ANTI-CANCER DRUGS

Dr Mwatonoka Joyce 1
 Outline
• Introduction
• Classification of anti-cancer drugs
• Anticancer drugs mechanisms of action
-Alkylating agents
-Antimetabolites
-Cytotoxic antibiotics
-Plant delivatives
-Hormones
-Monoclonal antibodies
-Miscellaneous
Dr Mwatonoka Joyce 2
 Introduction
• Cancer is a disease characterized by
uncontrolled multiplication and spread of
abnormal forms of the body's own cells
• A normal cell turns into a cancer cell because
of one or more mutations in its DNA, which
can be acquired or inherited

Dr Mwatonoka Joyce 3
 Cont…
• Cancer arises as a result of a series of genetic
and epigenetic changes, the main genetic
lesions being:
– inactivation of tumor suppressor genes
– the activation of oncogenes (mutation of the
normal genes controlling cell division and other
processes).

Dr Mwatonoka Joyce 4
 Cont…
• Cancer cells characteristics that distinguish
them from normal cells;
i. Uncontrolled proliferation
ii. Dedifferentiation and loss of function
iii. Invasiveness
iv. Metastasis

Dr Mwatonoka Joyce 5
Cont…

Dr Mwatonoka Joyce 6
 Acquired
8. CARCINOGENESIS
Normal Cell
(environmental DNA
damaging agents) Successful DNA repair
Chemicals DNA Damage
Radiation
Failure of DNA repair
viruses
Mutations in the genome of
somatic cells

Activation of growth Alteration of genes that Inactivation of cancer

promoting oncogene regulates apoptosis suppressor genes

Expression of altered gene products

Loss of regulatory gene product

•Clonal expansion
•Additional mutations
•Heterogeneity

MALIGNANT NEOPLASM

Dr Mwatonoka Joyce 7
 Cont…
• Because most of anticancer drugs are
antiproliferative, they also affect rapidly
dividing normal cells and are thus likely to
depress bone marrow, impair healing and
depress growth
• Most cause nausea, vomiting, sterility, hair
loss (reversible alopecia) and teratogenicity

Dr Mwatonoka Joyce 8
 Classification of anticancer drugs
• Cell cycle–specific (CCS) drugs; acts on
proliferating cells, are most effective in
hematologic malignancies and in solid tumors
in which a relatively large proportion of the
cells are proliferating
• Cell cycle–nonspecific (CCNS) drugs; can kill
both G0 and cycling cells (although cycling cells
are more sensitive). Are used in slow growing
tumors
Dr Mwatonoka Joyce 9
Dr Mwatonoka Joyce 10
 CCNS
• Alkylating agents – Cyclophosphamide,
Nitrosourea
• Platinum compounds- Cisplatin, Carboplatin
• Anthracyclines- Doxorubicin, Daunorubicin
• Antitumor Antibiotics- Dactinomycin,
Mitomycin C

Dr Mwatonoka Joyce 11
CCS Drugs
• GI – Etoposide
• S (Antimetabolites)
Folic acid analogues- Methotrexate
Purine analogues- 6-MP, 6-TG
Pyrimidine analogues- 5-FU, Capecitabine,
Cytarabine
• G2- Topoisomerase inhibitors ( Irinotecan,
Topoptecan), Bleomycin
• M – Vinca alkaloids ( Vincristine, Vinblastine)
Taxanes ( Paclitaxel, Docetaxel)
Dr Mwatonoka Joyce 12
Cell Cycle Specific (CCS) & Cell Cycle Non-Specific Agents
(CCNS)
 1. Alkylating agents
• Contain chemical groups that can form cross-
bridge covalent bonds with DNA, as well as
other nucleophilic substances in the cell
• Alkylating agents form a carbonium ion-a
cation, which is highly reactive and react
instantaneously with an electron donor
(nucleophile) such as an amine, hydroxyl or
sulfhydryl group

Dr Mwatonoka Joyce 14
 Cont…
• The major site of alkylation within DNA is the
N7 position of guanine
• To a lesser degree N1 and N3 of adenine, N3
of cytosine, and O6 of guanine, as well as
phosphate atoms and proteins associated with
DNA
• Eg; cyclophosphamide

