1. Cancer
May 2003
Dr Anshu P Gokarn

2. To understand oncology we shall discuss the
following …...
I. What is cancer ?
II. How cells continue dividing in an uncontrolled
manner in cancer.
 Normal cell cycle
 Abnormalities associated with normal process
III. Factors that control cancer
 Natural factors
 Risk factors
 Carcinogens
IV. Types of cancers
V. Treatment available for cancer
VI. Latest Treatment available
Dr Anshu P Gokarn

3. PART I
Basics of cancer
Dr Anshu P Gokarn

4. CANCER (Neoplasm) - What is it?
 New Growth
 Definition :
An abnormal mass of tissue, excessive
growth, uncoordinated with normal tissue
and persistent growth even after the
cessation of evoking stimuli.
Fundamental to origin of all Cancers is :
“Loss of responsiveness to normal growth control mechanisms”
Dr Anshu P Gokarn

5. Neoplasms – Their
Characteristics
 Enjoy a certain degree of autonomy
 Parasitic in nature (regardless of
local environment or host nutritional
status)
 Require endocrine support of host
 Dependent on host for blood supply
and nutrition
Dr Anshu P Gokarn

6. Part II
Dr Anshu P Gokarn

7. Dr Anshu P Gokarn

8. CELL DIVISION Proliferating cells enter cell cycle which
is :
G1 Phase Pre nucleic acid synthesis interval
S1 Phase Synthesis of DNA occurs
G2 Phase Post synthetic interval
M Phase Mitosis occurs, two G1 cells produced;
which either directly enter next cycle or
pass into non proliferating phase G0
G1 G2
Non-proliferating cells; a fraction of these
are colonogenic – may remain quiet for
G 0 Phase some time but can be recruited in cell cycle
if stimulated later
Dr Anshu P Gokarn

9. Normal cell cycle
Interphase – cell carries out it’s normal
activity but is resting from dividing
 Also called growth phase or metabolic
phase
 Prepares for next cell division
 Is divided into three stages
G1 phase - (cells metabolically active, synthesize proteins rapidly, grow
vigorously)
Lasts from minutes to hours or even years
G0 phase - Cells cease to divide permanently.
S Phase - DNA replication occurs .
Two future cells will receive identical copies of the genetic material
G2 phase - Final phase. Enzymes and other proteins needed for division are
synthesized and moved to their proper sites
M phase - Mitosis –Prophase, metaphase, anaphase and telophase occurs
Cytokinesis – division of cytoplasm –
Dr Anshu P Gokarn

10. Dr Anshu P Gokarn

11. How cancer develops
 Normal cell Transformation
carcinogen
 Step 1 Initiation (change in cellular
genetic material primes the cell to
become cancerous)
 Step II Promotion (cell becomes
cancerous)
Normal feedback mechanisms mediating cell growth are defective.
Faulty cells contact-signaling process (transduction defect)
Dr Anshu P Gokarn

12. Progression of a normal
cell to cancer
Tumour formation is a multi-step
process
Genes mutation occurs
Genetic changes confer a selective growth or survival advantage
 No response to normal regulatory signals
Grow in an uncontrolled manner, resulting in malignant disease
Dr Anshu P Gokarn

13. Cell transformation from normal to cancer
Dead cell
apoptosis
DNA repair
Mutation
Repair absent or faulty
Cancer cell
Dr Anshu P Gokarn

14. Part III
 A. Molecular basis of cancer
 B. Carcinogens
 C. The risk factors involved
Dr Anshu P Gokarn

15. Dr Anshu P Gokarn

16. How normal cell proliferation occurs :
 Growth factor binds to specific receptor
 Activates several signal transducing proteins on the inner surface
of the plasma membrane
 Signal reaches nucleus via 2nd messengers
 Activation of Nuclear Regulatory Factors initiate DNA
transcription (via transcription factors).
 Cell enters cell division.
Alterations/Mutations in any of these steps cause Cancer
Dr Anshu P Gokarn

17. Some more factors…
 Systems that regulate apoptosis
may be altered to cause cancer.
 Cell adhesion proteins can also undergo mutation and
contribute to metastasis.
 Several genes altered during conversion of a cell from
normal to malignant.
Dr Anshu P Gokarn

18. Carcinogenic genes
Genes may be either :
 Effectors of transformation also known as
Oncogenes
(eg. signal pathway molecules)
or
 Facilitators of transformation – also known
as tumor suppressor genes
They cause increase occurrence of mutations
in other genes e.g. p53 gene
 DNA repair genes
 Apoptosis genes
 Telomerase genes
Dr Anshu P Gokarn

19. Some cell cycle regulators
1. Integral membrane
tyrosine kinases ( erbB
and others )
2. growth factors ( sis and
hst )
3. ras and src gene families
4. Membrane associated
tyrosine kinases, serine-
threonine kinases ( mos
and raf )
5. nuclear oncoproteins
These proteins are expressed in most cells, but when a mutation
occurs, this expression is abnormal and cancer can arise.
Dr Anshu P Gokarn

20. Cellular genes controlling malignancy
Protooncogenes – Tumor suppressor
Positively influence genes – negatively
influence cell
growth growth
Mutation
Oncogenes
cancer
Dr Anshu P Gokarn

21. Proto-oncogenes
 Control cell proliferation and differentiation
 Expressed in all subcellular compartments (nucleus,
cytoplasm, cell surface)
 Act as protein kinases, growth factors, growth factor
receptors, or membrane associated signal
transducers
 Mutations in proto-oncogenes alter the normal
structure and/or expression pattern
Dr Anshu P Gokarn

22. Oncogenes
 Mutated types of normal Wild Type Genes (proto-oncogenes)
promote cancer development
 Act in a dominant fashion
– a mutation is needed in only a single allele for activation
– also referred to as gain of function mutations
 For oncogenes to be tumorigenic, they must be activated in
some way.
 Three known mechanisms of transforming oncogene activation:
translocations
amplification
point mutations
Dr Anshu P Gokarn

23. Oncogene mechanisms of activation
Changes to oncogenes confer advantage to affected cells
leading to transformation.
 Categorized into two groups
 Changes to the structure of an oncogene results in an
abnormal gene product (protein) with abnormal function
 Changes to the regulation of gene expression which results
in excessive or inappropriate production of the structurally
normal growth-promoting protein
Dr Anshu P Gokarn

24. Oncogene mechanisms of action
Extracellular
growth factor
Growth factor receptor
Signal transduced
and transmitted via
cytosol to the nucleus
Cell replication and transcription
Dr Anshu P Gokarn

25. Normal regulation of a gene that promotes cell
division
Dr Anshu P Gokarn

26. Growth Factors
 Mutations of genes encoding growth factors can render
them oncogenic (eg platelet derived growth factor).
 Tumors possessing receptors for PDGF are subject to
autocrine stimulation
 Growth factor gene itself may not be altered / mutated
but the products of other oncogenes such as ras cause
over-expression of growth-factor genes.
 Large number of growth-factors eg. TGF-α produced.
 TGF-α binds to endothelial growth factor to induce cell
proliferation
 Whole process occurs outside the cell
Dr Anshu P Gokarn

27. Growth Factor Receptor
 Mutations/Pathologic over-expression of growth
factor receptors have been detected in several tumors.
 Over-expression : eg. EGF receptor family
 c-erb B-1 is over expressed in squamous cell
carcinoma of lungs
 c-erb B-2 in breast cancers, adino-carcinoma of lungs,
ovaries and salivary glands.
 HER-2 and PDGF are amplified in human cancer
cells. These are the other types which can be over-
expressed.
Dr Anshu P Gokarn

28. Cytoplasmic Oncogenes
 Two important members in this
category are c-ras and c-abl
 ras Gene Family includes k-ras, h-ras
and m-ras
 Mutations in these three members of
the ras gene family – quite common Structure of ras
 eg. k-ras mutation prevalent in
pancreatic cancer & colonic cancer.
 Mutation in all three types in thyroid
cancer
Dr Anshu P Gokarn

29. Cytoplasmic Oncogenes
 abl Gene altered in 90% of CML
 Gene activated by chromosomal rearrangement with
another gene called bcr resultng in expression of
hybrid bcrabl protein eg. Philadelphia Chromosome
(reciprocal translocation of long arm f chromosome 22
occurs)
 abl possesses tyrosine kinase activity which is activated
in the bcrabl fusion protein.
Dr Anshu P Gokarn

30. Nuclear Oncogenes
 Bind to DNA elements in the promotors of specific
genes, enhancing (or occassionally inhibiting) gene
expression
Eg. eos, jun, erb A, mic
 Mic gene family consists of c-mic, N-mic and L-mic
– c-mic plays a part in regulating apoptosis
 Alterations in mic and bcl-2 (other oncogene indicated in
apoptosis) affects the balance between cell division an
death
 Combined with aberrant growth stimuli, it may result in
growth of malignant cells.
Dr Anshu P Gokarn

31. Tumor Suppressor Genes
 Have normal, diverse functions to regulate cell growth
in a negative fashion (restrain neoplastic growth; act as
cellular “brakes”)
 Act in a recessive fashion
– physical or functional loss of both alleles frees the
cell from constraints imposed by their protein
products
– also referred to as loss of function mutations
 Signal transduction regulation--NF1
 Transcription regulation--Rb and p53
 Cell surface/cell matrix molecules--NF2, APC, and
DCC – regulate cell adhesion
Dr Anshu P Gokarn

32. Tumor Suppressor Genes
 Products of TSGs receive and process growth
inhibitory signals from their surroundings.
 The result is the same as for unchecked stimulation of
cell growth: neoplastic growth deregulation
 Some products are responsible for normal cell
morphology, cell-cell interactions, and cell-matrix
interactions
Dr Anshu P Gokarn

33. Tumor Suppressor Genes
 Mechanisms of inactivation
– Structural inactivation
 Deletions
 Insertions
 Inactivating point mutations
– Functional inactivation (analogous to
regulatory alterations as seen in oncogenes:
normal gene, abnormal function eg Rb)
 In one clonal population it is possible to find a
combination of two mechanisms of inactivation, a
different one for each allele
Dr Anshu P Gokarn

