Cancer.pptx

CANCER
JYOTI RAGHAV
M.PHARM (PHARMACOLOGY)
II SEMESTER
GLA UNIVERSITY, MATHURA

About the
disease
01
Carcinogenesis:
Pathogenesis
and Etiology
02
Drug
classification
03
General principles in
chemotherapy of
cancer
04
Grading, staging
and diagnosis
05
Future Aspects and
Conclusion
06
Table of contents

Neoplasm or Tumour is a mass of
tissue formed as a result of
abnormal, excessive,
uncoordinated, autonomous and
purposeless proliferation of cells
even after cessation of stimulus
for growth which caused it.
INTRODUCTION

• Oncology : Branch of science dealing with
the study of neoplasms or tumours
• Neoplasms may be:
1. ‘benign’ when they are slow-growing and
localised without causing much difficulty to
the host,
2. ‘malignant’ when they proliferate rapidly,
spread throughout the body and may
eventually cause death of the host.
• The common term used for all malignant
tumours is CANCER.

• All tumours, benign as well as malignant, have 2 basic components:
'Parenchyma'
● comprised by
proliferating tumour
cells; parenchyma
determines the nature
and evolution of the
tumour.
‘Supportive stroma’
● composed of fibrous
connective tissue and
blood vessels; it
provides the framework
on which the
parenchymal tumour
cells grow.

Cancer is a disease caused when cells divide uncontrollably and spread
into surrounding tissues

Within a tumour, cancer cells are surrounded by a variety of immune
cells, fibroblasts, molecules, and blood vessels – that’s known as the
tumour microenvironment. Cancer cells can change the environment,
which in turn can effect how cancer grows and spreads.

CHARACTERISTICS OF CANCER CELLS
1. UNCONTROLLED PROLIFERATION: factors that lead to an
uncontrolled proliferation of cancer cells include:
• Growth factors (such as Epidermal Growth Factor, EGF: Insulin-like Growth
Factor, IGF, Platelet De rived Growth Factor, PDGF,
• Growth factor pathways: cytosolic and nuclear transducers.
• The cell cycle transducers:
Positive regulators of cell cycles ( cyclins, cyclin dependent
kinases (CDKS) )
Negative regulators of cell cycles ( Rb proteins, p53 protein and CDK
inhibitors )
• Disposal of abnormal cells by apoptosis
• Tumour directed angiogenesis of blood vessels
• Telomerase expression
2. DEDIFFERENTIATION: The neoplastic cell is characterised by
morphologic and functional alterations, the most significant of which are
‘differentiation' and 'anaplasia'.

Differentiation is defined as the extent of morphological and functional
resemblance of parenchymal tumour cells to corresponding normal cells. The
tissue can be described as 'well differentiated’, ‘poorly Differentiated’,
‘undifferentiated’, 'dedifferentiated’.
• Anaplasia is lack of differentiation and is a characteristic in feature of most
malignant tumours i.e. poorly differentiated malignant tumours have high
degree of anaplasia. As a result of anaplasia, noticeable morphological and
functional alterations in the neoplastic cells are observed.
3. INVASIVENES: Normal cells are not found outside their tissue of origine.g.,
cardiac cells are not found in liver. If any cell accidentally escapes,it would
undergo apoptosis and die. The cancer cells, because of mutations in their genes,
haveno such constraint over them and can slip inside nearby organs.
• BENIGN TUMOURS: Most benign tumours form encapsulated or
circumscribed masses that expand and push aside the surrounding normal
tissues without actuallyinvading, infiltrating or metastasising.
• MALIGNANT TUMOURS: tumours invade via the route of least resistance,
though eventually most cancers recognise no anatomic boundaries. Often,
cancers extend through tissue spaces, permeate lymphatics, blood vessels,

Peritumour spaces and may penetrate a bone by growing through nutrient
foramina. More commonly, the tumours invade thin- lymphat walled capillaries
and veins than thick-walled arteries.
4. METASTASIS : defined as spread of tumour by invasion in such a way that
discontinuous secondary tumour mass/masses are formed at the site of lodgement.
• Cancer cells can disseminate to distal organs through blood and lymphatics and
grow, e.g., bony malignancy occurring in femur can metastasise in lungs.
• The tumour induced growth of new blood vessels locally makes the metastasis
even easier. A series of genetic modification confers resistance on them
towards normal regulatory factors and enables them to establish
“extraterritorially”.

Cancer cells can break away from original tumor and travel through the
blood or the lymph system to distant locations in the body, where they
exit the vessels to form additional tumors. This is called METASIS.