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Dr Mwatonoka Joyce 16
Dr Mwatonoka Joyce 17
 2. Antimetabolites
These block or subvert one or more of the
metabolic pathways involved in DNA synthesis
a) Folate antagonists eg; methotrexate
• Folates are essential for the synthesis of
purine nucleotides and thymidylate, which in
turn are essential for DNA synthesis and cell
division
• Methotrexate inhibits dihydrofolate reductase

Dr Mwatonoka Joyce 18
 Cont…
• Dihydrofolate reductase converts the folate
substrate (polyglutamates) first to
dihydrofolate (FH2), then to FH4
• FH4 functions as an essential cofactor carrying
the methyl groups necessary for the
transformation of 2´-deoxyuridylate (DUMP)
to the 2´-deoxythymidylate/deoxythymidine
monophosphate (DTMP) required for the
synthesis of purines and DNA
Dr Mwatonoka Joyce 19
Dr Mwatonoka Joyce 20
Dr Mwatonoka Joyce 21
 Cont…
b) Purine antagonists – e.g 6-mercaptopurine,
inhibits several enzymes for purine biosynthesis.
Also forms metabolites like 6-
methylmercaptopurine ribotide (MMPR) which
contribute to its cytotoxic action. Fludarabine in
its trisphosphate form inhibits DNA polymerase
c) Pyrimidine antagonist – eg 5-fluorouracil, also
inhibit thymidylate synthetase hence inhibiting
thymidilate synthesis
-Cytarabine; inhibits DNA polymerase
Dr Mwatonoka Joyce 22
 3. Cytotoxic Antibiotics
• Is a widely used group of drugs that mainly
produce their effects through direct action on
DNA
• As a rule, they should not be given together
with radiotherapy, as the cumulative burden
of toxicity is very high

Dr Mwatonoka Joyce 23
 a) Doxorubicin
• DNA intercalation, Doxorubicin forms
complexes with DNA through G bases in both
of the DNA strands and prevents
Topoisomerase II activity consequent in cell
cycle disruption and cell death
• Topoisomerase II (a DNA gyrase); relaxes DNA
super coils by nicking to facilitate DNA
replication/during RNA transcription

Dr Mwatonoka Joyce 24
Cont…

Dr Mwatonoka Joyce 25
 b) Dactinomycin
• Intercalates in the minor groove of DNA
between adjacent guanosine-cytosine pairs,
interfering with the movement of RNA
polymerase along the gene and thus
preventing transcription
• It affects mRNA and protein synthesis
• Also has an effect on topoisomerase II

Dr Mwatonoka Joyce 26
 c) Bleomycins
• Are a group of metal-chelating glycopeptide
antibiotics that degrade preformed DNA,
• DNA-Bleomycin-Fe+2 complexes undergo
oxidation, the released electrons react with
oxygen to form superoxide or hydroxyl radicals
which attack phosphodiester bonds causing
chain fragmentation and release of free bases
• Bleomycin is most effective in the G2 phase, but
it is also active against non-dividing cells
Dr Mwatonoka Joyce 27
Cont…

Dr Mwatonoka Joyce 28
 4. Plant derivatives;
a) Vinca Alkaloids
• Are derived from the Madagascar periwinkle
• The principal members are vincristine,
vinblastine and vindesine
• The drugs bind to tubulin and inhibit its
polymerisation into microtubules, preventing
spindle formation in dividing cells and causing
arrest at metaphase
• Their effects become manifest only during
mitosis
Dr Mwatonoka Joyce 29
Cont…

Dr Mwatonoka Joyce 30
 b) Taxanes
• Derived from the bark of the yew tree
• They bind on microtubules, stabilising them (in
effect 'freezing' them) in the polymerised
state, achieving a similar effect to that of the
vinca alkaloids by arresting mitosis