34. The p53 gene…..
 Tumor suppressor gene, present in most human
cancers
Function of p53 gene :
 To halt the cell in its cycle before DNA
replication of the chromosomal DNA has been
damaged.
 This pause allows time for DNA repair,
preventing mutations from becoming
permanent.
Uses
 Ex: to assess cancer origin, to define cancer cell
immuno-phenotype, to detect cellular products
( hormones, cytokines, etc. ), to predict tumor
behavior with specific markers.
Dr Anshu P Gokarn

35. The role of p53 in development of cancer
In normal cells, p53
regulates cell growth by
controlling cell proliferation
and cell death.
Mutations in p53 lead to
loss of growth suppressive
functions, leading to
uncontrolled growth.
Dr Anshu P Gokarn

36. Growth Inhibitory Factors
 Mutations in genes encoding soluble factors that bind
to cell membrane, transmit growth inhibitory signals,
favour uncontrolled cell growth
 eg. Breast cancer – 1 (brca-1 protein)
 Increased mutations of brca-1 have increased risk of
breast and ovarian cancers
Dr Anshu P Gokarn

37. DNA Repair Genes
 “Humans literally swim in a sea
of environmental carcinogens.”
 Cells can repair damage caused
by ionizing radiation, sunlight,
dietary/chemical carcinogens and
replication errors which occur
spontaneously in dividing cells.
 If errors accumulate, cells are at
risk of neoplastic transformation
Dr Anshu P Gokarn

38. Apoptosis Regulating Genes
 Apoptosis is programmed cell death
 There are both proapoptotic genes (cell
death agonists such as bax, bcl-xS, bad, bid)
and antiapoptotic genes (cell death
antagonists such as bcl-2, bcl-xL)
 The prototypic gene in this category is bcl-
2
Dr Anshu P Gokarn

39. Cancer: apoptosis
Apoptosis (programmed or
physiological cell death)
 Process in which single cells are
removed from midst of living tissue
without disturbing architecture or
function or eliciting an inflammatory
response.
 Normal inbuilt response is present in its genetic material.
 Deregulated apoptosis : pathogenesis of neoplasms
 Apoptosis : End result of chemotherapeutic drug action
Dr Anshu P Gokarn

40. bcl-2 family
Antiapoptosis Proapoptosis
(Death antagonists) (Death agonists)
bcl-2 ba
x
Cell accumulation Apoptosis
Dr Anshu P Gokarn

41. bcl-2 family
Antiapoptosis Proapoptosis
(Death antagonists) (Death agonists)
bax
bcl-2 bcl-xS
bcl-xL bad
bid
Dr Anshu P Gokarn

42. Telomerase Genes
 With each cell division, shortening of specific tracts of
DNA at the ends of chromosomes occurs
 These tracts are called telomeres
 Telomeres are composed of repetitive DNA sequences
 Once shortened beyond a certain point, cells die
 Telomere shortening, therefore, acts as a clock that
counts cell divisions
Dr Anshu P Gokarn

43. Telomerase Genes
 In germ cells, telomere shortening is prevented by the
enzyme complex telomerase
 Telomerase adds back any repetitive telomere
sequences lost after a cell division
 Most somatic cells lack telomerase
 For a cell to divide indefinitely, it must prevent
telomere shortening
 Tumor cells do this by activating telomerase
Dr Anshu P Gokarn

44. Molecular Basis of Multistep
Carcinogenesis
 No single gene can transform cells in
Normal cell proliferation
vitro
 Every human cancer analyzed reveals
multiple genetic alterations involving
activation of several oncogenes and loss
of two or more tumor suppressor genes.
 The specific temporal order of
mutations determines the propensity
for tumor development
Dr Anshu P Gokarn Aggressive cancer cell

45. Localization and function of cancer associated genes
Dr Anshu P Gokarn

46. How cancer develops (The Pathological changes)
Stages of development of cancer
Dr Anshu P Gokarn

47. Cancer :Initiation to metastasis
Dr Anshu P Gokarn

48. Dr Anshu P Gokarn

49. Carcinogen
Carcinogen are chemicals that cause cancer
Carcinogen may be:
Environmental / Industrial
 Benzene leukemia
 Vinyl chloride liver
 Asbestos lung, pluera
 Arsenic lung
Associated with lifestyle
 Alcohol esophagus, mouth and throat
 Betel nuts mouth, throat
 Tobacco head, neck, lung, esophagus,
bladder
Dr Anshu P Gokarn

50. Carcinogens
Drug induced
 Alkylating agents leukemia, bladder
 DES liver,
vagina (if exposed before birth)
 Oxymetholone liver
Susceptible cell + carcinogen
cancerous cell
Dr Anshu P Gokarn

51. Dr Anshu P Gokarn

52. Risk Factors
 Family history
Ex: breast cancer, colorectal cancer
 Chromosomal abnormalities
ex : Down’s Syndrome with acute leukemia
 Environmental factors
Ex : UV radiation / sunlight --- skin
cancer
ionizing radiation /
atomic bomb explosion ---- leukemia
smoking ---- lung cancer
Dr Anshu P Gokarn

53. Risk factors
 Diet
Ex : 1. Smoked / pickled food cancer stomach more
2. High fiber diet - less colorectal cancer
 Alcohol
Ex: liver cancer
 Occupational hazard
Ex :asbestos with lung cancer
 Geographic location :
Ex : Japanese : colon / breast cancer - less
stomach cancer ---- - more
Dr Anshu P Gokarn

54. Risk Factors
 Viral infection
Ex: cytomegalovirus : Kaposi’s sarcoma
Hepatitis B virus : liver cancer
HIV virus : lymphomas
Parasitic infection
Ex: schistosoma : bladder cancer
Immune status
Ex : immunosuprressants / immunosuppressed status
More chances
Dr Anshu P Gokarn

55. PART IV
Dr Anshu P Gokarn

56. Types of tumors
 Benign tumor
Tumor is localized,cannot spread to other
sites,amenable to local surgical removal,patients
life is not at danger, capsule present
 Malignant tumor c/a cancer
Adhere to any part that they seize in an obstinate
manner
Lesion can invade / destroy surrounding areas,
can metastasize, patient’s life is at risk
Capsule is absent
Dr Anshu P Gokarn

57. Characteristics of benign and malignant tumors
 Differentiation (lack of differentiation a hallmark of
malignant cells)
 Rate of growth ( in malignant tumors correlates with
their level of differentiation)
 Local invasion (most benign tumors have a fibrous
capsule around them which separates them from the
host tissue)
 metastasis
Dr Anshu P Gokarn

58. Comparison
characteristics Benign malignant
Well differentiated. Lack of differentiation
1.Differentiation Structure typical of Structure atypical
tissue of origin
Progressive / slow Erratic/ slow to rapid
2. Rate of growth Standstill / regression
Cohesive and expansile; Locally invasive;
well demarcated;no invades surrounding
3. Local invasion
infiltration into tissue
surrounding
Dr Anshu P Gokarn

59. comparison
characteristics benign malignant
4. Metastasis Absent Frequently present
5. Bleeding Absent present
6. survival No threat to life Serious threat to life
Dr Anshu P Gokarn

60. Benign tumor
Dr Anshu P Gokarn

61. Malignant tumor (spreading)
Dr Anshu P Gokarn

62. Structure of a tumor
Stroma
(blood vessels,
connective tissue)
Parenchyma
(Decides the biological
behaviour)
Dr Anshu P Gokarn

63. Structure of a tumor
Dr Anshu P Gokarn

64. Dr Anshu P Gokarn

65. Nomenclature
Benign
 Fibrous – fibroma
 Cartilagenous – chondroma
 Epithelial -- microscopic / macroscopic
appearance/ cell of origin
Ex: Adenoma -- generally displays
glandular appearance
Papilloma – located on the surface
finger like processes
Polyp --- mass projecting above
mucosal surface ex:
gut
Cystadenoma -- hollow cystic masses
Dr Anshu P Gokarn

66. Nomenclature
Malignant
 Arising from mesenchyme --- sarcomas
Fibrous tissue --- fibrosarcoma
Chondrocytes --- chondrosarcoma
 Arising from epithelium ----carcinomas
squamous cell carcinoma
adenocarcinoma
Dr Anshu P Gokarn

67. Nomenclature
Melanoma in skin
 Poorly differentiated carcinoma
 Mixed Tumors ex: salivary glands
Exceptions to the rule
 Lymphoma
 Melanoma
 Mesothelioma malignant
 seminoma
Dr Anshu P Gokarn

68. Nomenclature
Malignant
 Arising from white blood cells
Leukemias
Ex : Acute Lymphoblastic Leukemia
 Arising from monocytes, macrophages
Lymphomas
Ex : Hodgkin’s disease
Dr Anshu P Gokarn

69. Nomenclature
Lung cancer-
Tumors arising from the
respiratory epithelium(bronchi,
bronchioles, alveoli)
 Treatment Decisions Of Lung
Cancers
Depends On The Histological
Appearance of the tumors
Dr Anshu P Gokarn

70. According to WHO classification……
Four major cell types make 88% of all primary lung
neoplasms
They are:
Squamous / epidermoid carcinoma
Small cell also called as oat cell carcinoma
Adenocarcinoma (including bronchioalveolar)
Large cell (large cell anaplastic) carcinoma
The remainder include undifferentiated carcinomas,
carcinoids, bronchial gland tumors (including adenoid
cystic and mucoepidermoid carcinomas) and the rarer
tumors.
Dr Anshu P Gokarn

71. Differences between Small cell type and
Non- small cell type
Small cell type Non small cell type
 (scant cytoplasm,small  (Abundant cytoplasm,
hyperchromatic nuclei, pleomorphic nuclei,
indistinct nucleoli, diffuse prominent nucleoli,
sheets of cells glandular/squamous
architecture)
 At presentation they have
spread so much that surgery  Localized
not helpful.
 Managed primarily by  Amenable to surgery and
chemotherapy and/or radiotherapy but not
radiotherapy. chemotherapy.
Dr Anshu P Gokarn