TISSUES OF ORIGIN BENIGN MALIGNANT
A. Epithelial Tumours
• Glandular epithelium Adenoma Adenocarcinoma
B. Non-epithelial (Mesenchymal)
Tumours
• Bone Osteoma Osteosarcoma
Examples of cancer :
I. TUMOURS OF ONE PARENCHYMAL CELL TYPE
II. MIXED TUMOURS
TISSUE OF ORIGIN BENIGN MALIGNANT
Salivary glands Pleomorphic adenoma Malignant mixed salivary
tumour

III. TUMOURS OF MORE THAN ONE GERM CELL LAYER
TISSUES OF ORIGIN BENIGN MALIGNANT
Totipotent cells in gonads or in
embryonal rests
Mature teratoma Immature teratoma

Immune system cells can detect and attack cancer cells. But some cancer
cells can avoid detection or thwart an attack. Some cancer treatments
can help the immune system better detect and kill cancer cells.

Prevalence
Africa
(17.2%)
American(13.1%)
Asia (59.5%)

Most often, cancer causing genetic changes accumulates slowly as a
person ages, leading to a higher risk of cancer later in life.

CARCINOGENESIS:
Pathology and
Etiology
02

carcinogenesis: means mechanism of induction of
tumours (pathogenesis of cancer); agents which can
induce Tumour are called carcinogens
Molecular
pathogenesis
of cancer
Physical
carcinogens
and radiation
carcinogenesi
s
Chemical
carcinogens
and chemical
carcinogenesis
Biologic
carcinogens
and viral
oncogenesis

A DNA change can cause genes involved in normal cell growth to
become ONCOGENES. Unlike normal genes, oncogenes cannot be
turned off, so they cause uncontrolled cell growth.

Genetic changes that causes cancer can be inherited or arise from certain
environmental exposue. Genetic changes can also happens because of
errors that occur as cells divide.

Molecular pathogenesis of cancer

Chemical carcinogens and chemical carcinogenesis

Physical carcinogens and radiation carcinogenesis

Biologic carcinogens and viral oncogenesis

ETIOLOGY OF CANCER:
1. Viruses: e.g hepatitissulting B virus (HBV) and human papilloma
virus (HPV).
2. Environmental and occupational hazards:
• exposure to ionising, and UV radiation
• exposure to various chemical carcinogens like azodyes, asbes tos,
benzene and polyvinyl chloride.
3. Diet and habits:
• high fat and low-fiber diet;
• tobacco smoking and alcohol consumption.
4. Genetic factors:
• inherited genetic mutations, expression of oncogenes and repression
of tumour suppressor genes.
FACTORS CAUSING CANCER

5.Use of drugs: likeimmunosuppressants and some alkylatingagents.
Point mutations ingenes, which often result due to action of certain viruses and chemical carcinogens.
Two types of genetic changesusually lead to cancer:
1.Activation of proto-oncogenes tooncogenes: Proto-oncogenes are normalgenes which control
normalcell division, apoptosis and differentiation. Theseget transformedto oncogenes by carcinogens.
About 100types of oncogenes havebeen identified.
2.Repression or inactivation of tumour suppressor genes (antioncogenes): Thesegenes protect
normalcells from malignant changes; but indifferent cancers, mutations of these genes occurwhich lead to
their inactivation. About 35types of tumour suppressor genes have been found.

In normal cells, tumour suppressor genes prevent cancer by slowing or
stopping cell growth. DNA changes that inactivate tumour suppressor
genes can lead to uncontrolled cell growth and cancer

Cancer is caused by changes to DNA. Most cancer-causing DNA
changes occur in sections of DNA called Genes. These changes are also
called Genetic changes.

Each person’s cancer has a unique combination of genetic changes.
Specific genetic changes may make a person’s cancer more or less likely
to respond to certain treatments.

DRUG P.K AND P.D. USES SIDE EFFECTS
CYCLOPHOSPHAMIDE
• inactive
Liver: Transformation into
active metabolites
(aldophosphamide,
phosphoramide mustard)
• solid tumours:
Immunosuppressant
property
Alopecia and cystitis (due
to another metabolite
acrolein)
IFOSFAMIDE Longer and dose-
dependent t½.
To protect the bladder,
MESNA, a –SH compound
is mostly given with it.
Mesna is excreted in urine-
binds and inactivates the
vasicotoxic metabolites of
ifosfamide and
cyclophosphamide.
Bronchogenic, breast,
testicular, bladder, head
and neck carcinomas,
osteogenic sarcoma and
some lymphomas.
Neurotoxicity (mental
changes, hallucinations,
seizures, coma) and
haemorrhagic cystis than
other alkylating agents.
CHLORAMBUCIL • Very slow acting
• Active on lymphoid
tissue
Chronic lymphatic
leukaemia ( drug of choice
for long-term maintenance
therapy)
Non Hodgkin lymphoma,
few solid tumours

DRUGS P.K AND P.D USES SIDE EFFECTS
MELPHALAN Multiple myeloma
Advanced ovarian cancer.
Bone marrow depression
BENDAMUSTINE
• nitrogen mustard
alkylating agent
• i.v. infusion
• Rapidly degraded,
plasma t½ = 30 min.
Chronic lymphatic
leukaemia
Non-Hodgkin lymphoma.
Myclosuppression,
Dyspnoea.
Thio-TEPA
• ethylenimine,
Does not require to form
an active intermediate.
Ovarian and bladder
cancer.
High toxicity
ALTRETAMINE
• Hexamethyl melamine
(HMA) which acts by
alkylating DNA and
Sticular, proteins.
Recurrent ovarian
carcinoma for palliative
treatment.
and neurological effects
(mental confusion, ataxia,
hallucinations, peripheral
neuritis). Kidney
dysfunction (dose limiting
toxicity.)
TEMOZOLOMIDE
• orally active triazine
methylating agent
Glioma and other
malignant brain tumours
(drug of choice);
• Melanoma.
Similar to dacarbazine.

