracil (5FU – CBC, Flocil)
O
F
HN
O
N
H
5-Fluoro - 2, 4- (1H, 3H) pyrimidindione.
O
O
CF3OF
Fluoroxy tri
fluoro methane
HN F
HN
O Fluorination
N
H
Uracil
O
N
H
Fluorouracil
Use: It is effective in palliative management of carcinoma of the breast, colon,
pancreas, rectum and stomach in patient who cannot be cured by surgery. It is also
used in the treatment of skin and basal cell carcinomas.

57. S
H
N
N
N
H2N N
H
2-Amino-7H-purin-6-thiol
It is a guanine analogue, belongs to the family of drugs called
antimatabolites. Its act by integrated into DNA and RNA, which
result in the inhibition of synthesis and metabolism of purine
nucleotides.

58. Topoisomerase Poisons
Three chemically distinct classes of anticancer
agents can be classified as topoisomerase
poisons:
• Camptothecins,
• Epipodophyllotoxins
• Anthracyclines (discussed under
antineoplastic antibiotics).

60. Topoisomerases are enzymes that control the degree of
DNA supercoiling and, in so doing, maintain proper DNA
structure during replication and transcription to RNA.
Topoisomerase IIα (TopIIα) cleaves doublestranded DNA
during the replication phase via a transesterifi cation
reaction involving a topoisomerase tyrosine residue and a
terminal 5′ phosphate but, through a reverse transesterifi
cation, repairs its own damage after replication is
complete. Topoisomerase I (TopI) functions in essentially
the same way, but cuts and relegates a single DNA strand.
Antineoplastic agents that
MECHANISM OF ACTION

61. Epipodophyllotoxins

62. Classification of Antibiotics:
 Adriamycin (Anthracyaline Antibiotics)
 Mitomycin
 Bleomycin
C
 Actinomycin D

63. Adriamycin and Daunorubicin：
Properties:
 Adriamycin and Daunorubicin are tetracycline rings
with the sugar daunosamine. They are DNA
intercalating agents that block the synthesis of DNA
and RNA.
 These
of cell
 These
agents are primarily toxic during the S phase
cycle.
agents imparts a red tinge to the urine.
 Adramycin is used to treat acute leukemias, lymphoma,
and a number of solid tumors.

64. Mitomycin C:
Mechanism:
 Mitomycin C is an antineoplastic antibiotic that
alkylates DNA and thereby causes strand
breakage and inhibition of DNA synthesis.
Indications:
 It is primarily used in combination with
vinvristine as salvage therapy for breast cancer.
Adverse Effects:
 Mitomycin produces delays and prolonged
affects
myelosuppression that preferentially
platelets and leukocytes.

65. Actinomycin D:
 Actinomycin D intercalates DNA and thereby
prevents DNA transcription and messenger RNA
synthesis.
 The drug is given intravenously, and its clinical use
is limited to the treatment of trophoblastic
(gestational) tumors and the treatment of
pediatric tumors, such as Wilms’ tumor and Ewing’s
sarcoma.

66. Bleomycin:
Mechanism:
 The drug has its greatest effect on neoplastic
cell in the G2 phase of the cell replication
cycle.Although bleomycin intercalates DNA, the
major cytotoxicity is believed to result from
ironcatalyzed free radical formation and DNA
strand breakage.
Indications:
 It is useful in Hodgkin’s and non-Hodgkin’s
lymphomas, testicular cancer, and several other
solid tumors.
Adverse Effects:
 Bleomycin produces very little myelosuppression.
The most serious toxicities of Bleomycin are
pulmonary and mucocutaneous reactions.

67. Antibiotics

73. Anthracycline-based antineoplastic agents
act by poisoning TopIIα through the
stabilization of the ternary drug–enzyme–
DNA cleavable complex. Like the
topoisomerase poisons discussed earlier,
they allow DNA to be cut and covalently
linked to the conserved topoisomerase Tyr
residue but inhibit the resealing reaction.
MECHANISM OF ACTION

74. Antitubulin: Mitotic spindles serve as molecular railroads
with "North and South Poles" in the cell when a cell
starts to divide itself into two new cells. These spindles
are very important because they help to split the newly
copied DNA such that a copy goes to each of the two
new cells during cell division. These drugs disrupt the
formation of these spindles and therefore interrupt cell
division vinca alkaloids and taxanes;

ribosome: harringtonines；
Interfere the function of

Influence amino acid supply: L-asparaginase
Bind tubulin, destroy spindle to produce mitotic arrest.


75.  Tubulin-Binding Agents
Vinca Alkaloids: The cellular mechanism of
action of vinca alkaloids is the prevention of
microtubule assembly, causing cells to arrest
in the late G2 phase by preventing formation
of mitotic filaments for nuclear and cell
division.