72. Benign Neoplasms of the Lung
Represents less than 5 % of all primary tumors
 Bronchial adenomas
 Hamartomas
 Chondromas
 Fibromas
 Lipomas
 Haemangiomas etc.
Dr Anshu P Gokarn

73. Cancer of stomach
 85% of stomach cancers are
adenocarcinomas
 15% - lymphomas / leiomyosarcomas
 Adenocarcinomas ---
 Diffuse type (individual cells infiltrate and thicken the
stomach
 Intestinal type (neoplastic cells form gland like tubular
structure)
Dr Anshu P Gokarn

74. Tumors of the small intestine
 Benign tumors
Adenomas – Islet cell adenoma (From the
pancreas)
Brunner’s gland adenoma( from the
duodenal mucosal
glands)
Polypoid adenomas
Leiomyomas – from smooth muscle of the
intestine
Lipomas – In the distal ileum and at
ileocecal valve
Angiomas – They cause intestinal bleeding
Dr Anshu P Gokarn

75. Tumors of the small intestine Contd…..
Malignant tumors
 Ampullary carcinomas – arise from biliary / pancreatic ducts
 Adenocarcinomas – Most common carcinoma of small bowel (50%
incidence)
 Lymphomas – may be primary / secondary
 Primary -ex : Non-Hodgkin’s Lymphoma, Involves the ileum,
duodenum and jejunum in decreasing order of frequency.
 Secondary lymphomas – involvement of the intestine by a lymphoid
malignancy extending from involved retroperitoneal or mesenteric
lymph nodes
 Carcinoid Tumors – From distal duodenum to the ascending colon
 Leiomyosarcomas
Dr Anshu P Gokarn

76. Tumors of the liver
 Benign liver tumors
 Hepatocellular adenomas – In right lobe of the liver
 Focal nodular hyperplasia- predominantly in
women
 Solid tumor in the right lobe with a fibrous core
 Hemangioma
 Malignant tumors
 Hepatocellular carcinomas
Dr Anshu P Gokarn

77. Breast cancer
 Ductal adenocarcinoma - most common
 Lobular carcinoma - the second malignant breast
tumour
 Medullary carcinoma is rare
 Hyperplasia is a proliferation without criteria of
malignancy
 Fibroadenomas are benign breast tumours
Dr Anshu P Gokarn

78. Solid tumors
 Comprise a group of malignancies arising from the
various systems or organs with distinct behaviour
patterns, requiring different management
 Multimodal approach followed in management of
solid tumors
 Surgery - the primary modality for most of the solid
tumors
 Radiotherapy also can be used as a primary
modality followed by adjuvant therapy
Dr Anshu P Gokarn

79. Solid tumors Contd…..
 Chemotherapy
 systemic,
 local or
 regional
Regional chemotherapy - intra-tumoral,
intracavitary or
intra-arterial
Systemic chemotherapy – to prevent early disseminated
aggressive lesions
Dr Anshu P Gokarn

80. Dr Anshu P Gokarn

81. Various types of cancers
 Haematological malignancies
 Acute Lymphocytic Leukemia Multiple myeloma
 Acute Granulocytic leukemia Hodgkin’s Disease
 Acute myelomonocytic Low grade(nodular)
leukemia lymphomas
 Chronic granulocytic leukemia High grade lymphomas
 Chronic Lymphocytic Burkitt’s tumor
leukemia Mycosis Fungoides
Dr Anshu P Gokarn

82. Various types of tumors
Solid tumors
 Adrenocortical carcinoma  Head and neck
 Bronchogenic carcinoma squamous cell
small cell or oat cell  Hepatocellular
 Squamous cell, large cell carcinoma
anaplastic and
 Malignant insulinoma
adenocarcinoma or islet cell carcinoma
 Malignant melanoma
 Cervix squamous cell
 Ovary
 Colon carcinoma  Pancreatic
 Endometrial carcinoma adenocarcinoma
 Gastric adenocarcinoma  Prostate
Dr Anshu P Gokarn

83. Various types of cancers
 Pediatric solid tumors
 Wilm’s tumor
 Ewing’s sarcoma
 Embryonal
Rhabdomyosarcoma
 Retinoblastoma
 Neuroblastoma
 Osteogenic sarcoma
Dr Anshu P Gokarn

84. Dr Anshu P Gokarn

85. Metastases
 Development of secondary implants discontinuous
with the primary tumor, possibly in remote areas.
 Not all cancerous cells have an equal ability to
metastasize
Ex:
 basal cell carcinoma and cancers of CNS invade
locally but rarely metastasize
 Bone sarcomas have already metastasized to lungs at
discovery
Dr Anshu P Gokarn

86. Metastases
Occurs by following routes
1. Hematogenous
2. Lymphatic
3. Seeding of cancer cells
4. Direct implantation
Common sites of metastases
Dr Anshu P Gokarn

87. Metastases
Hematogenous
 Favoured by sarcomas (carcinomas
are by no means shy about using it ! )
 Liver and lungs – most frequently
affected
 Spread by this route very fast
 Some tumors have propensity to
invade veins
Dr Anshu P Gokarn

88. Metastases
Lymphatic spread
 More typical of carcinomas
 Pattern of lymph node involvement depends on site
of involvement, natural lymphatic pathways for
drainage
ex: lung carcinomas of respiratory passage first
metastasize to the regional bronchial lymph nodes;
then to tracheo - bronchial / hilar lymph nodes
 Cells may traverse all the lymph nodes to enter the
vascular compartment
Dr Anshu P Gokarn

89. Metastases
Seeding of cancers
 Invasion of natural body cavities
 Ex: carcinoma of colon can penetrate wall of the gut
and reimplant at distant sites.
 Cancer ovary disseminates through peritoneal cavity
Direct spread
With surgeon’s gloves
Or
With surgical instruments
 Rarely seen in practice
Dr Anshu P Gokarn

90.  What happens to the patient ?
Dr Anshu P Gokarn

91. Signs and symptoms
 Pain
 Loss of weight / muscle wasting
 Loss of appetite/anaemia
 Ulceration at the site
 Bleeding
 Rapid growth in size
 Immunosuppression –repeated infections
 Depending on the location of the tumor
pitutary adenoma - hypopituitarism
Renal carcinoma - renal ischaemia/hypertension
Hormone production --Neoplasm of endocrinal gland
Dr Anshu P Gokarn

92. Signs and
symptoms
Dr Anshu P Gokarn

93. Diagnosis of cancer
 History
 Age
 Sex
 Family, personal history
 Geographic location
 Screening
 Radiological examination ---- MRI
CT- Scan
X ray chest
Dr Anshu P Gokarn

94. Diagnosis of cancer
Screening
 To detect possibility of cancer
 Early detection
Disadvantage
 Though not definitive reduction in number of deaths
 Costly
 Psychological or physical repurcussions
 High number of false positive/ false negative results
seen
Dr Anshu P Gokarn

95. Diagnosis of cancer
Screening tests widely used
In women
 Pap staining --- cancer cervix
 Mammogram – breast cancer
In men
 Prostate specific antigen ---- prostate cancer
Other tests
Xray chest
Sputum cytology lung cancer
Stool examination for occult blood rectal cancer
Rectal examination rectal cancer
pelvic examination cervical cancer
Dr Anshu P Gokarn

96. Diagnosis of cancer
Molecular / Morphologic methods
Tissue Biopsy
 Indicated
almost all types of cancers
 Advantages
Invasive method but highly diagnostic
 Disadvantage
Margins may not be representative / centre
may be necrotic . Selection of appropriate site
necessary
Dr Anshu P Gokarn

97. Diagnosis of cancer
Frozen section biopsy
Advantages
 determines nature of lesion
 Helps evaluate the margins of excised
cancer
 Quick method
 Patient spared the trauma of repeated
operation
Dr Anshu P Gokarn

98. Diagnosis of cancer
Fine needle aspiration cytology
 Indicated
For readily palpable lesions of breast, thyroid,lymph
nodes, salivary glands
 Advantages :
obviates need for surgery
Deeper structures can be examined
 Disadvantages
 Sampling errors due to small sample size may occur
Dr Anshu P Gokarn

99. Diagnosis of cancer
Cytologic smears
 Indicated in:
Carcinoma cervix, endometrial carcinoma,
bronchogenic carcinoma,bladder,
prostate,joints,, abdominal tumors, pleural
tumors
 Advantages
100 % true positive diagnosis
Dr Anshu P Gokarn

100. Diagnosis of cancer
Biochemical methods
1. Biochemical assays
Indications
 To determine prognosis
 To detect new cases
 Tumor associated enzymes
 Hormones
 Tumor markers : alpha fetoprotein,
carcinoembryonic antigen
2. Radioimmunoassay
Dr Anshu P Gokarn

101. Tumor Markers
 Normal metabolic constituents / biochemical products
found in abnormal amount / at inappropriate time of
life
 Aids in detecting viable tumor tissue in the blood
Ex : Fetal proteins re-expressed in adult life
 Tumor markers used to monitor progress of individual
patients of malignancy
Ex : alpha-fetoprotein for testicular tumors
Dr Anshu P Gokarn

102. Radioimmunoassay
 Highly specific antibodies raised against tumor
antigens and labelled with flourescein stain /.
 Used in immunohistochemical techniques to detect
tumor cell products such as enzymes, hormones,
receptors
 Used to differentiate between benign and malignant
tumors
 To differentiate between histological subtype of
similar tumors
 To select the most appropriate therapy
Dr Anshu P Gokarn

103. Dr Anshu P Gokarn

104. Grading of cancer
 Grading
Helps to estimate
 The aggressiveness of the tumor
 Level of malignancy
 To predict the prognosis
Done depending on the degree of
anaplasia
Grade I -- IV
Dr Anshu P Gokarn

105. Staging
 Based on size of primary lesion
 Extent of spread to regional lymph nodes
 Presence/absence of lymph nodes
 CT Scan/ MRI/Exploratory laparotomy to conduct
staging
 Of more value than grading
Dr Anshu P Gokarn