DRUG P.K AND P.D USES SIDE EFFECTS
BUSULFAN Produces little effect on
lymphoid tissue and g.i.t.
Chronic phase of
myelocytic leukaemia (2nd
choice drug to imatinib)
Hyperuricaemia,
Pulmonary fibrosis and
Skin pigmentation, sterility
.
NITROSOUREAS
• Highly lipid soluble
• cross blood-brain
barrier
• Meningeal leukaemias
• Brain cancer.
(delayed- 6 weeks to
develop)
Visceral fibrosis and renal
damage
DACARBAZINE (DTIC)
• Activation in liver.
• Acts by methylating DNA and
interfering with its function.
• Hodgkin’s disease
(Combination regimens
)
• Malignant melanoma.
• Neuropathy
• myelosuppression
PROCARBAZINE (inactive)
After activation procarbazine
methylates and depolymerizes
DNA (chromosomal damage).
Alcohol causes hot
flushing and a
disulfiram-like reaction in
patients taking
procarbazine. Males may
suffer sterility.
Combination regimens
for Hodgkin’s and related
lymphomas, and is an
alternative drug for brain
tumours.
Sedation and other CNS
effects
Interact with foods and
drugs.

PLATINUM
COORDINATION
COMPOUNDS

DRUG P.K AND P.D USE SIDE EFFECTS
CISPLATIN Excreted unchanged in
urine
• T1/2= 72 hrs.
• Negligible amounts
enter brain.
• Metastatic testicular
• ovarian carcinoma.
• Solid tumours. E.g.
those of lung, bladder,
esophagus, stomach,
liver, head and neck.
Highly emetic drug
(Antiemetics are routinely
administered before
infusing)
Renal impairment
(dependent on total dose
administered) (Normal
saline (1-2L) is infused i.v.
before cisplatin to reduce
its renal toxicity)
Tinnitus, deafness,
sensory neuropathy and
hyperuricaemia.
A shock-like state
(sometimes occurs during
i.v. infusion.infused)

CARBOPLATIN
• 2nd generation Pt
compound
Rapidly eliminated by the
kidney with a plasma t1/2
of 2-4 hours.
• Ovarian carcinoma of
epithelial origin,
• Squamous carcinoma
of head and neck,
small cell lung cancer,
breast cancer and
seminoma.
• Nephrotoxicity,
ototoxicity and
neurotoxicity are low.
• Thrombocytopenia
(Dose-limiting
toxicity)
OXALIPLATIN
• 3rd generation Pt
complex
• Colorectal cancer
• Gastroesophageal and
pancreatic cancers
• Peripheral
neuropathy ( Dose-
limiting toxicity)
• Acute neuropathy
(triggered by exposure
to cold)
• Myelosuppression,
diarrhoea and acute
allergic reactions

Mechanism of
action of
methotrexate

Mechanism of action of PEMETREXED

METHOTREXATE
(Mtx)
• Oldest, highly
efficacious
antineoplastic drugs
Absorbed orally, 50%
plasma protein bound,
Little metabolize, Largely
excrete unchanged in
urine,
Salicylates, sulfonamides,
dicumerol displace it from
protein binding sites.
Aspirin and
sulfonamides enhance
toxicity of Mtx by
decreasing its renal tubular
secretion.
Non-Hodgkin lymphoma,
breast, bladder, head and
neck cancers, osteogenic
sarcoma, etc.
Has immunosuppressant
property useful in
rheumatoid arthritis,
psoriasis and many other
antoimmune disorders
Repeated low doses cause
megaloblastIc anaemia,
High doses produces
pancytopenia,
Mucositis, Diarrhoea,
Desquamation and
bleeding in the g.i.t.
PEMETREXED
• Newer congener of Mtx
NSAIDs should be avoided
as they decrease
pemetrexed clearance and
may increase toxicity.
Meoepithelioma , Non
small cell lung carcinoma
(premetrexed + cisplatin),
• Breast, bladder and
colorectal cancer.
• mucositis, diarrhoea,
myelosuppression,
• Hand foot syndrome
(Dexamethasone)
Myelosuppresion ( low
dose folic acid +vit B12
pretreatment)

MERCAPTOPURINE (6-
MP) and THIOGUANINE
(6-TG)
• Absorbed orally
• Azathioprine and 6-MP
are oxidised by
xanthine oxidase and
their metabolism is
inhibited by allopurinol;
• Childhood acute
leukaemia,
choriocarcinoma
• Bone marrow
depression
• Reversible jaundice
• Hyperuricaemia
AZATHIOPRINE Autoimmune diseases
(rheumatoid arthritis,
ulcerative colitis, etc.) as
well as in organ
transplantation.
FLUDARABINE Chronic lymphatic
leukaemia and non-
Hodgkin’s lymphoma that
have recurred after
treatment.
• Myalgia, arthralgia
• Myelosuppression and
opportunistic infections
(it is a potent
suppressant of CMI).

