ANTI - CANCER
DRUGS
The Classification of
Anticancer Drugs
According to the cycle or phase
specificity of the drug:
cell cycle nonspecific agents (CCNSA)
cell cycle specific agents (CCSA)
CCNSA ： drugs that are active
throughout the cell cycle.
CCSA: drugs that act during a
specific phase of the cell cycle.
Cell cycle specific agents and Cell
cycle
Non-specific agents
Cell Cycle Nonspecific Agents (CCNSA)
drugs that are active throughout the
cell cycle
Alkylating Agents
Platinum Compounds
Antibiotics
Cell cycle specific agents and Cell
cycle
Non-specific agents
Cell Cycle Specific Agents (CCSA)
drugs that act during a specific
phase of the cell cycle
S Phase Specific Drug:
Aantimetabolites, Topoisomerase
Inhabitors
M Phase Specific Drug:
Vinca Alkaloids, Taxanes
G2 Phase Specific Drug:
Bbleomycin
Mechanism of Anticancer
Drugs
• Block nucleic acid (DNA, RNA) biosynthesis
• Directly destroy DNA and inhibit DNA
reproduction
• Interfere transcription and block RNA
synthesis
• Interfere protein synthesis and function
• Influence hormone homeostasis
Alkylating Agents
• 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.
Alkylating Agents
Mechanism of Action
• Nitrogen mustards inhibit cell reproduction by
binding irreversibly with the nucleic acids
(DNA). The specific type of chemical bonding
involved is alkylation. After alkylation, DNA is
unable to replicate and therefore can no
longer synthesize proteins and other
essential cell metabolites. Consequently, cell
reproduction is inhibited and the cell
eventually dies from the inability to maintain
its metabolic functions.
Classification of Alkylating
Agents
Bis Chloroethyl Amines ：
Cyclophosphamide, Chlormethine, Chlorambucil,
Sarcolysine
Nithrosoureas ：
Carmustine ， Lomustine
Ethyeneammonium or Aziridines ：
Thiotepa ， triethylene melamine
Alkysulfonates ： Busulfan
Adverse Effects of Alkylating
Agents
• Myelosuppression is the dose-limiting
adverse effect for alkylating agents.
• Nausea and vomiting are common as
are 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.
Alkylating Agents——
Mustine
• Mustine must be injected
intravenously because it is highly
reactive. It disappears very rapidly
from the blood, the activity of
Mustine lasts only a few minutes.
• The main indication for Mustine is in
treatment of Hodgkins lymphoma
disease but it may also be useful in
other malignancies.
Alkylating Agents——
Cyclophosphamide
Cyclophosphamide can also be given orally.
Indications ：
It is used in the treatment of chronic
lymphocyctic leukemia, non-Hodgkin’s
lymphomas, breast and ovarian cancer, and a
variety of other cancers.
It is also a potent immunosuppressant, it is used
in the management of rheumatoid disorders and
autoimmune nephritis.
Adverse Effects:
Alopecia, nausea, vomiting, myelosuppression,
and hemorrhagic cystitis.
Alkylating Agents——
• Melphalan is a nitrogen mustard that
is primarily used to treat multiple
myeloma (plasma cell myeloma),
breast cancer, and ovarian cancer.
Alkylating Agents——
Nitrosoureas
Carmustine, Lomustine, Semustine
Pharmacokinetics:
• Nitrosoureas are highly lipophilic and
reach cerebrospinal fluid
concentrations that are about 30% of
plasma concentrations.
Indications:
• Because of their excellent CNS
penetration, carmustine and
lomustine have been used to treat
brain tumors.
Platinum Compound
Cisplatin:
Mechanism of Action:
• Cisplatin binds to guanine in DNA
and RNA, and the interaction is
stabilized by hydrogen bonding. The
molecular mechanism of action is
unwinding and shortening of the
DNA helix.
Platinum Compound
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.
Adverse Effect:
• Cisplatin produces relatively little
myelosuppression but can cause severe
nausea, vomiting, and nephrotoxicity.
Platinum Compound
Carboplatin:
Indication:
• Carboplatin has a similar spectrum
of activity, but it is approved only as
a second-line drug for ovarian
cancer.
Alkylating Agents——
Alkysulfonates
Busulfan
Indications:
• Busulfan is administered orally to treat chroic
granulocytic leukemia (a cancer of the white blood cells)
and other myeloproliferative disorders. MPDs
are blood cancers caused by changes in the stem cells inside bone marrow
Adverse Effects:
• Busulfan produces advers effects related to
myelosuppression. It only occasionally produces
nausea and vomitting. In high doses, it
produces a rare but sometimes fatal pulmonary
fibrosis, ”busulfan lung”.
Antimetabolites
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.