106. Staging
 Method
TNM classification
T = extent of primary tumor
N = regional lymph node involvement
M = Metastases
Dr Anshu P Gokarn

107. TNM classification
 T0 ---- excised tumor
 T1,T2,T3, – increase in size of
primary lesion
 N0, N1,N2,N3—indicate
advancing nodal involvement
 M0, M1 – Presence/ Absence of
metastases
Dr Anshu P Gokarn

108. TNM Classification: ex: Breast cancer
Primary Tumor
 TX primary tumor cannot be assessed
 TO No evidence of primary tumor
 Tis Carcinoma in situ: intraductal carcinoma, lobular
carcinoma in situ or Pagets disease of the nipple with no tumor
 T1 tumor 2 cm or less in greatest diameter
 T1a 0.5 cm or less in greatest diameter
 T1b > 0.5 cm but < 1 cm in greatest diameter
 T1c > 1cm but < 2 cm in greatest diameter
 T2 Tumor > 2cm but < 5 cm in greatest diameter.
 T3 Tumor>5 cm in greatest diameter.
 T4 Tumor any size with direct extension into chest wall of skin
 T4a Extension to chest wall .
 T4b Oedema
 T4c Both(T4a and T4b)
 T4d Inflammatory carcinoma
Dr Anshu P Gokarn

109. TNM Classification: ex: Breast cancer
Regional Lymph Nodes
 NX Regional lymph nodes cannot be assessed (ex:
previously removed)
 N0 No regional Lymph Node metastasis
 N1 Metastasis to ipsilateral axillary lymph nodes fixed
to one another or to other structures.
 N3 Metastases to ipsilateral internal mammary node(s)
Distant Metastases
 MX Presence of distant metastases cannot be assessed
 M0 No distant metastases
 M1 Distant metastases
Dr Anshu P Gokarn

110. Investigations to define TNM classification
Tumor
 Palpation
 Inspection including endoscopy
 Radiology
 Cytology / aspiration /biopsy
Nodes
 Palpation
 Aspiration
 Biopsy
 Radiology (CT scanning)
Dr Anshu P Gokarn

111. Investigations to define TNM status
Metastases
 Biochemical screening(ex : liver function tests)
 Radionuclide scans(ex : liver,brain, bones)
 Ultrasound of liver
 Radiology (Xray chest, CT scan- liver, brain, thorax)
 Laparoscopy
 Laparotomy
Dr Anshu P Gokarn

112. PART - V
Dr Anshu P Gokarn

113. Cancer treatment
Types :
 Radiotherapy
 Chemotherapy
 Immunotherapy
 Endocrine Therapy
 Surgery
Dr Anshu P Gokarn

114. Chemotherapy
The treatment of cancer with drugs which kill
malignant cells or modify their growth and leave
host cells unharmed or at least recoverable.
AIM
To Cure Or Prolong Remission
Palliation
Adjuvant Chemotherapy – drugs are used to mop
up any residual malignant cells (micrometastases)
after surgery or radio-therapy.
Dr Anshu P Gokarn

115. Purine Pyrimidine PALA-I nhibits pyrimidine
synthesis synthesis synthesis
Pentosan- Inhibits
adenisine deaminase
Hydroxyurea- inhibits
ribonucleotide reductase
6-mercaptopurine, 6- Ribonucleotide
thioguanine
5-Fluorouracil- inhibits TMP
Inhibits purine ring Deoxyribonucleotides s synthesis
biosynthesis
Gemcitabine,Cytarabine,Fludara
Inhibits nucleotide bine, -Inhibits DNA synthesis
bioconversions
DNA
Methotrexate- inhibits Platinum analogues,alkylating
dihydrofolate reduction- agents,Mitomycin,,cisplatin,
blocks TMP and purine Procarbazine,Dacarbazine- forms
RNA adducts with DNA
synthesis
L-asparginase- deaminates
Camptothecin,Etoposide,T asparagine- inhibits protein
eniposide,Daunorubicin – Proteins
synthesis
blocks topoisomerase
function Paclitaxel, Vinca alkaloids,
Enzymes microtubules colchicine- inhibits function of
microtubule
Dr Anshu P Gokarn

116. Anti tumor drug action to the cycle
DNA synthesis (G2) Premitotic
(S) interval
S-Phase specific
Cytosine arabinoside (M) Mitosis
Hydroxurea Vincristine, vinblastine,
S Phase specific, self Paclitaxel
limiting
6 Mercaptopurine
Methtrexate
G 0 (resting
(G 1) phase)
Dr Anshu P Gokarn

117. Anti tumor drug action to the cycle
Phase Non-Specific
 Alkylating drugs
 Nitrosoureas,
 Anti tumor antibiotics
 Procarbazine,
 Cis-platinum,
 Dacarbazine
Dr Anshu P Gokarn

118. Treatment Of Cancer
DRUG ACTION
 Cycle Specific : only active cycling cells killed Toxicity is
generally expressed in S -phase e.g. anti-metabolite
 Cycle Non-Specific : kills cells in both resting or active
cycling phase (i.e. tumor with low growth fraction - e.g. solid
tumors). Non cycling cells are allowed to re-enter the cycle
between drug courses.
e.g. alkylating agents; doxorubicin; anthracyclines; MOPP
regime
Dr Anshu P Gokarn

119. Alkylating agents
 Nitrogen mustards
ex: Mechlorethanamine, cyclophosphamide,
Melphalan, Uracil mustard, Chlorambucil
 Ethylenimines
ex: Triethylenemelamine (TEM)
Triethylene Thiophosphamide (Thio-TEPA)
 Alkyl Sulfonates
ex: Busulfan
Dr Anshu P Gokarn

120. Alkylating agents
Mechanism of action
 Cells are destroyed by alkylation
 Alkyl groups are added to constituents of DNA
inhibiting DNA synthesis
 Interference with the replication and transcription of
Messenger RNA occurs
Indications
 Hodgkin’s disease
 Lymphomas, chronic leukemias
 Bronchial, ovarian carcinoma
 seminomas
Dr Anshu P Gokarn

121. Alkylating agents - Cyclophosphamide
 Mechanism of action similar but thrombocytopenia is less
severe while alopecia like side effects are more.
 The drug does not produce any CNS side effects.
 Essential component for various drug combinations for
Non-Hodgkin’s lymphoma.
 Administered by both oral and Intravenous route
 Can be given as single agent for Burkitt’s Lymphoma
Dr Anshu P Gokarn

122. Alkylating agents (busulfan)
 More effective on the myeloid series of cells
 Causes depression of platelet and granulocyte
production
Indication
 In chronic myeloid leukemia
Dr Anshu P Gokarn

123. Nitrosureas
 EX: carmustine, Lomustine, Streptozotocin
 Alkylates the DNA and kills cells in all phases of cell
cycle
 Have high lipophilicity , so can be given in Brain
malignancies.
 Indicated in gastrointestinal neoplasms and brain
tumors.
 Significant response in Hodgkin’s disease
 May cause renal failure and myelosuppression.
 Streptozotocin does not cause myelosuppression.
Dr Anshu P Gokarn

124. Antimetabolites
II) Folic acid antagonists
Ex: methotrexate
 Purine analogues
Ex : 6- mercaptopurine, Azathioprine
 Pyrimidine analogues
Ex : cytosine arabinoside, 5- fluorouracil
Dr Anshu P Gokarn

125. Antimetabolites
Mechanism of action
 Blocks the action of the metabolite by preventing the
combination of the metabolite with it’s enzyme
Or
 Itself combines with the enzyme to get transformed
into a metabolically inactive compound which is
harmful to the cell
Dr Anshu P Gokarn

126. Antimetabolites
Folic acid antagonists : Methotrexate
Folic acid
Methotrexate
TetraHydrofolic Folate reductase +
acid No THF synthesis
DNA synthesis No DNA synthesis
Indications
 Acute Lymphatic Leukemia
 Choriocarcinoma
 Soft tissue sarcoma
 Breast cancer
 Acute Myeloid Leukemia
Dr Anshu P Gokarn

127. Antimetabolites: (Purine antagonists)
 Interferes with the synthesis and interconversion
of purines
6- Mercaptopurine
6-mercaptopurine ribonuclide
inhibits
inhibits
Purines synthesis DNA
Dr Anshu P Gokarn

128. Purine antagonists
Indications
 Acute Leukemia mainly in children
 Choriocarcinoma
 Chronic Myelogenous leukemia (CML)
Dr Anshu P Gokarn

129. Pyrimidine antagonists
(5- Fluorouracil)
 Fluorinated analogue of pyrimidine
 Binds to thymidylate synthetase to prevent the
production of thymine(basic component of DNA)
 Incorporates in place of uracil in RNA
Indications
 Carcinoma of colon, ovaries, rectum, stomach, breast
Cytosine arabinoside
 Pyrimidine analogue used in inducing remission in acute
myeloid leukemia
Dr Anshu P Gokarn

130. Procarbazine
Mechanism of action
 Undergoes metabolic activation to generate the cytotoxic
reactants which methylate DNA.
 Exposure to Procarbazine leads to damage of the DNA,
RNA and the protein synthesis which occurs in vivo
Indications
 Used in combination with other drugs of the MOPP regime
in Hodgkin’s disease.
 Has shown activity against brain tumors, small cell
carcinoma of the lung, myeloma and melanoma
Dr Anshu P Gokarn

131. Hydroxyurea
Mechanism of action
 Interferes with the activity of ribonucleoside
diphosphate reductase .
 This enzyme converts ribonucleotide to
deoxyribonucleotides and is the rate limiting step in
the biosynthesis of DNA.
Indication
 Used as a myelosuppressant in myeloproliferative
disorders ex: chronic granulocytic leukemia,
polycythemia vera and essential thrombocytosis
Dr Anshu P Gokarn

132. Gemcitabine : newer antimetabolite.
 Mechanism of action
 Weak inhibitor of DNA polymerase
 Potent inhibitor of ribonucleotide reductase
 Incorporates into DNA and leads to DNA strand
termination.
 Indications
 First line therapy in pancreatic acncer and non small
cell lung cancer
Dr Anshu P Gokarn