Dr Mwatonoka Joyce 31
 5. Hormones
• Hormone-dependent tumors have steroid
receptors in the malignant cells
• Their growth can be inhibited by hormones
with opposing actions, by hormone
antagonists or by agents that inhibit the
endogenous hormone synthesis
• Hormones or their analogues that have
inhibitory actions on target tissues can be
used in treatment
Dr Mwatonoka Joyce 32
 Cont…
• Such procedures alone rarely effect a cure but
do mitigate the symptoms of the cancer
• Glucocorticoids such as prednisolone and
dexamethasone have marked inhibitory effects
on lymphocyte proliferation and are used in
the treatment of leukaemias and lymphomas

Dr Mwatonoka Joyce 33
 Cont…
• Oestrogen; Diethylstilbestrol and ethinyloestradiol
used clinically in the palliative treatment of
androgen-dependent prostatic tumours. However,
they have been largely replaced by the GnRH
analogues because of fewer adverse effects
• Estrogens inhibit the growth of prostatic tissue by
blocking the production of LH in the pituitary
gland, thereby decreasing the synthesis of
androgens in the testis

Dr Mwatonoka Joyce 34
 Cont…
• Gonadotrophin-releasing hormone
analogues; inhibit gonadotrophin release.
Used to treat advanced breast cancer in
premenopausal women and prostate cancer.
• The transient surge of testosterone secretion
that can occur in patients treated in this way
for prostate cancer can be prevented by an
antiandrogen such as cyproterone

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Dr Mwatonoka Joyce 36
 Hormone antagonists
• Antioestrogens eg; tamoxifen competes with
endogenous oestrogens for the oestrogen
receptors and therefore blocking the proliferation
actions of estrogen on mammary epithelium
• Antiandrogens, flutamide and bicalutamide, may
be used either alone or in combination with other
agents to treat tumours of the prostate. They are
also used to control the 'flare' that is seen when
treating patients with gonadorelin analogues

Dr Mwatonoka Joyce 37
 6. Monoclonal antibodies
• Are immunoglobulins, of one molecular type,
produced by hybridoma cells in culture, that react
with defined target proteins expressed on cancer cells
• In some cases, binding of the antibody to its target
activates the host's immune mechanisms and the
cancer cell is killed by complement-mediated lysis or
by killer cells
• Other attach to and inactivate growth factor
receptors on cancer cells, thus inhibiting the survival
pathway and promoting apoptosis
Dr Mwatonoka Joyce 38
 Cont…
• Rituximab used (in combination with other
chemotherapeutic agents) for treatment of certain
types of lymphoma. It lyses B lymphocytes by
binding to the calcium channel-forming CD20
protein and activating complement. It also
sensitises resistant cells to chemotherapeutic
drugs
• Alemtuzumab is another monoclonal antibody
that lyses B lymphocytes, and is used in the
treatment of resistant CLL
Dr Mwatonoka Joyce 39
 7. Miscellaneous agents
• Crisantaspase; is a preparation of the enzyme
asparaginase
• It breaks down asparagine to aspartic acid and
ammonia, active against tumour cells that
have lost the capacity to synthesize
asparagine and therefore require an
exogenous source, such as those of ALL
• The drug has a fairly selective action

Dr Mwatonoka Joyce 40
PRINCIPLES OF COMBINATION
CHEMOTHERAPY

• Use drugs active as a single agent

• Use drugs with different mechanisms of action
• Use drugs with different mechanisms of resistance
• Use drugs with different side-effects
• Be aware of drug-drug interactions
 COMMON COMBINATION CHEMOTHERAPY
REGIMENS
Cancer Type Drugs Acronym

Breast Cancer Cyclophosphamide, methotrexate, 5-FU Doxorubicin CMF AC AT

(Adriamycin), cyclophosphamide Doxorubicin
(Adriamycin), Paclitaxel (Taxol)
Hodgkin’s disease Mustine, Vincristine (Oncovin), Procarbazine, MOPP ABVD
Prednisone Doxorubicin (Adria), bleomycin, vinblastine,
dacarbazine
Non- Cyclophosphamide, doxorubicin, vincristine, prednisone CHOP
Hodgkin’slympho
ma
Germ cell tumor Bleomycin, etoposide, cisplatin BEP