Classification of
Antimetabolites
Folic acid Antagonists: MTX
Purine Antagonists: 6MP
6TG
Pyrimidine Antagonists ： 5FU
araC
HU
Antimetabolites——
Folic Acid Antagonist
Methotrexate （ MTX ）
Mechanism of Action ：
Thestructures 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.
Antimetabolites——
Folic Acid Antagonist
Methotrexate （ MTX ）
Indications ：
• The use of MTX in the treatment of
choriocarinoma, a trophoblastic tumor, was
the first demonstration of curative
chemotherapy.
• It is especially effective for treating acute
lymphocytic leukemia and for treating the
meningeal metastases of a wide range of
tumors.
Antimetabolites——
Folic Acid Antagonist
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.
Antimetabolites——
Purine Antagonists
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 with MTX for this purpose.
Adverse Effects:
• Well tolerate.
• Myelosuppression is generally mild with
[Link]-term mercaptopurine use
may cause hepatotoxicity.
Antimetabolites——
Pyrimidine Antagonists
5-Fluorouracil (5-FU)
Mechanism of Action ：
• Fluorouracil is an analogue of thymine in which the
methyl group is replaced by a fluorine atom. It has
two active metabolites: 5-FdUMP and 5-FdUTP. 5-
FdUMP inhibits thymidylate synthetases and
prevents the synthesis of thymidine, a major
building block of DNA. 5-FdUTP is incorporated into
RNA by RNA polymerase and interferes with RNA
function.
Antimetabolites——
Pyrimidine Antagonists
5-Fluorouracil (5-FU)
Indications ：
• Fluorouracil is exclusively used to
treat solid tumors, especially breast,
colorectal, and gastric tumors and
squamous cell tumors of the head
and neck.
Antimetabolites——
Pyrimidine Antagonists
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.
Antimetabolites——
Pyrimidine Antagonists
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.
Adverse Effects:
• High doses of cytarabine can damage the liver,
heart, and other organs.
Antibiotic
Classification ofs
Antibiotics:
• Adriamycin (Anthracyaline Antibiotics)
• Mitomycin C
• Bleomycin
• Actinomycin D
• Mechanism of action
• The anthracyclines ( doxorubicin , daunorubicin, idarubicin ,
epirubicin , mitoxantrone ) intercalate between base pairs, inhibit
topoisomerase II, and generate free radicals. They block the
synthesis of RNA and DNA and cause DNA strand scission.
Membrane disruption also occurs. Anthracyclines are CCNS drugs.
Antibiotics
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 agents are primarily toxic during the S
phase of cell cycle.
• These agents imparts a red tinge to the urine.
• Adramycin is used to treat acute leukemias,
lymphoma, and a number of solid tumors.
Antibiotics
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
vincristine as salvage therapy for breast
cancer.
Adverse Effects:
• Mitomycin produces delays and prolonged
myelosuppression that preferentially affects
platelets and leukocytes.
Antibiotics
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.
Antibiotics
Bleomycin:
Mechanism:
• The drug has its greatest effect on
neoplastic cell in the G2 phase of the cell
replication [Link] 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.
Plant
Allaloids
• Tubulin-Binding Agents
• A group of proteins found in high levels in the cell
cytoplasm (fluid inside a cell but outside the cell's
nucleus). Tubulins are the building blocks of microtubules
(narrow, hollow tubes inside a cell), which are involved
in cell division and cell movement.
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.
***During mitosis, chromosome movement and segregation are arranged by a
specialized structure known as the mitotic spindle.
**Mitotic spindle, composed of a bipolar array of microtubules. The fundamental
structure of microtubules comprises of α/β-tubulin**
Plant Allaloids
• 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.
Plant Allaloids
• Tubulin-Binding Agents (Taxanes Group)
• Paclitaxel:
Taxanes enhance all aspects of tubulin
polymerization, an action that is the
opposite to that of vinca alkaloids, but
they are also cytotoxic, emphasizing the
dynamic importance of tubulin
polymerization as a target for cytotoxic
drugs.
Paclitaxel, Docetaxel
Taxanes (Paclitaxel,
Docetaxel)
•The first compound of this series, paclitaxel
(TAXOL, others), was isolated from the bark
of the Western yew tree in 1971
•Mechanism of Action: these drugs are
antimitotic agent that blocks cancer cell
growth by stopping cell division, resulting in
cell death. By stabilizing microtubules and
disrupting mitotic spindle formation,
paclitaxel specifically targets cancer cells
and reduces their ability to proliferate.
• Mechanism of action
• [Link] and docetaxel interfere with the
mitotic spindle. They act differently from vinca
alkaloids, since they prevent microtubule
disassembly into tubulin monomers.
• 2. They enhance polymerization of tubulin.