133. Radioactive isotopes
 Radiations emitted by these isotopes produce
ionization in the cells thereby disrupting the cellular
metabolism.
 Cell destruction follows
Indications
 Radioactive iodine for thyroid cancer
 Radioactive gold for malignant pleural/ peritoneal
effusions, in prostatic / pelvic cancers
Ex : Radioiodine, Radiogold, Radiophosphorus
Dr Anshu P Gokarn

134. Antibiotics
Mechanism of action
 Blocking DNA dependent RNA synthesis
(actinomycin D, Rubidomycin)
 Causing breaks in single / double stranded DNA
(bleomycin)
Indications
Actinomycin D - Wilm’s tumor, choriocarcinoma ,
Hodgkin’s lymphoma
Mitomycin ---- CML, Hodgkin’s Disease
Rubidomycin --acute leukemia in children
Doxorubicin ---Remission in ALL, lymphoblastic
lymphosarcoma
Dr Anshu P Gokarn

135. Antibiotics (contd…..)
 Bleomycin ---- epidermoid carcinoma of skin, respiratory
passage, oral cavity,
 Mithramycin --embryonal cell carcinoma of testes, in
 hypercalcaemia due to malignancy, Paget’
disease
Mitoxantrone
 Analogue of doxorubicin
 Has low cardiotoxicity potential
 Indicated in acute granulocytic leukemia, breast cancer.
Dr Anshu P Gokarn

136. Antimitotic plant products (Vinca alkaloids)
Act by:
Inhibiting mitosis
Binds to tubulin and prevents the formation of mitotic spindle
Uses
Vinblastine in
Hodgkin’s disease(remission in 50- 60% cases)
Methotrexate resistant choriocarcinoma, lymphosarcoma
Vincristine in
Acute Lymphatic Leukemia
Vinorelbine in
Non small cell lung carcinomas along with cisplatin
In breast cancer
Causes lesser neurotoxicity and modest thrombocytopenia
than other vinca alkaloids.
Dr Anshu P Gokarn

137. Antimitotic plant products
(Paclitaxel)
Mechanism of action
Binds to microtubules and inhibits their depolymerization
(molecular disassembly) into tubulin.
Paclitaxel blocks a cell's ability to break down the mitotic
spindle during mitosis (cell division)
Paclitaxel inhibits mitosis but unlike vinca alkaloids promotes
microtubule formation.
Indications
In Cisplastin resistant tumors of ovary
Cancers of breast, lung, oesophagus, head and neck
Dr Anshu P Gokarn

138. Docetaxel
Mechanism of Action
Like paclitaxel, it prevents the breakdown of mitotic spindle
Clinical trials indicate it's about twice as effective as paclitaxel
Indication:
Breast cancer
Non small cell Lung cancer
Other uses:
Head and neck cancer, Small cell lung cancer
Mesothelioma, Ovarian cancer, Prostate cancer
Orothelial transitional cell cancer
Dr Anshu P Gokarn

139. Natural Products (Camptothecins)
Irinotecan, Topotecan
 Combines with the Topo-isomerase I and inhibits its function
 An intermediate complex formed creating single stranded DNA
break(cleavable complex)
 This relieves the DNA torsion
 Camptothecins stabilize the cleavable complex
 Accumalation of single stranded breaks in DNA which after series
of reactions becomes irreversible leading to cell death
 Active in S phase
Indications
 Ovarian cancer, Small cell lung cancer,
 Colon cancer
Dr Anshu P Gokarn

140. Natural Products
(Epipodophyllotoxins)
Etoposide
 Form a ternary complex with Topoisomerase II and DNA
 Results in double stranded DNA breaks and resealing of the break that follows
the binding of DNA with Topoisomerase is inhibited
 Enzyme remains bound to the free end of the broken DNA strand leading to
accumalation of DNA breaks and cell death.
 Cells in S /G2 phase most susceptible
Indications
 In testicular cancer, small cell lung, breast cancers.
 Hodgkin’s disease, Non- Hodgkin’s Lymphoma, Acute granulocytic Leukemia,
Kaposi’s sarcoma
Dr Anshu P Gokarn

141. Hormones and Hormone antagonists
Mechanism of action
 Act in a different manner from the cytotoxic drugs and can be
combined with them in certain malignancies
 Are slow in their effect
 Inhibit cell growth and differentiation
Ex androgens in breast cancer
estrogens in prostate cancer
 Stimulation of differentiation of cells which regain the body’s
ability to respond to regulatory mechanism
Ex: estrogens in breast cancer in postmenopausal women
Dr Anshu P Gokarn

142. Hormone and hormone antagonists
 Selective lysis of leukemic lymphocytes
Ex : in ALL (Acute Lymphocytic Leukemia)
 Inhibition of circulating concentration of a substance which
stimulates the malignant cells
Ex: Thyroxine suppresses thyroid cancers by inhibiting TSH
levels
 Androgens in Mammary tumors in post-menopausal
women
Particularly useful in bone metastases because they promote
recalcification
 Flutamide
Nonsteroidal compound used in metastatic cancer o prostate
Dr Anshu P Gokarn

143. Hormones and hormone antagonists
Tamoxifen
 Nonsteroidal oestrogen it competes with the circulating
estrogen for binding to estrogen receptors
 At low concentrations – estrogen receptor positive cells are
blocked by the drug (cytostatic effect)
 At higher concentrations – (cytotoxic effects)
Estrogen receptor positive/ negative cells are destroyed.
Indication
 Postmenopausal women with breast cancer
Dr Anshu P Gokarn

144. Hormone and hormone antagonists
Steroids
 Direct lympholytic effect
Suppress mitosis in lymphocytes
(due to this effect used in ALL / Malignant lymphoma)
 Prevents accelerated erythrocyte destruction (prevents
anaemia )
 Counter haemolytic/Haemorrhagic) complications due to
thrombocytopenia in CML/ CLL
 In cerebral edema due to intracranial tumors metastases
 To control hypercalcemia due to certain tumors or following
drug therapy
 In combination with cytotoxic drugs to produce symptomatic
relief and sense of well being
Dr Anshu P Gokarn

145. L- Asparginase
Acts by depleting asparginase from the host
and denying the malignant cells the metabolite
Indications
 In reticulum cell carcinoma
 Lymphoblastic leukemia
CisPlatinum
 Gets converted into active form in the cell
 Behaves like alkylating agent and attacks the DNA
Indications
 Ovarian and testicular tumors
Dr Anshu P Gokarn

146. Newer agents : Carboplatin
 Mechanism of action is similar to cisplatin.
However:
 Carboplatin is less reactive than cisplatin.
 Relatively well tolerated in clinical practice.
 Carboplatin is an effective remedy in patients with responsive
tumors but unable to tolerate cisplatin because of impaired
renal function, refractory nausea, significant hearing
impairment, or neuropathy..
 Can be used in high dose therapy.
Indications
 In bladder cancer, head and neck cancer.
Dr Anshu P Gokarn

147. Newer agents : Oxaliplatin
 Unlike carboplatin and cisplatin it has a high volume of
distribution.
 Unlike cisplatin, oxaliplatin in combination with 5-FU is
active in colorectal cancer.
 Oxaliplatin, does not yield a cross-resistance.
 Less toxic than cisplatin
 Indications
 Ovarian cancer, germ cell cancer, cervical cancer,
colorectal cancer.
Dr Anshu P Gokarn

148. Newer agents : Nedaplatin
 Nedaplatin – A recent addition to platinum compounds.
 Along with 5FU effective in squamous cell carcinoma of oral
region.1
 Indicated in head and neck, testicular, lung, oesophageal,
ovarian, and cervical cancer. 2
 Yields cross resistance with other platinum compounds .2
 Less toxic than cisplatin.2
1. Ita M et al. Oral Oncol 2003 Feb;39(2): 144-9
2. Desoize B, Madoulet CCrit Rev Oncol Hematol 2002 Jun;42(3):317-25
Dr Anshu P Gokarn

149. Drugs commonly used to treat major types of
cancer: Hematological Malignancy
Leukemia: (ALL)
Cancer Type/ Drugs used Alternative / Other drugs with
Incidence secondary drugs reported activity
Acute Induction: Daunorubicin Thioguanine
Lymphocytic Vincristine + Doxorubicin Teniposide
Leukemia prednisone Cyclophaosphamide
Methotrexate
for cytarabine
Incidence : 2.1% CNS prophylaxis
of all cancers Maintenance –
and cancer Methotrexate +
deaths mercaptopurine
Dr Anshu P Gokarn

150. Drugs commonly used to treat major types of
cancer: Hematological Malignancy
Leukemia: (Acute granulocytic Leukemia)
Cancer Type/ Drugs used Alternative/ Other drugs with
Incidence secondary drugs reported activity
Acute Doxorubicin or Amsacrine Azacitidine
granulocytic daunorubicin + Mitoxantrone Mercaptopurine
leukemia cytarabine Etoposide
OR
Cytarabine +
Thioguanine
OR
Cytarabine,
vincristine +
Prednisone
Dr Anshu P Gokarn

151. Drugs commonly used to treat major types of
cancer: Hematological Malignancy
Leukemia: AML
Cancer Type/ Drugs used Alternative/ Other drugs with
Incidence secondary drugs reported activity
Acute Doxorubicin / Etoposide
myelomonocytic daunorubicin +
or monocytic cytarabine
leukemia OR
Cytarabine +
thioguanine
OR
citarabine,
vincristine +
prednisone
Dr Anshu P Gokarn

152. Drugs commonly used to treat major types of
cancer: Leukemia and Multiple
myeloma
Leukemia : CLL
Cancer Type/ Drugs used Alternative / Other drugs with
Incidence secondary drugs reported activity
Chronic Hydroxyurea Busulfan Mercaptopurine
Granulocytic Interferon alpha Plicamycin
leukemia
Chronic Chlorambucil Prednisone
Lymphocytic Cyclophosphamide
Leukemia
Dr Anshu P Gokarn