Stomach cancer Epirubicin, cisplatin, 5-FU ECF

Bladder cancer Methotrexate, vincristine, doxorubicin, cisplatin MVAC

Colorectal cancer 5-FU, folinic acid, oxaliplatin FOLFOX

 General toxicity of
anticancer drugs
1.GIT TOXICITY
NAUSEA AND VOMITING
anorexia mucositis, stomatitis,
diarrhoe,constipation Xerostomia

MECHANISM – CTZ STIMULATION

Cisplatin ,mustine ,dacarbazine,

DRUGS-
all alkylating agents eg
cyclophosphamide etc
TREATMENT---
 ONDANSETRON ,GRANISETRON, PALANOCETRON (5HT3
ANTAGONIST )
 APREPITANT (NK1 antagonist,substance p antagonist)
 METOCLOPRAMIDE
 PROCHLORPERAZINE
 CORTICOSTEROIDS
 AMIFOSTINE (XEROSTOMIA)
2.BONE MARROW SUPRESSION (PANCYTOPENIA)
7-10 DYS

 NEUTROPENIA – INFECTION

 THROMBOCYTOPENIA

 ANEMIA

 LYMPHORETICULAR TISSUE
candida, herpes, p.carinii, toxoplasma
DRUGS CAUSING BONE MARROW SUPRESSION

 Altretamine
 Amsacrine
 Carboplatin
 Chlorambucil
 Cyclophosphamide
 Cytarabine
 Dactinomycine
 Danorubicin
 Gemcitabine etc
3.SKIN
 alopecia ( reappears after chemotherapy)
 dermatitis
 Hyperpigmentation

4.REPRODUCTIVE SYSTEM
oligospermia and impotence
amenorrhoea ,ovu.inhibion,mutagenesis

.5 Delayed Wound Healing

Hair follicle cells:
Partial or complete alopecia may occur, but this is usually
temporary. Scalp cooling can reduce hair loss with some
chemotherapy agents.

Reproductive organs:
.Both sexes are affected and sterility can result, particularly
after therapy with cyclophosphamide or cytarabine.
Because of the mechanisms of action of cytotoxic drugs,
most have teratogenic activity.
. Pregnant women should not be exposed to cytotoxic
drugs for treatment or as members of the healthcare team.
Alkylating agents or procarbazine can cause permanent
male infertility.
.Drugs that mimic or affect the activity of sex hormones are
frequently used for the treatment of breast or prostate
cancer; these inevitably produce adverse effects on sexual
Growing tissues in children :
Of particular concern in children is the possibility that
intensive cytotoxic chemotherapy can impair growth.
Children treated with cytotoxic drugs for malignancy also
have an increased risk (approximately 10%) of
developing a second malignancy, which is often
leukaemia.

Extravasation of intravenous drug :

If anticancer drugs leak from a vein into the surrounding
tissues, they can cause severe local tissue necrosis.

Tumour lysis syndrome:

Rapid breakdown of malignant cells and the release of
their intracellular contents can produce hyperuricaemia
(from breakdown of nucleic acids), hyperkalaemia,
hyperphosphataemia and hypocalcaemia (due to
precipitation of calcium phosphate), with consequent
Tumour lysis syndrome can be ameliorated by good
hydration (>2.5 L/day) and by use of allopurinol (a
xanthine oxidase inhibitor) to reduce production of
uric acid, or in those at high risk, rasburicase
(recombinant urate oxidase) to enhance uric acid
breakdown .