DRUG P K AND P.D USES SIDE EFFECTS
FLUOROURACIL (5-FU) 5-FU is rapidly
metabolized by dihydro
pyrimidine dehydrogenase
(DPD) resulting in a
plasma t½ of 15-20 min
after i.v. infusion.
• Solid malignancies of
colon, rectum,
stomach, pancreas,
liver, urinary bladder,
head and neck.
• Bone marrow and g.i.t.
causing
myelosuppression,
mucositis, diarrhoea,
nausea and vomiting.
• Peripheral
neuropathy (hand-
foot syndrome)
CAPECITABINE
• orally active prodrug
of 5-FU.
Absorption = converted to
deoxy-5-fluorouridine
(liver) , Taken up by cells,
hydrolysed to 5-FU by
thymidine phosphorylase (
breast and colorectal
cancer cells)
Metastatic colorectal
cancer (capecitabine +
oxaliplatin)
Metastatic breast cancer (
2nd line treatment with
docetaxel)
• Hand-foot syndrome
• diarrhoea
DOXYFLURIDINE
• 2nd generation oral
prodrug of 5-FU
Degradation of 5-FU by
dihydropyrimidine
dehydrogenase in the gut wall
(orally active)
Inside cell= converted to 5-FU
by pyrimidine phosphorylase,
• Gastrointestinal
cancers metastatic to
liver, hepatic and
breast carcinoma.
• Diarrhoca,
• stomatitis,
• bone marrow
depression,
• hearing loss
• neuritis.

Cytarabine (Cytosine
arabinoside, Ara-C)
Cell cycle specific (‘S’
phase)
Rapid i.v. injection (100
mg/m²) 2-3 times daily for
5-10 days, or by
continuous i.v. infusion
over 5-7 days (Because it
is rapidly deaminated and
cleared from plasma)
Leukaemias and
lymphomas,
Most effective drug for
induction of remission in
acute myelogenous as well
as lymphoblastic
leukaemia in children and
in adults.
Bone marrow suppression-
leukopenia,
thrombocytopenia,
anaemia, mucositis and
diarrhoea.
Delayed pulmonary
complications may occur.
GEMCITABINE
• Difluoro analogue of
deoxycytidine
• i.v. infusion,
• Rapidly deaminated
and excreted in urine
with a t½ of 15 min.
Nonresectable or
metastatic carcinoma of
pancreas, non-small cell
lung cancer, ovarian and
bladder carcinoma.
• Myelosuppression
• Paresthesias,

Vinca alkaloids
• mitotic inhibitors
• Cell cycle specific: act in
mitotic phase.
• Interfere with
cytoskeletal function.
• Chromosomes fail to
move apart
during mitosis: metaphase
arrest occurs.

Vincristine (oncovin) Induce remission in child
hood acute lymphoblastic
leukaemia, acute myeloid
leukaemia, Hodgkin’s
disease, Wilms’ tumour,
Ewing’s sarcoma,
neuroblastoma and
carcinoma lung.
Peripheral neuropathy and
alopecia.
Ataxia, nerve palsies,
autonomic dysfunction
(postural hypotension,
paralytic ileus, urinary
retention) and seizures.
Syndrome of inapropriate
secretion of ADH (SIADH)
can occur.
Vinblastine Hodgkin’s disease, Kaposi
sarcoma, neuroblastoma,
non-Hodgkin’s lym phoma,
breast and testicular
carcinoma.
Local tissue necrosis
SIADH
Vinorelbine Non-small cell lung(
primary indicatios)
advanced breast and
ovarian carcinoma (2nd line
drug).
Neutropenia ( dose
limiting toxicity)

Paclitaxel
• Complex diterpin
taxane
• Source: bark of the
Western yew tree
• Metastatic ovarian,
breast carcinoma after
failure of first line
chemotherapy and
relapse cases.
• Advanced cases of
head and neck
cancer, small cell lung
cancer, esophageal
adenocarcinoma,
urinary and hormone
refractory prostate
cancer. AIDS related
Kaposi’s sarcoma.
• Acute anaphylactoid
reactions
(Pretreatment with
dexamethasone, H,
and H, antihistaminics)
• Reversible
myelosuppression
(mainly
granulocytopenia) and
stocking and glove’
neuropathy. Nausea,
chest pain, arthralgia,
myalgia, mucositis and
edema
Docetaxel
formulated in polysorbate
medium (produces less
acute hypersensitivity
reactions)
Breast and ovarian
cancer (first line drugs),
Small cell cancer lung, pan
creatic, gastric and
head/neck carcinomas
Neutropenia,
Arrhythmias, fall in BP,
fluid retention,