153. Drugs commonly used to treat major types
of cancer:
Hematological malignancy
Multiple Myeloma
Cancer Type/ Drugs used Alternative / Other drugs with
Incidence secondary drugs reported activity
Multiple Myeloma Melphalan OR Doxorubicin Vincristine+
Cyclophosphamide vincristine doxorubicin+
+ Prednisone Dexamethasone
Dr Anshu P Gokarn

154. Drugs commonly used to treat major types of
cancer: Hematological Malignancy
Cancer Type/ Drugs used Alternative / Other drugs with
Incidence secondary drugs reported activity
Hodgkin’s disease ABVD MOPP Lomustine
(Doxorubicin, regime(chlormusti Carmustine
bleomycin, ne, vincristine,
Incidence: Chlorambucil
vinblastine, procarazine,
0.5% of all cancers Thiotepa
dacarbazine) prednisone)
and 0.3% of cancer Etoposide
deaths
Dr Anshu P Gokarn

155. Drugs commonly used to treat major types of
cancer: Hematological Malignancy
Cancer Type/ Drugs used Alternative / Other drugs with
Incidence secondary drugs reported activity
Nodular lymphoma Cyclophosphamid fludarabine Lomustine
(Non Hodgkin’s e, vincristine, Carmustine
Lymphoma) prednisone Interferon alpha
2.4% of all cancers
Burkitt’s tumor cyclophosphamid carmustine methotrexate
(Non Hodgkin’s e
Lymphoma)
2.4% of all cancers
Mycosis fungoides Methotrexate Mechlorethamine
Dr Anshu P Gokarn

156. Drugs commonly used in Pediatric solid tumors, brain
tumors, germ cell tumors and sarcomas
Cancer Type/ Incidence Drugs used Alternative / Other drugs
secondary with reported
drugs activity
Wilm’s Tumor Dactinomycin + Doxorubicin Cyclophos
Incidence: 1.6% of all vincristine -phamide
cancers and 1.8% of
cancer deaths
Ewing’s sarcoma Cyclophosphamide+ Dactinomycin
0.2% of all cancers doxorubicin+
vincristine
Embryonal Doxorubicin Dactinomycin Thiotepa
rhabdomyosarcoma Cyclophosphamide Methotrexate
Vincristine
alternating with
cisplatin + etoposide
Dr Anshu P Gokarn

157. Drugs commonly used to treat major types of
cancer
Cancer Type/ Drugs used Alternative / Other drugs with
Incidence secondary drugs reported activity
Retinoblastoma cyclophosphamide Carboplatin
Neuroblastoma Cyclophosphamide Doxorubicin Etoposide
OR vincristine Cisplatin or
carboplatin
Vinblastine
Prednisone
Osteogenic Doxorubicin+ Cisplatin or Melphalan
sarcoma cisplatin, Methotrexate + Mitomycin
0.2 % of all folinic acid
cancers
Dr Anshu P Gokarn

158. Drugs commonly used to treat major types of
cancer: solid tumors
Cancer Type/ Drugs used Alternative / Other drugs with
Incidence secondary drugs reported activity
Adrenocortical mitotane
carcinoma
Bladder Cisplatin or Methotrexate , Fluorouracil,
Incidence: 4.6% of doxorubicin vinblastine, cyclophosphamide
all cancers and Thiotepa mitomycin
3.4% of all cancer Methotrexate
deaths vinblastine
Colon carcinoma Fluorouracil mitomycin Tegafur
11.6% of ll cancers Semustine
Doxorubicin
Dr Anshu P Gokarn

159. Drugs commonly used to treat major types of
cancer: solid tumors
Cancer Type/ Drugs used Alternative / Other drugs with
Incidence secondary drugs reported activity
Bronchogenic Doxorubicin+ Etoposide + Procarbazine,
carcinoma small cyclophosphamide+ cisplain Altretamine
cell or ‘oat cel’ vincristineOR Paclitaxel
16.8% of all Cyclophosphamide
cancers + lomustine+
methotrexate
Squamous cell, Cisplatin + Methtrexate, Mitomycin
large cell vincristine OR cyclophosphamide
anaplastic and cisplatin + Methotrexate
adenocarcinoma etoposide
16.8% of all
cancers
Dr Anshu P Gokarn

160. Drugs commonly used to treat major types of
cancer: solid tumors
Cancer Type/ Incidence Drugs used Alternative / Other drugs with
secondary reported activity
drugs
Endometrial carcinoma Megestrol OR Doxorubicin Fluorouracil,
1.5% of all cancers and Medroxyprogest cyclophosphamide
0.7% of all cancer deaths erone
Gastric adenocarcinoma Fluorouracil Semustine, Tegafur
5% of all cancer deaths Mitomycin mitomycin
and 5.8% of cancer Doxorubicin
deaths
Hepatocellular Doxorubicin Fluorouracil, Tegafur
carcinoma etoposide
0.5% of all cancer deaths cisplatin
Dr Anshu P Gokarn

161. Drugs commonly used to treat major types of
cancer: solid tumors
Cancer Type/ Drugs used Alternative / Other drugs with
Incidence secondary drugs reported activity
Cervix squamous Cisplatin Bleomycin,mitom Methotrexate,
cell ycin, Fluorouracil,
1.8% of all cancers Vincristine,
and 1.2 % of Cyclophosphamide
cancer deaths doxorubicin
Head and Neck Cisplatin+ Bleomycin Methotrexate, Vinblastine
cancer OR methotrexate OR
Paclitaxel Epirubicin
fluorouracil+
leucovorin Doxorubicin
carboplatin
Malignant Streptozotocin + Dacarbazine
Insulinoma doxorubicin OR
2.7% of all cancers fluorouracil
and 4.2 5 of all
cancer deaths
Dr Anshu P Gokarn

162. Drugs commonly used to treat major types of cancers
Solid tumors
Cancer Type/ Incidence Drugs used Alternative / Other drugs with
secondary reported activity
drugs
Malignant Melanoma Dacarbazine Cisplastin Hydroxycarbamide
1.5% of all cancers and Semustine
0.8% of all deaths
Ovary Cisplatin + Doxorubicin FluorouracilChlora
Incidence: 2.3% of all cyclophosphamide OR mbucil, Thiotepa
cancers and 2.7% of + Doxorubicin altretamine Melphalan,
cancer deaths
Prostate Stilbestrol Cyclophosph Estramustine
Incidence: 5% of all amide
cancers and 6.2% of Doxorubicin
cancer deaths
Dr Anshu P Gokarn

163. Nonmelanoma skin cancer:Incidence : 12.2% of all cancers
Cancer Type/ Incidence Drugs used
1. Basal cell carcinoma 5 Fluorouracil – tretament of
superficial variety
Intralesional intereferon useful
2. Squamous cell carcinoma 13 Cis retinoic acid -1 mg orally daily
+ interferon (3 million units s.c.)
Combinations with cisplatin may help
in few cases
Dr Anshu P Gokarn

164. Likely therapies in future for malignant melanoma
 Melanomas often express cell-surface antigens which may
be recognized by host immune cells.
 Number of such antigens present such as:
 MAGEs – 1,-2,-3
 Tyrosinase –an enzyme involved in melanin synthesis
 MART antigen
 These antigens may make it possible to develop
vaccination strategies against melanoma.
Dr Anshu P Gokarn

165. Drugs commonly used to treat major types of
cancer: solid tumors
Cancer Type/ Incidence Drugs used Alternative / Other drugs
secondary drugs with reported
activity
Pancreatic Fluorouracil Mitomycin Tegafur
adenocarcinoma Doxorubicin
2.7% of all cancer deaths
Sarcomas(Bone) Doxorubicin + Cyclophosphamide
0.2% of all cancer and Dacrabazine Vincristinemethotr
cancer deaths exate
Ifosfamide
Testicular Vinblastine + Melphalan
0.5% of all cancers and 1 Ifosfamide+ Doxorubicin
% of cancer deaths cisplatin OR Bleomycin
etoposide+
bleomycin+
cisplatin
Dr Anshu P Gokarn

166. Drugs commonly used to treat major types of
cancer: solid tumors
Cancer Type/ Drugs used Alternative / Other drugs with
Incidence secondary drugs reported activity
Brain neoplasms Carmustine or PCV(Procarbazine Plicamycin
1.3% of all cancers lomustine +Lomustine+Vincri
stine)
Choriocarcinoma Methotrexate OR Chlorambucil
Dactinomycin
Etoposide+
cisplatin
Renal cell Medroxyprogester Vinblastine Interferon alpha
1.6% of all cancers one
and 1.8% of all
cancer deaths
Dr Anshu P Gokarn

167. Drugs commonly used to treat major types of
cancer: solid tumors
Cancer Type/ Drugs used Alternative / Other drugs
Incidence secondary drugs with reported
activity
Breast CMF+
P Doxorubicin+ Vinblastine,
(cyclophosphamide, vincristine if CMF thiotepa,
methotrexate, fluorouracil + P used as Melphalan,
Incidence:
, prednisone) OR primary otherwise Mitomycin
11.1 % of all Doxorubicin combination of
cancers and drugs not used
0.3% of cancer Cyclophosphamide previously/ single
deaths Additive (where
agents not used
hormones indicated): previously
Stilbesterol,
testolactone,tamoxifen,me
gestrol, depending on
menopausal and tumor
hormone receptor status
Dr Anshu P Gokarn

168. Drugs commonly used to treat major types of
cancer: solid tumors
Cancer Type/ Drugs used Other drugs with
Incidence reported activity
Thyroid cis[platin
0.4% of all cancers doxorubicin
Larynx Cisplatin+ Bleomycin OR Vinblastine
methotrexate oR
0.8% of all cancers
fluorouracil
Dr Anshu P Gokarn

169. Drugs commonly used to treat major types of
cancer: solid tumors
Cancer Type/ Drugs used Other drugs with
Incidence reported activity
Salivary glands Cisplatin+ Bleomycin Vinblastine
0.1% of all cancers OR methotrexate oR
fluorouracil
Gall Bladder Radiotherapy has
0.5% of al cancers not yielded good
results
Esophagus Cisplatin
2.2 % of all Paclitaxel
cancers
Dr Anshu P Gokarn