• 3. The microtubules are stabilized and their
depolymerization is prevented
• 4. Abnormal bundles of microtubles are
produced throughout the cell.
• Uses: Approved indications of paclitaxel are
metastatic ovarian and breast carcinom.
Epipodophyllotoxin (
TOPOISOMERASE-2 INHIBITOR)
•Etoposide : It is a semisynthetic derivative of
podophyllotoxin a plant glycoside Mechanisms of
action
•1. Etoposide, It induces DNA breakage through its
inhibition of topoisomerase-II enzyme.
•2. Resealing of DNA strand is prevented.
•3. The drug is most active in the late S and early
G2 phases of the cell cycle.
•4. Teniposide is an analog with very similar
pharmacologic characteristics.
Uses of Etoposide:
• These agents are used in
combination drug regimens for
therapy of lymphoma, and lung,
germ cell, and gastric cancers.
TOPOISOMERASE-1 INHIBITORS
Camptothecin analogues
• Topotecan, is semisynthetic analogues of
camptothecin, an antitumour principle obtained
from a Chinese tree.
• They act in a manner similar to etoposide, but
interact with a different enzyme (DNA
topoisomerase-1).
• Their binding to this nuclear enzyme allows
single strand breaks in DNA, but not its
resealing after the strand has untwisted.
• They damage DNA during replication; act in
the S phase and arrest cell cycle at G2 phase.
Topotecan
•Used in metastatic carcinoma of ovary
and small cell lung cancer.
•Combined with cisplatin, it has been
used in cervical cancer.
•Toxicity is bone marrow depression,
especially neutropenia. Other adverse
effects are pain abdomen, vomiting
anorexia and diarrhea.
Protein tyrosine kinase
inhibitors:
• Mechanism of action
• 1. It inhibits the tyrosine kinase activity a protein
product of the bcr-abl oncogene that is commonly
expressed in chronic myelogenous leukemia (CML).
• 2. In addition to its activity in CML, imatinib is
effective for treatment of gastrointestinal stromal
tumors that express the c-kit tyrosine kinase, which
is also inhibited. Uses: Chronic myeloid leukaemia
• Hydroxyurea (HU)
• 1. This drug has unique and surprisingly
diverse biological effects as an anti-leukemic
drug, radiation sensitizer.
• 2. HU inhibits the enzyme ribonucleoside
diphosphate reductase, which catalyzes the
reductive conversion of ribonucleotides to
deoxyribonucleotides, a rate-limiting step in
the biosynthesis of DNA.
• 3. The drug is specific for the S phase of the
cell cycle.
• Enzymes: L-Asparaginase (L-ASP)
• The enzyme is obtained from E-coli, necessary for the
production of proteins. Cancer cells lack the enzyme L-ASP
synthase.
• Mechanism of Action
• 1. Most normal tissues are able to synthesize L-asparagine in
amounts sufficient for protein synthesis, but lymphocytic
leukemias lack adequate amounts of asparagine synthetase,
and derive the required amino acid from plasma.
• 2. L-ASP, by catalyzing the hydrolysis of circulating asparagine
to aspartic acid and ammonia, deprives these malignant cells
of asparagine, leading to cell death.
• 3. L-ASP is used in combination with other agents, including
methotrexate, doxorubicin, vincristine, and prednisone for
the treatment of ALL and for high-grade lymphomas.
Hormones
• Several types of hormone-dependent
cancer (especially breast, prostate, and
endometrial cancer) respond to treatment
with their corresponding hormone
antagonists.
• Estrogen antagonists are primarily used in
the treatment of breast cancer, whereas
androgen antagonists are used in the
treatment of prostate cancer.
Corticosteroids are particularly useful in
treating lymphocytic leukemias and
lymphomas.
Hormones
Estrogens:
• Estrogens inhibit the effects of
endogenous androgens and androgen-
dependent metastatic prostatic carcinoma.
Diethylstilbestrol is usually the agent of
choice.
• Cardiac and cerebrovascular complications
and carcinoma of the male breast are
potential adverse effects.
Hormones
Progenstins:
• Progestins are useful in the management
of endometrial carcinoma and back-up
therapy for metastatic hormone-dependent
breast cancer.
Hormones
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.
Pre-menopausal women
• It is the most common medication of this
type recommended to premenopausal
women. Most often tamoxifen is given after
treatment for breast cancer is complete, to
prevent the cancer from recurring.
Hormones
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.
Hormones
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.
Problems With Cancer
Chemotherapy
• Drug Resistance
• Drug Toxicity
Drug Toxicity
• 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.
Immunomodulating Drugs
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
Immunomodulating Drugs
Immunopotentiator :
• Enhance antitumor immunity and are used
to treat neoplastic disease.
• Recombinant Interferons and Cytokines.
Thanks
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