Estramustine
• Complex of estradiol
with a nitrogen mustard
normustine
• Weak estrogenic but
no alkylating property.
• Binds to ß-tubulin and
inter feres with its
organization into
microtubules,
(antimitotic action)
1st pass metabolism (liver
into active as well as
inactive metabolites) which
are eliminated mainly in
faeces.
advanced or metastatic
prostate cancer ( gets
concentrated in prostate)
that is nonresponsive to
hormone therapy.
• myelosuppression
(small amount is
hydrolysed into
estradiol and
normustine)
• Estrogenic adverse
effects, viz.
gynaecomastia,
impotence, fluid
retention, increased
risk of
thromboembolism and
impaired glucose toler
ance.
• Angioedema and
other hypersensitivity
reactions

Etoposide
• Semisynthetic
derivative of
podophyllotoxin
(glycoside)
• arrests cells in the G2
phase and causes
DNA breaks by
affecting DNA
topoisomerase-2
function.
• Resealing of the strand
is prevented.
• Oral bioavailability =
50%
• oral dose is double
than i.v. dose.
• Testicular tumours
• lung cancer
• Hodgkin’s and other
lymphomas
• carcinoma bladder
and stomach.
• Alopecia
• leucopenia
• g.i.t. disturbances

Camptothecin analogues
Example: Topotecan, Irinotecan
• These are two semisynthetic analogues of camptothecin, an antitumour
substance obtained from a Chinese tree.
• Their binding to DNA topoisomerase I 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 • Metastatic carcinoma
of ovary, small cell
lung cancer after
primary chemotherapy
has failed.
• Cisplatin +Topotecan
= used in cervical
cancer.
• Bone marrow
depression, especially
neutropenia.
Irinotecan (Prodrug)
Active metabolite SN-38 is
inactivated by
glucuronidation in the liver.
Individuals expressing the
UGTIA1*28 allele of
glucuronyl transferase
enzyme are more
susceptible to irino tecan
induced diarrhoea and
neutropenia, because they
fail to inactivate SN-38.
• Decarboxylated in liver
to the active metabolite
SN-38.
• Cholinergic effects
(because it inhibits
AChE) – suppressed
by prior atropinization.
• Metastatic/advanced
colorectal carcinoma;
also in cancer
lung/cervix/ ovary and
stomach
• Combined with 5-FU
and leucovorin.
• diarrhoea. ( Dose
limiting toxicity)
• Neutropenia,
thrombocytopenia,
haemorrhage,
bodyache and
weakness

Actinomycin D
(Dactinomycin)
• Blocking RNA
transcription (due to
interference with
template function of
DNA)
• Single strand breaks in
DNA.
• Wilms’ tumour,
childhood
rhabdomyosarcoma.
• Dactinomycin + Mtx for
cure of
choriocarcinoma,
• Ewing’s sarcoma,
metastatic testicular
carcinoma.
• Stomatitis, diarrhoea,
erythema and
desquamation of skin,
alopecia and bone
marrow depression.
Aclarubicin
• Not yet approved by
US-FDA,
Haemato logical
malignancies. Aclarubicin
intercalates in DNA and
interacts with both
topoisomerase 1 and 2 to
inhibit RNA and protein
synthesis.
Less cardiotoxic
Mucositis,
alopecia and
hyperuricaemia.

(Anthracycline antibiotics)
Daunorubicin
(Rubidomycin),
Doxorubicin:
Acute myeloid and
lymphoblastic leukaemia
Solid tumours, (e.g breast,
thyroid, ovary, bladder and
lung cancers, sarcomas
and neuroblastoma)
Cardiotoxicity (within 2-3
days, causing ECG
changes, arrhythmias and
hypotension)
CHF (due to
cardiomyopathy)
Marrow depression,
alopecia, stomatitis,
vomiting and local tissue
damage
Urine may be coloured red
Idarubicin
(analogue of daunorubicin)
Acute myeloid leu kaemia
in which it is generally
combined with cytarabine.
Less cardiotoxic,
bone marrow depression,
stomatitis, alopecia,
vomiting, abdominal
cramps
Epirubicin Component of regimen for
adjuvant therapy of breast
carcinoma.gastroesophage
al, pancreatic, ovarian,
Alopecia, hyperpig
mentation of skin and oral
mucosa, painful oral
ulcers, fever.