170.  PART - VI
Dr Anshu P Gokarn

171. Newer approaches to cancer Therapy
 Measuring initial tumor growth factors or oncogenes helps
in:
1. Selecting the patients for more intensive therapy.
Ex: epidermal growth factor receptor in bladder and
breast cancer.
Nuclear oncoprotein p53 in breast cancer.
2. Helps in identifying patients who may show relapse or
good response.
Dr Anshu P Gokarn

172. Newer approaches to cancer therapy
In Cytotoxic treatment
 Most of the drugs interfere with DNA metabolism
 Additionally they possess activity on the newer targets
for therapy.
 Major advances with germ cell tumor, lymphomas and
leukemias but less success with common solid tumors
like lung, breast and colorectal cancer
Dr Anshu P Gokarn

173. Advances in Cytotoxic Drug Treatment
Dr Anshu P Gokarn

174. Newer approaches to cancer therapy
 1. Topoisomerase inhibitors
What are Topoisomerases ?
 Nuclear enzymes involved in multiple
cellular processes like DNA replication and
separations of daughter chromosomes.
 Are of two types – Type I and Type II
Dr Anshu P Gokarn

175. Type II Topoisomerase inhibitors
Act mainly by inhibiting Topoisomerase II
Drug in this class:
 Epipodophyllotoxins (Etoposide) – In Lung
cancer
 Anthracyclines (Doxorubicin) – In breast cancer
 Amsacrine derivatives
 Anthrapyrazole group (CI-941)
Dr Anshu P Gokarn

176. Topoisomerase Type I inhibitors
 Less widely available
 Ex: Camptothecin
 Unaceeptable gastroinrestinal toxicity observed
 Newer types being developed
 Ex: Analogue of camptothecin – 9 amino-
camptothecin
 Has significant activity in colon cancer
xenografts an area where Topoisomerase II
inhibitors have minimal impact.
Dr Anshu P Gokarn

177. Newer approaches to cancer therapy
2. New Antimetabolites: Gemcitabine
 Anti-Folates like methotreaxte have been the most widely used
till date.
 Nowadays drugs which inhibit thmidylate synthase being
developed.
 Recently Gemcitabine developed
 Gemcitabine gets converted to metabolites that inhibit DNA
polymerase.
 Active on Non Small Cell Lung cancer and breast cancer.
Dr Anshu P Gokarn

178. Newer approaches to cancer therapy
3. Modulation of drug resistance
 Normally mdr1 gene encodes a glycoprotein which acts as
an energy dependent efflux pump for many cytotoxic
drugs.
 Many new drugs modulate this glycoprotein
 Ex: antiestrogens
 These drugs modify the activity of p- glycoprotein which
is present in the renal and biliary canaliculi. Suppression
of this p-glycoprotein may lead to altered
pharmacokinetics of the cytotoxic drug.
Dr Anshu P Gokarn

179. Dr Anshu P Gokarn

180. New Drug Targets
 Inhibitors of Signal Transduction and second messenger
systems
 Angiogenesis
 Receptor targeting
 Monoclonal Antibodies
 Immunotherapy agianst Tumor antigens or mutant
oncogenes
 Molecular targets
Dr Anshu P Gokarn

181. Molecular Therapy………
 Drugs developed using past paradigms attack both
cancerous and healthy cells, often causing devastating
short- and long-term side effects. Moreover, individual
patient responses to conventional agents vary, even in
cases where cancers appear to be identical
 Molecularly targeted therapies hold the promise of being
more highly selective, drastically reducing the incidence of
side effects in patients.
Dr Anshu P Gokarn

182. Research Avenues for Molecular Targeting
Influence the cancer cell to
re-regulate itself, or assume
a more normal state.
Turn on self-destruct
pathways that cause a
cancer cell to commit
suicide
Stimulate the body's immune
system to reject the cancer
Prevent the cell from acquiring
the capacity to repeatedly
replicate itself.
Interfere with a cell's capacity to use
surrounding tissue to support its
growth - e.g., through angiogenesis
Dr Anshu P Gokarn

183. Application of gene therapy to cancer
 Strategy: to introduce novel genes into cancer cells to
convert them into "foreign" tissue grafts so they will
be rejected by the patient's own immune system.
 Following gene therapy, the cancer cells will be
recognised as a genetically unrelated graft in the
cancer patients and therefore will be rejected by the
patient's own immune system.
 Two Phase I clinical trials employing this strategy had
been completed. Preliminary results are encouraging.
 A Phase 2 clinical trial is presently in progress.
Dr Anshu P Gokarn

184. Gene Therapy (contd……)
 Novel non-viral gene delivery lipid vehicles to deliver genes to
cancer cells are also being designed and synthesized by this
research group.
 The aim is to improve the efficiency of which cancer cells can take
up novel exogeneous genes.
Dr Anshu P Gokarn

185. Gene Therapy (contd…..)
Techniques that are possible
 1. Immunomodulation by using tumor infiltrating
lymphocytes
This strategy mostly used in malignant Melanoma.
 2. Certain genes are transcribed in malignant and fetal
tissues but are not transcribed in adult tissue
 Ex:
 α fetoprotein in hepatomas and germ cell tumors
 Carcinoembryonic antigen in a range of adenocarcinomas
particularly colonic tumor
 Vectors used to construct promoters of these particular
proteins.
Dr Anshu P Gokarn

186. Oligonucleotides
 Involves down regulation of expression of important
genes such as oncogenes which may be overexpressed in
cancer cells.
 Achieved by three techniques
1. Antisense approach
2. Targeting specific mRNAs
3. Antigene approach aimed at blocking transcription at its
genetic location.
Dr Anshu P Gokarn

187. Antisense approach: Principle
 Translation is inhibited by
degradation of mRNA by
RNAase H
OR
 Inhibition of binding of
ribosomal subunits.
Dr Anshu P Gokarn

188. Antisense approach
 Normal flow of genetic
information where a gene
is transcripted into an
mRNA and translated into
a corresponding protein
Antisense oligonucleotide
hybridization to the
complementary target and
causes a block of protein
translation
Antisense oligonucleotides are
taken up by the cell, hybridize to
their target mRNA and block
protein expression
Dr Anshu P Gokarn

189. Inhibitors of signal transduction and second
messenger systems
Mutation (ras)
Over-expression of
growth factor G proteins regulating
receptors adenylate cyclase
Increased intracellular signalling by second messenger
systems like protein kinase C/ C-AMP dependent
protein kinase
Trials on for Bryostatin – antagonises protein kinase C
C-AMP analogues ex: 8 Chlorocyclic AMP– inhibits tumor growth
with little tissue toxicity
Dr Anshu P Gokarn

190. Inhibitors of signal transduction and
second messenger systems
 Activation of Tyrosine kinases has a transforming
role.
 Epidermal growth factors inhibitors ex: tyrosine
analogues, may be useful.
Dr Anshu P Gokarn

191. What is a telomere
 The DNA molecule of a typical chromosome contains a linear array of genes
(encoding proteins and RNAs) interspersed with non-coding DNA.
 Included in the non-coding DNA are:
1. long stretches that make up the centromere and
2. long stretches at the ends of the chromosome, the telomeres.
When telomeres are completely or almost completely lost, cells may
reach a point at which they crash and die.
Dr Anshu P Gokarn

192. Telomerase Inhibitors
 Telomerase is the enzyme that replenishes
shortened telomeres and allows cells to reproduce indefinitely.
 Found in only a few normal human cells, telomerase is present in as many as
90% of human cancers.
 This makes telomerase an attractive candidate for highly selective cancer
drugs
 Certain normal human cells can only undergo 30-50 doublings before their
telomeres are too short and doubling stops.
 Cancer cells must undergo about 80 doublings before a tumor mass is large
enough to be detected
Dr Anshu P Gokarn

193. Telomerase Inhibitors
 B.-S. Herbert, A. E. Pitts, et al. at the
University of Texas Southwestern
Medical Center have shown that
inhibitors of telomerase can
remortalize transformed human
breast epithelial cells and
human prostate cancer cells in
culture, ultimately leading to
their cell death.
 The telomerase inhibitors used in this study are 2'-0-
MeRNA oligonucleotides directed towards the essential
RNA component (hTR) of human telomerase.
Dr Anshu P Gokarn

194. Receptor Targeting
 External domain of the receptor – the new target
 Recombinant DNA technology used
 Either single molecule prepared or fusion protein with
other molecule prepared.
 High specificity and affinity provided
 Ex: IL-6 receptor in Myeloma
 IL-2 receptor in lymphomas
 C-erb-2 / epidermal growth factor receptor – breast
cancer.
 In fusion proteins – anticancer component provided by
diphtheria / pseudomonas exotoxin
 Phase I studies in bladder cancer
Dr Anshu P Gokarn

195. Angiogenesis inhibitors
Tumor invasiveness and metastasis
require neovascularization (formation of
new blood vessels)
Tumor cells cannot grow as a mass
above 2 to 3 mm because diffusion is
insufficient for oxygen and glucose
requirements, unless the tumor induces a
blood supply.
 Angiogenesis
Mechanism of induction of a new blood
supply from pre-existing vascular bed
Drugs which inhibit angiogenesis are angiogenesis inhibitors
Dr Anshu P Gokarn

196. Angiogenesis inhibitors…..
Like:
 Suramin analogues
 Antibodies to
proliferating
endothelium
 Angioinhibins
 Collagenase inhibitors
Angiogenesis inhibitors can be used with hypoxically active drugs
for better effects.
Hypoxically active drugs – drugs activated under reducing
conditions to generate toxic metabolites that can bind to DNA and
Dr Anshu P Gokarn generate strand breaks.