76.  Tubulin-Binding Agents
 Vinca alkaloids:
Vinblastine,vincristin, vindesine and vinorelbine are all
alkaloids derived from the periwinkle plant (Vinca rosea).
Indications:
 Vinblastine is used in combination with Bleomycin and
Cisplatin for metastatic testicular tumors.
 Vincristine is used in combination with prednisone to
induce remission in childhood leukemia.
 Vinorelbine is used to treat non-small-cell lung
cancer and breast cancer.

79.  Tubulin-Binding Agents
 Paclitaxel:
Taxane enhance all aspects of tubulin
polymerization an action that is the opposite to
tha of vinca alkaloids, but they are also cytotoxic,
emphasizing the dynamic importance of tubulin
polymerizatio as a target for cytotoxic drugs.
Paclitaxel, Taxotere

82.  Interfere the Function of Ribosome:
 Cephalotaxus Alkaloids
Harringtonine
Homoharringtonine
:

83. These drugs bind to hormone receptors to block
the actions of the sex hormones which results
inhibition of tumor growth.
Estrogens and estrogen antagonistic drug
Androgens and androgen antagonistic drug
Progestogen drug
Glucocorticoid drug
gonadotropin-releasing hormone inhibitor:
leuprolide, goserelin
aromatase inhibitor: aminoglutethimide,
anastrazole
in







84.  Several types of hormone-dependent cancer
(especially breast, prostate, and endometrial
cancer) respond to treatment with their
corresponding hormone antagonists.
 Estrogen antagonists
treatment of breast
antagonists are used
are primarily used in the
cancer, whereas androgen
in the treatment of prostate
cancer. Corticosteroids are particularly useful in
treating lymphocytic leukemias and lymphomas.

85. Estrogens:
 Estrogens inhibit the effects of endogenous
androgen and androgen-dependent metastatic
prostati carcinoma. Diethylstilbestrol is usually
the agent of choice.
 Cardiac and cerebrovascular complications and
carcinoma of the male breast are potential
adverse effects.

86. Progenstins:
 Progestins are useful in the management of
endometrial carcinoma and back-up therapy for
metastatic hormone-dependent breast cancer.

87. Antiestrogen: Tamoxifen
 Tamoxifen is the drug of choice in postmenopausal
women with or recovering from metastatic breast
cancer. It is most effective in patients who have
estrogen receptor-positive tumors.
 Tamoxifen is also used as adjunvctive therapy to
oophorectomy to leuprolide or goserelin in
premenopausal women with estrogen receptor-
positive tumors.

88. Androgens:
 Androgen activity in breast cancer is similar to
that of estrogens, perhaps for the same
mechanistic reasons.
 Virilizing effects and hepatic toxicity make them
unacceptable to most patients.
 Fluoxymesterone is the most widely used agent.
 Danazol has use in hematology in aplastic anemia
and congenital anemias.

89. Glucocorticoids:
 They are integral components of curative therapy
for acute lymphoblastic leukemia, non-Hodgkin’s
lymphoma, and Hodgkin’s disease.
 Glucocorticoids have essential roles in the
prevention of allergic reaction, emesis control,
relief of intracranial hypertension or spinal cord
compression in neurologic complications, and pain
relief.

90.  Drug
 Drug
Resistance
Toxicity

91.  De novo Resistance
 Acquired Resistance
 Multidrug Resistance (MDR)

92. De novo resistance:
 De novo resistance can be de novo genetic (i.e.
the cells are initially inherently resistant), or can
arise because drugs are unable to reach the
target cells because of permeability barriers such
as the blood-brain barrier.

93. Acquired Resistance:
 Acquired drug resistance may result from genomic
mutations, such as the induction or deletion of
enzymes involved in drug inactivation or drug
activation, respectively.

94. Multidrug Resistance (MDR):
 P-glycoprotein transports many naturally occurring
drugs out of neoplastic cells, and its induction may
lead to multidrug resistance.
 As scientific understanding of the mechanisms of
dru resistance increases, new treatments may be
developed to counteract resistance.

95.  The most common toxicities of antineoplastic drugs
result from inhibition of cell replication in the
bone marrow, gastrointestinal epithelium, and hair
follicles. Many antineoplastic drugs also stimulate
the chemoreceptor trigger zone in the medulla and
thereby elicit nausea and vomiting.

96. Immunosuppressive Agents:
 Act to suppress immune mechanisms and are
used to treat autoimmune diseases or to prevent
graft rejection following tissue transplantation.
 Ciclosporin, Tacrolimus, adrenocortical
hormones,
antimetabolites, alkylating agent,
antilymphocyte globulin, Mycophenolate Mofetil

97. Synthesis of chlorambucil
Chlorambucil

98. Mercaptopurine
Synthesis of Mercaptopurine

99. Synthesis of Busulphan

100. Synthesis of Methotrexate

101. Synthesis of 5- fluro uracil

102. Synthesis of Cyclophosphamide

103. Thanks!