Bleomycin
(mixture of closely related
glycopeptide antibiotics
having potent antitumour
activity.) chelates copper
or iron, produces
superoxide ions and
intercalates between DNA
strands-causes chain
scission and inhibits
repair.
Rate of fluid collection in
malignant pleural or
peritoneal effusion can be
reduced by
intrapleural/intra peritoneal
injection of bleomycin.
Testicular tumour
(cisplatin + vinblastine or
etoposide)
Squamous cell carcinoma
of skin, oral cavity, head
and neck, genitourinary
tract and Hodgkin’s
lymphoma.
Mucocutaneous toxicity,
pulmonary fibrosis,
Allergic and hypotensive
reaction (after bleomycin
injection)
Mitomycin C

Hydroxyurea Well absorbed orally
Eliminated in urine
Plasma t½ of 4 hours.
Chronic myeloid
leukaemia, psoriasis and
polycythae mia vera.
Solid tumours,
radiosensitizer before
radiotherapy, sickle cell
disease (adults-1st line
drug).
Myelosuppression,
GIT disturbances,
cutaneous reactions,
including pigmentation,
L-Asparaginase (L-
ASPase)
Acute lymphoblastic
leukac mia along with
Mtx., prednisolone,
vincristine, etc.
hyperglycaemia, raised
triglyceride levels,
pancreatitis, liver damage,
clotting defects and CNS
symptoms.
Tretinoin Prolonged remission in acute
promyelocytic leukaemia (APL)
–induction therapy with
tretinoin + daunorubicin/
doxorubicin (complete
remission in 95% patients of
APL)
Dryness of skin, eye,
nose, mouth, pruritus,
epistaxis, rise in serum
lipids, hepatic
transaminases and
intracranial pressure.
‘retinoic acid syndrome’

Arsenic trioxide Resistant/relapsed cases
of APL after tretinoin
treatment,
1st line therapy of API.
Along with tretinoin an
anthracycline,
Nausea, dizziness,
malaise, fatigue, sensory
disturbances, effusions,
breathlessness,
hyperglycaemia, Q-T
prolongation, A-V block.
(Treatment- corticosteroid)

Imatinib Absorbed orally,
metabolized in liver (
degrading enzyme is
CYP3A4, and potential
interactions can occur with
inducers and inhibitors of
this isoenzyme)
T1/2 = 18 hours
Chronic phase of CML,
Metastatic c-kit-positive
GIST,
Dermatofibrosarcoma
protuberans.
Fluid retention, periorbital
edema, pleural effusion,
myalgia, liver damage and
CHF.
Dasatinib T1/2 = 3-5 h Philadelphia chromosome
+ive cases of CMI.
Low blood counts,
bleeding, hyperten sion
and pleural effusion.
It can prolong Q-T interval.
BCR-ABL tyrosine kinase inhibitors

Nilotinib 30% bioavailable orally, In accelerated phase of
CML.
Q-T prolongation
EGF receptor (HER 1) inhibitors
Gefitinib Oral bioavailability = 60%.
Primarily metabolized by
CYP3A4.
T1/2 = 40 h
Gefitinib has been found
effective in selected
patients of non-small cell
lung cancer which has
EGFR activat ing
mutation.
Drug interactions with
inducers/ inhibitors of
CYP3A4 are likely.
Erlotinib Similar to gefitinib Advanced/metastatic
pancreatic cancer
(Erlotinib + gemcitabine)
Serious hepatic
dysfunction in patients
with preexisting liver
disease.

Cetuximab Advanced/metastatic
squamous carcinoma of
head and neck in
combination with radiation
and/ or cisplatin based
chemothrapy.
Acneform skin rash,
itching, headache and
diarrhoea.
Anaphylactoid reactions
EGFR/HER2 inhibitors
Trastuzumab T1/2= 6 days (weekly
dosing)
Early stage HER2 positive
but ER/PR negative
carcinoma breast that has
spread to lymph node.
HER2 over expressing
gastric carcinoma.
Relapse cases (
Trastuzumab + taxanes)
i.v. infusion consisting of
flu-like symptoms, chills,
fever, malaise, back/neck
pain and dyspnoea.
Specific toxicity=
decrease in LVEF and
cardiomyopathy

Lapatinib Metastatic HER2
positive breast cancer
that is nonresponsive to
trastuzumab (
capecitabine+ Lapatinib).
Metastatic
postmenopausal breast
cancers- ER positive and
overexpress HER2 (
aromatase inhibitor +
Lapatinib)
Fatigue, abdominal pain,
diarrhoea, decreased
LVEF, heart failure and Q-
T prolongation.
Angiogenesis inhibitors
Several cancers over-express VEGF-receptor, and inhibitors of this receptor have been developed
as antitumour drugs.

Bevacizumab
• i.v. infusion every 2-3
weeks.
Metastatic colorectal
cancer ( 5-FU +
bevacizumab).
Deafness due to
neurofibromatosis.
Rise in BP, arterial
thromboembolism leading
to heart attack and stroke,
vessel injury, nose bleeds,
rectal bleed and other
haemor rhages, heart
failure, proteinurea,
gastrointestinal
perforations, and healing
defects.
Sunitinib
• Orally daily in 4 week
cycles
Metabolized by CYP3A4
and t1/2 is -100 hours.
Metastatic renal cell
carcinoma and imatinib
resistant g.i. stromal
tumour (GIST).
Hypertension, rashes,
diarrhoea, fatigue,
weakness, bleeding,
proteinurea,
hypothyroidism,
neutropenia, rarely CHF.