197. Angiogenesis inhibitors in clinical
trials
 Thalidomide and TNP-470, a synthetic analogue of fumagillin
have shown efficacy in Kaposi,s sarcoma.
 2- methoxyestradiol – in phase I trial for Breast cancer; has
shown efficacy against melanoma.
 Thrombospondin 1 in basal cell and squamous cell carcinoma
 Col –III is a synthetic metalloproteinase inhibitor (in phase I
trial)
 SU 6668 inhibits VEGF, FGF, and EGF receptor signalling.
(in phase II trial )
Dr Anshu P Gokarn

198. Common targets for angiogenesis inhibitors
Attack Points for angiogenesis inhibitors include specific cell
surface and intracellular targets
1. Initial drugs including pentosan
polysulphate, were heparin like.
2.Blocking a receptor’s
autophosphorylation interferes with
subsequent signal transmission
3. Some occupy a particular growth factor
4. Blocks cell surface proton pumps which
interferes with several receptors.
5. Proliferating endothelial cells require
specific cell surface contacts such as those
mediated by Integrin αγβ3
6. Blockade of the process may induce
endothelial cell death.
7. Body has its own tissue inhibitors of
Dr Anshu P Gokarn matrix metalloproteinases(TIMPs)

199. Newer developments in monoclonal Antibodies
 Two step strategy used
 Initially antibody allowed to
localize itself for several days.
 Then second binding protein
which recognizes the first and
has the therapeutic agent
attached is administered.
Ex: biotin on the first antibody and streptavidin as
the second protein.
Dr Anshu P Gokarn

200. Dr Anshu P Gokarn

201. Monoclonal antibodies
 Rituximab and Trastuzumab are monoclonal antibodies
approved by FDA
 Rituxan – for treatment of B-cell Non-Hodgkin’s
Lymphoma that has not responded to chemotherapy.
 Herceptin – in treatment of metastatic breast cancer
 These antibodies are also being tested in lymphomas,
leukemias, colorectal cancer, lung cancer, brain tumors
,and prostate cancers.
Dr Anshu P Gokarn

202. ADEPT Mechanism
ADEPT – Antibody dependent enzyme prodrug therapy
Toxin is generated by1 enzyme attached to the antibody from a nontoxic
Step an Step 2
precursor.
Advantage is that cytotoxic drug produced locally that will be active against
tumor cels that have not bound the antibody well. Repeated daily doses can be
given
Dr Anshu P Gokarn

203. Immunotherapy
 Antibodies designed specially to recognize
a specific cancer
 When coupled with natural toxins, drugs
or radioactive substances, the antibodies
will seek out their target cancer cells and
deliver their lethal load
 Alternatively toxins combined with
lymphokines and routed to cells equipped
with receptors for Lymphokines.
Dr Anshu P Gokarn

204. Immunotherapy against tumor antigens or
mutant oncogenes
 Endogenous antigens presented by HLA class I
molecules.
 Selective loss of HLA (Human leukocyte
antigens) alleles occurs in many epithelial
tumors.
 Upregulation of HLA with combined therapy
with interferons may prove to be beneficial.
 Beneficial specially when vaccine technology is
used for immunization against tumor antigens or
mutant oncogenes like p 53, H-ras, mutant K-
ras.
Dr Anshu P Gokarn

205. Dr Anshu P Gokarn

206. Vaccines in cancer
 Dendritic cells are potent initiators
of anti-tumor responses.
 They involve the activation of
cytotoxic T cells which eliminate
the tumor cells.
 Dendritic cells are being primed with
Tumour cell lysates, tumour peptides, or DNA, to induce
tumour-specific immunity against various human cancers.
 These DCs are expected to be valuable tool in the
immunotherapeutic treatment of patients with metastatic
tumor
Dr Anshu P Gokarn

207. Smart drugs searching out problem cells
 Specially designed toxins are linked with agents that bind
selectively with components on the surface of cancer cells .
 A single piece molecule with two step mode of action has been
developed
 One component of the molecule carries the tumor identifier and
the other carries the active agent.
 Two tumor cell identifiers (IL-13 and SS1) are being developed to
selectively seek out, recognize, attach to and deliver active drug to
destroy cancer cells while leaving healthy cells intact.
Dr Anshu P Gokarn

208. Neopharm ,FDA and National
cancer institute have developed
two highly selective tumor targeting
agents
1.Tumor targeted cytotoxin called
as IL-13-PE38
Normal cell
Antimesothelin monoclonal
2.
antibody called as SS1-PE 38
The PE-38 component of both the
drugs is a naturally occuring
cytotoxin.
It destroys the cancer cell after it is Cancer cell
introduced into the cell.
Dr Anshu P Gokarn

209. IL-13 targets receptors in the
kidney , brain, berast, head and
neck and Kaposi’s sarcoma
SS1 seeks out and attaches to
sites normally present in large
numbers on the surface of
specific cancer cells.
IL13-PE38 (delivered systemically)- fro treating renal cancer
IL13-PE38 (delivered intratumorally)- for treating glioblastoma (brain
cancer)
SS1-PE38(delivered systemically)- antimesothelin monoclonal antibody
delivery system
Dr Anshu P Gokarn

210. Rasburicase – approved by the FDA
Anticancer therapy leads to tumor lysis
Leads to accumalation of uric acid in plasma
Leads to tumor lysis syndrome which may lead to acute renal
failure.
Rasburicase helps convert uric acid into a soluble
byproduct(allantoin) which is readily excreted by the kidneys.
Dr Anshu P Gokarn

211. Biological Response Modifiers
 They are antibodies, cytokines and other immune system
substances that can be produced in the laboratory for use
in cancer treatment.
 They include:
1. Interferons
2. Interleukins
3. Colony stimulating factors
4. Monoclonal antibodies and
5. Vaccines
Dr Anshu P Gokarn

212. Interferons
 They are cytokines which occur naturally in the body.
 Three major types:
1. Interferon alpha
2. Interferon beta
3. Interferon gamma
 They improve the way a cancer patients immune system
reacts to cancer cells.
 Additionally they also slow their growth or promote their
development into more normal behaviour.
 Interferon Alpha used in – hairy cell leukemia, malignant
melanoma, CML, AIDS related Kaposi’s sarcoma.
 May also be useful in metastatic kidney cancer and Non-
Hodgkin’s Lymphoma
Dr Anshu P Gokarn

213. Biological Response Modifiers
levamisole
 Acts by modulating cell mediated immune response
 Restores/ augments cutaneous delayed hypersensitive
response
BCG
 Boost’s the production of antibodies
 Direct injection of tuberculosis bacteria into
Melanoma decreases the size of tumor
Dr Anshu P Gokarn

214. Interleukins
 Interleukins are also cytokines produced naturally in the
body
 IL-2 (Aldesleukin) is the most widely used
 It stimulates the growth and activity of many immune
cells like lymphocytes that can destroy cancer cells.
 IL-2 indicated in metastatic kidney cancer and
metastatic melanoma
Dr Anshu P Gokarn

215. Colony Stimulating Factors(CSF)
 Also called as Haematopoeitic growth factors
 They encourage the bone marrow stem cells to divide and
develop into white blood cells, platelets and red blood
cells.
 CSF are particularly useful when combined with high
dose chemotherapy
 Some ex;
 G-CSF (Filrastim) and GM-CSF(sargramostin)
Dr Anshu P Gokarn

216. Imatinib Mesylate
 Inhibits specific protein tyrosine
kinase which is targeted to platelet
derived growth factor.
 It specifically inhibits constitutively
active fusion protein arising from the
Philadelphia chromosome of CML and
c-kit(CD117) in GIST
Impairs BCR-ABL mediated transfer of phosphates to its
substrates.
BCR-ABL is a protein unique to leukemia cells and its tyrosine kinase activity is
essential for its ability to induce leukemia BCR-AABL mutation is present in
almost all patients with CML,
Dr Anshu P Gokarn

217. What are protein Kinases?
 Enzymes that transfer phosphate from adenosine
triphosphate to specific amino acids on substrate
proteins (Phosphorylation).
 Phosphorylation of these proteins leads to activation
of signal transduction pathways.
 Signal transduction pathways play a critical role in
cell growth, differentiation and death.
Several protein kinases are deregulated and overexpressed in
human cancers and serve as an attractive target for anticancer
therapy.
Dr Anshu P Gokarn

218. Disrupted regulation of oncogene : bcrabl gene
responsible for CML
Dr Anshu P Gokarn

219. Mechanism of action of BCR-ABL and of its inhibition by Imatinib
BCR-ABL oncoprotein with a molecule
of adenosine triphosphate in the kinase
pocket.Substrate activated by one of its
tyrosine residues
Imatinib ocupies the kinas epocket,
action of BCR-AABl is inhibited.
Phosporylation is prevented
Dr Anshu P Gokarn

220. Imatinib Mesylate(ST1571)
Indicated in :
1.CML in blast crisis, in accelerated phase,
or in chronic phase after interferon alpha
therapy
2.In unresectable and/ or metastatic
malignant gastrointestinal stromal
tumor(GIST).
Dr Anshu P Gokarn

221. Points where imatinib scores over other
conventional therapy
Conventionally hydroxyurea or interferon alpha is used.
 However cytogenic response is faster with imatinib than with
interferon alpha.1
 Phosphorylation of BCR-ABL substrates reduced markedly in
leukemic cells.1
 Mild to moderate side effects which are reversible on cessation of
treatment.1
 Oral therapy may improve patient compliance.
 With interferon resistant chronic phase CML had a complete
haematologic response and almost half had a major cytogenic
response. So it is drug of choice in interferon resistant CML.1
 Can be combined with farnesyltransferases may also be useful.1
1. Savage D, Karen H et al. N Eng J Med, 346(9);2002 Feb
Dr Anshu P Gokarn

222. Points where imatinib scores over other
conventional therapy
 Long plasma half life so convenient once
daily dosing.
Useful in patients with relapses after
allograft transplantation2.
At a dose of 400 mg, twice daily it is well
tolerated during the first 8 weeks, side effects
diminish with continuing treatment.3
A possible additive effect of INF and imatinib suggest that a concurrent
use of these agents may also be effective than single use particularly in
advanced stages of CML where imatinib has activity but resistance
develops.4
2. (Olavarria E et al. Blood 2002 May 15;99(10) :3861-2)
3. Oosterom Van et al. Lancet 2001, 358(9291): 1421-3
4. Talpaz M. Semin Hematol 2001 Jul;38(3 suppl 8):22-7
Dr Anshu P Gokarn