Peripheral neuropathy Pain, tingling, numbness and

cold sensations may occur in the hands and feet due
to damage to sensory nerves, although motor and
autonomic nerves can also be affected.
Chemotherapy-induced peripheral neuropathy
occurs most commonly with vinca alkaloids, taxanes
and platinum compounds. It is progressive and may
be irreversible.
SPECIFIC TOXICITIES
 DELAYED TOXICITIES
 Carcinogenecity- Lymphomas,leukaemias

 Mutagenecity

 Teratogenecity

 Hyperuricemia (ALLOPURINOL.FLUID INTAKE,CORTICOSTEROIDS)

 Infertility

 CNS DEPRESSION
Mitotane
neuropathy,ototoxicity
 MAESURES AND AGENTS USED TO REDUCE THE TOXICITY
OF ANTICANCER DRUGS
 Pulse therapy
 Selective exposure of tumor to drug
 5H3 ANTAGONIST

ONDANSETRON ,GRANISETRON,
PALANOCETRON
 Colony stimulatimg factors ARPITANT ,
PROCHLORPERAZINE
(BMS) CORTICOSTEROIDS

GCSF- FILGRASTIM,LENOGRASTIM,PEGFILGRASTIM,
GMCSF-SARGRAMOSTIM,MOLGRAMOSTIM
FOR RBC-DARBOPOIETIN ALPHA,ERYTHTOPOIETIN
FOR PLATELETS – OPRELVEKIN ,PLATELET TRANSFUSION S

 Bone marrow transplantation in pts of severe BMD

FOLINIC ACID MEGALOBLASTIC ANEMIA (METHOTREXATE)

MESNA HAMORHAGIC CYSTITIS

ACETYLCYSTEINE ( CYCLOPHOSPHAMIDE )

ONDANSETRON NEPHROTOXICITY(CISPLATIN)
HYDRATION, AMIFOSTINE SOD.METABISULPHIDE

ALLUPURINOL,FLUIDS HYPERURICEMIA
CORTICOSTEROIDS

HYDRATION HYPERCALCEMIA
I/V BISPHOSPHONATES

PLATELET/GRANULOCYTE BLEEDING/INFECTION
DEXRAZOXANE - CARDIACTOXICITY (DOXORUBICIN)
STRATEGIES IN CANCER CHEMOTHERAPY
A. Cancer Treatment Modalities
Chemotherapy is used in three main clinical settings:

1. Primary induction chemotherapy—Drug therapy is

administered as the primary treatment for many
hematologic cancers and for advanced solid tumors for
which no alternative treatment exists.

Although primary induction can be curative in a small

number of patients who present with advanced
metastatic disease (eg, lymphoma, acute myelogenous
leukemia, germ cell cancer, choriocarcinoma, and several
childhood cancers), in many cases the goals of therapy are
palliation of cancer symptoms, improved quality of life,
and increased time to tumor progression.
2. Neoadjuvant chemotherapy—The use of
chemotherapy in patients who present with
localized cancer for which alternative local
therapy, such as surgery, exist is known as
neoadjuvant chemotherapy. The goal is to render
the local therapy more effective.

3. Adjuvant chemotherapy—In the treatment of

many solid tumors, chemotherapy serves as an
important adjuvant to local treatment
procedures such as surgery or radiation. The goal
is to reduce the risk of local and systemic
recurrence and to improve disease-free and
overall survival.
B. Principles of Combination Therapy

Chemotherapy with combinations of anticancer drugs

usually increases log-kill markedly, and in some cases
synergistic effects are achieved. Combinations are
often cytotoxic to a heterogeneous population of
cancer cells and may prevent development of
resistant clones. Drug combinations using CCS and
CCNS drugs may be cytotoxic to both dividing and
resting cancer cells.

The following principles are important for selecting

appropriate drugs to use in combination
chemotherapy:
(1) Each drug should be active when used alone
against the particular cancer.
(2) The drugs should have different mechanisms of
action.
C. Rescue Therapy
Toxic effects of anticancer drugs can sometimes be
alleviated by rescue strategy. For example, high doses of
methotrexate may be given for 36–48 h and terminated
before severe toxicity occurs to cells of the
gastrointestinal tract and bone marrow.

Leucovorin, a form of tetrahydrofolate that is

accumulated more readily by normal than by neoplastic
cells, is then administered. This results in rescue of the
normal cells because leucovorin bypasses the
dihydrofolate reductase step in folic acid synthesis.

Mercaptoethanesulfonate (mesna) “traps” acrolein

released from cyclophosphamide and thus reduces the
incidence of hemorrhagic cystitis. Dexrazoxane inhibits
free radical formation and affords protection against the