Sorafenib Advanced/metastatic
renal cell carcinoma
(2nd choice drug to
sunitinib)
Anorexia, weak ness,
arthralgia, flu-like illness,
hand-foot skin reaction,
hypertension,
haemorrhages and
proteinuria,
Proteasome inhibitor
Bortezomib Multiple myeloma which
over expresses NFKB,
both for first line combined
therapy (along with
cytotoxic drugs), as well
as for relapsed disease. It
peripheral neuropathy.
Diarrhoea, fatigue, bone
marrow depression,
especially
thrombocytopenia.

Rituximab autoimmune diseases. Chills, fever, urticarial
rashes, pruritus, dyspnoea
and hypotension.
CD20 inhibitor
mTOR inhibitors
Everolimus (oral) and
Temsirolimus (i.v.)
Advanced renal cell
cancer, refractory mantle
cell lymphoma and
advanced hormone
receptor positive but
HER2 negative breast
cancer.

Glucocorticoids Acute childhood
leukaemia and
lymphomas.
Corticosteroids Malignany and
chemotherapy associated
complications like
hypercalcaemia,
haemolysis, bleeding due
to thrombocytopenia,
retinoic acid syndrome,
increased intracranial
tension and mediastinal
edema due to
radiotherapy.
Hypercorticism
• modify the growth of hormone-dependent tumours.
• All hormones are only palliative.

Estrogens carcinoma prostate
Selective estrogen receptor modulators: tamoxifen
Selective estrogen receptor down regulator: fulvestrant
Antiandrogen
Flutamide ,
Bicalutamide
Antagonise androgen
action on prostate
carcinoma cells and have
palliative effect in
advanced/metastatic
cases.

Finasteride
Dutasteride
have palliative effect in
advanced carcinoma
5-a reductase inhibitor
GnRH agonists
Palliative effect in advanced estrogen/androgen dependent carcinoma of breast and prostate.
Progestins Temporary Remission in
some cases of advanced
or recurrent (after
surgery/radiotherapy) and
metastatic endometrial
carcinoma.
Palliative treatment of
metastatic carcinoma breast
that has become unresponsive
to tamoxifen.

GENERAL
PRINCIPLE OF
CHEMOTHERAPY
04

There are four main approaches to treat cancer: (1) Surgical
resection, (2) Radiotherapy, (3) Chemotherapy and (4)
Immunotherapy (use of du monoclonal antibodies).
Chemotherapy of cancer, as compared to antibacterial is
chemotherapy, presents potential problems.
1. Analogy with bacterial chemotherapy:
● bacterial (prokaryotic cells) are qualitatively different from
human cells (eukaryotic cells). But, cancer cells and normal
cells are so similar that normally a drug which is cytotoxic to
cancer cells is cytotoxic to normal cells also. Hence,
selectivity of an anticancer drug is very limited.
● Infecting microorganisms are amenable to immunological
and other host defence mech anisms. This is absent or
minimal against cancer cells.

2. For effective cure : single clonogenic malignant cell is
capable of producing progeny that can kill the host. To
effect cure, all malignant cells must be killed or removed.
● Survival time: related to the number of cells that escape
chemotherapeutic attack
3. In any cancer, Rate of proliferation Of cells and susceptibility
to cytotoxic drugs is different from normal cells. These Drugs
kill cancer cells by first order kinetics, i.e. a certain fraction of
cells present are killed by one treatment.
4. Combined modality approach: Drug regimens or number
of cycles of combined chemotherapy which can effectively
palliate large tumour burdens may be curative when applied to
minute residual tumour cell population after surgery and/or
irradiation.

5. Goal of cancer chemotherapy: complete remission.
● drugs are often used in maximum tolerated doses. Intensive
regimens used at an early stage in the disease yield better
results.
6. Total tumour cell kill: a combination of 2-5 drugs is given in
intermittent pulses to achieve total tumour cell kill, giving time in
between for normal cells to recover. However, few tumours are
still treated with a single drug.
Kinetic scheduling: On the basis of cell cycle
specificity/nonspecificity of the drugs and the phase of cell cycle
at which the drug exerts its toxicity.
Cytotoxic drugs are either cell cycle nonspecific (CCNS) or cell
cycle specific (CCS).

(a) Cell cycle nonspecific: These drugs kill resting as well as
dividing cells, e.g. benda mustine, cyclophosphamide,
chlorambucil, etc.
(b) Cell cycle specific : These drugs kill only actively dividing
cells. Their toxicity is gen erally expressed in S phase.
However, these drugs may show considerable phase
selectivity, e.g.
● G1 : Etoposide.
● S: Mtx, cytarabine, fludarabine, 6-TG, 6-MP, 5-FU,
hydroxyurea, capecitabine, gemcitabine. G₁: Bleomycin,
etoposide, topotecan, irinotecan.
● M: Vincristine, vinblastine, vvinorelbine paclitaxel, docetaxel.
7. Resistance : Tumours often become resistant to any drug
that is used repeatedly due to selection of less responsive
cells. Such selection is favoured if low dose of a single drug is
used.

Several mechanisms of tumour resistance have been
recognized.
1. Multidrug resistance is overexpression of MDR I gene which
increases the concentration of P-glycoprotein (an efflux
transporter) on the surface of cancer cells, resulting in pumping out
of the chemotherapeutic agents.
2. Resistance to methotrexate:
● decreased uptake of the drug into the tumour cell,
● Alteration in the structure of dihydrofolate reductase (DHFR)
enzyme, resulting in a reduced drug affinity
● Increase in DHFR content in tumour cell as a re sult of its gene
amplification.
3. A drug may be inactivated by resistant tumour by enzymatic
metabolism, e.g., cytarabine (pyrimidine nucleoside deaminase)
and bleomycin (bleomycin hydrolase).

4. Resistance to alkylating agents by:
● Rapid repair of drug-induced DNA damage,
● an increase in cell thiol contents, which in turn can serve as an
alternative target of alkylation
5. Antimetabolites may be ineffective because of insufficient
activation of the drug.
6. There may be drug-induced alteration in the activity
of target enzyme, e.g., modified topoisomerase-II in case of
resistance to doxorubicin.

GRADING,
STAGING, AND
DIAGNOSIS
05

GRADING
Grading is defined as the gross appearance and
microscopic degree of differentiation of the tumour.
Thus, grading is done on patholologic basis.
• Grade 1: Well-differentiated (less than 25% anaplastic cells)
• Grade II: Moderately-differentiated (25-50% anaplastic cells)
• Grade III: Moderately-differentiated (50-75% anaplastic cells)
• Grade IV: Poorly-differentiated or anaplastic (more than 75%
anaplastic cells)
staging means extent of spread of the tumour within the patient. Staging
is done on clinical grounds.
STAGING

1. TNM staging: T for primary tumour, N for regional nodal involvement,
and M for distant metastases.
• TO to T4: In situ lesion to largest and most extensive primary tumour.
• NO to N3: No nodal involvement to widespread lymph node
involvement.
• M0 to M2: No metastasis to disseminated haematogenous metastases.
2. AJC staging: American Joint Committee staging divides all cancers
into stage 0 to IV, and takes into account all the 3 components of the
preceding system (primary tumour, nodal involvement and distant
metastases) in each stage.

Histological
Methods
Cytological
Methods
Histochemistry
and
cytochemistry
Electron
microscopy
Immunohistochemistry
DIAGNOSIS
Tumour
markers
Other modern aids:
Flow cytometry
In situ hybridization
Molecular diagnostic
techniques
DNA microarray analysis o
tumour

Preferred combination
1. Acute leukaemia: Vincristine+Amethopterine (Mtx) + 6-MP
+ Prednisolone
2. Colon cancer: 5-FU+Leucovorin + Oxaliplatin
3. Hodgkin’s disease: Adriamycin (Doxorubicin) + Bleomycin
+Vinblastine+ Dacarbazine
4. Non-Hodgkin’s lymphoma: Cyclophosphamide +
Hydroxydaunorubicin(Doxorubicin) + Oncovin (Vincristine)
+Prednisolone + Rituximab
5. Testicular cancer: Bleomycin + Etoposide + Platinum
(Cisplatin)

FUTURE ASPECTS
AND
CONCLUSION
06

1. telomerase inhibitors are now being considered
as potential anti cancer drugs of future.
2. Several angiogenesis inhibitors and
metalloproteinase inhibitors are being explored
(e.g., antiangiogenic peptides such as endostatin
and angiostatin) for pharmacological intervention in
the treatment of cancer.
3. Small molecule inhibitors of CDKS (e.g.,
flavopiridol) are being explored as newer
anticancer drugs.
4. Recently monoclonal antibodies have been used
as the missile of biological “smart bombs” carrying
a radiopharmaceutical (e.g…Ibritumomab-Y90) or
biological toxin

(e.g.,Gemtuzumab ozogamicin) warhead to a specific
target (e.g., non-Hodgkin’s lymphoma and acute
my eloid leukaemia, respectively).

Conclusions
Hence cancer is second leading cause of
deaths following heart diseases one should
care about its prevention before the
occurrence of disease by varies examinations
and if disease is already exists then one
should go for its regular treatment. Recent
treatment mainly includes radiation therapy,
cell based immunotherapy, gene therapy,
chemotherapy are most widely used methods
used for treatment of various type of cancers.

● KD TRIPATHI (2021). Essentials of
Medical Pharmacology. The Health
Sciences Publisher, Page no. 915
● HL Sharma, KK Sharma, (2018).
PRINCIPLES OF
PHARMACOLOGY, Paras Medical
Publisher, Page no. 853
● HARSH MOHAN (2015).Textbook
of PATHOLOGY, The Health
Sciences Publishers
● https://www.cancer.gov/about-
cancer/understanding/what-is-
cancer
References

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