Presentation on Abnormal cell growth by Kanishk Luhach (M.Pharm) and Yatrik Shah

1. Uploaded By:
Aminu Abubakar Kende

2. DEFINITION
NEOPLASM
Neoplasm is an abnormal mass of tissue as a result of
neoplasia.
Neoplasia (new growth in Greek) is the abnormal
proliferation of cells. The growth of the cells exceeds,
and is uncoordinated with that of the normal tissues
around it.

3. Types of Neoplasms:
1. Benign- grows slowly and is encapsulated, no tissue
destruction- no infiltration, no spread to distant sites- no
metastasis
2. Malignant- grow rapidly, the tumor infiltrates and destroys
surrounding tissues, it causes metastases throughout the
body, possibly with lethal results

4. Microscopic Features
1. Benign- growth by compression of surrounding tissues,
highly differentiated- resembling normal tissue of origin, cells
similar to normal presenting a uniform appearance, well-formed
blood vessels, necrosis is unusual, metastasis does not occur
2. Malignant- growth is aggressive by invasion of surrounding
tissues, tumour is poorly or well differentiated, most malignant
tumours do not resemble the normal tissue of origin, anaplasia
(the neoplastic cells have no morphologic resemblance to
normal tissues)
Cytological irregularities include: Enlarged hyperchromatic
irregular nuclei with large nucleoli, marked variation of nuclear
shape- polymorphism, increased mitotic activity- abnormal
mitoses, increased nuclear-cytoplasmic ratio, blood vessel
numerous and poorly formed, necrosis and haemorrhages are
common, typically- metastasis to distant sites

5. CLASSIFICATION ACCORDING TO TISSUE FROM WHICH
THEY DEVELOP:
1. Carcinoma is a cancer of the epithelial tissue, including cells of the
skin, testis, ovary, mucus-secreting glands, melanin-secreting cells,
breast, cervix, colon, rectum, stomach, pancreas, and esophagus.
2. Lymphoma is a cancer of the lymphatic tissue, including the lymph
capillaries, lacteals, spleen, various lymph nodes, and lymph
vessels. The thymus and bone marrow may also be affected.
Specific lymphomas include Hodgkin lymphoma (cancer of the lymph
nodes and spleen, formerly called Hodgkin's disease) and malignant
lymphoma.
3. Sarcoma is a cancer of the connective tissue, including cells found
in the muscle and bone.

6. CLASSIFICATION ACCORDING TO TISSUE FROM WHICH
THEY DEVELOP:
4. Glioma is a cancer of the glial (support) cells of the central
nervous system.
5. Leukemias are cancers of the blood or blood-forming organs.
When leukemia develops, the body produces a large number of
abnormal blood cells. In most types of leukemia, the abnormal
cells are white blood cells.

7. EPIDEMIOLOGY
In 2002, 11 million new cancer cases and 7 million cancer
deaths were estimated worldwide. When broken down by
region of the world, ~45% of cases were in Asia, 26% in
Europe, 14.5% in North America, 7.1% in Central/South
America, 6% in Africa, and 1% in Australia/New Zealand.
Lung cancer is the most common cancer and the most
common cause of cancer death in the world.
Breast cancer is the second most common cancer worldwide;
however, it ranks fifth as a cause of death behind lung,
stomach, liver, and colorectal cancer.

8. It has been estimated that nine modifiable risk factors are
responsible for more than one-third of cancers worldwide.
These include
1.smoking
2.alcohol consumption
3.obesity
4.physical inactivity
5.low fruit and vegetable consumption
6.unsafe sex
7.air pollution
8.indoor smoke from household fuels
9.contaminated injections

9. DISTRIBUTION OF CANCER INCIDENCES AND DEATH GLOBALLY

11. The Cell Cycle
An understanding of cell-cycle kinetics is essential for the
proper use of antineoplastic agents . Many of the most effective
cytotoxic agents act by damaging DNA.
Their toxicity is greater during the S, or DNA synthetic, phase of
the cell cycle, while others, such as the vinca alkaloids and
taxanes, block the formation of a functional mitotic spindle in M
phase. These agents have activity against cells that pass
through the most vulnerable phase of the cell cycle.
Accordingly, human neoplasms that currently are most
susceptible to chemotherapeutic measures are those with a
high percentage of cells undergoing division.

12. Although differences in the duration of the cell cycle occur
between cells of various types, all cells display a similar pattern
during the division process:
(1)a phase that precedes DNA synthesis (G1)
(2)a DNA synthesis phase (S)
(3)an interval following the termination of DNA synthesis (G2)
(4)the mitotic phase (M) in which the cell, containing a double
complement of DNA, divides into two daughter G1 cells.
(5)Each of these daughter cells may immediately re-enter the
cell cycle or pass into a nonproliferative stage, referred to as
G0.

13. (6). The G0 cells of certain specialized tissues may differentiate
into functional cells that no longer are capable of division.
On the other hand, many cells, especially those in slow-
growing tumors, may remain in the G0 state for prolonged
periods, only to re-enter the division cycle at a later time.
Each transition in the cell cycle is controlled by the activity of
specific cyclin-dependent kinases (CDKs), which are activated
by their corresponding small regulatory proteins called cyclins,
and inhibited by proteins such as p16.
Mutations or loss of p16 or other components of the so-called
retinoblastoma pathway such as retinoblastoma protein itself,
or enhanced cyclin or CDK activity, will lead to relentless
proliferation in tumor cells.

15. G1 is the gap period between mitosis and the beginning of DNA
synthesis. Resting cells (cells that are not preparing for cell
division) are said to be in a subphase of G1, G0.
S is the period of DNA synthesis, G2 the premitotic interval, and
M the period of mitosis.
If a cell expresses normal p53 protein, DNA damage activates
a normal checkpoint function and damaged cells undergo
apoptosis, or programmed cell death, when they reach the
G1/S boundary.

16. If the p53 gene product is mutated or absent and the
checkpoint function fails, damaged cells will not be diverted to
the apoptotic pathway but will proceed through S phase.
At the G2-M interface, other checkpoint proteins monitor DNA
integrity and may delay progression into M phase.
Absence or mutation of these checkpoints allows cells to pass
through mitosis and survive DNA damage. These cells can
proceed through S phase and some will emerge as a mutated
and potentially drug-resistant population.

17. Cancer Genetics
Cancer arises through a series of somatic alterations in DNA
that result in unrestrained cellular proliferation. Most of these
alterations involve actual sequence changes in DNA (i.e.,
mutations).
They may arise as a consequence of random replication
errors, exposure to carcinogens (e.g., radiation), or faulty DNA
repair processes.
While most cancers arise sporadically, familial clustering of
cancers occurs in certain families that carry a germline
mutation in a cancer gene.

18. The Clonal Origin and Multistep Nature of Cancer:
Nearly all cancers originate from a single cell. Multiple
cumulative mutational events are invariably required for the
progression from normal to fully malignant phenotype.
The process can be seen as Darwinian microevolution in
which, at each successive step, the mutated cells gain a
growth advantage resulting in an increased representation
relative to their neighbors.
It is believed that five to ten accumulated mutations are
necessary for a cell to progress from the normal to the fully
malignant phenotype.

19. Five cumulative mutations (T1, T2, T4, T5, T6) can be seen here.

20. Progressive somatic mutational steps in the development
of colon carcinoma:
Genetic instability (microsatellite or chromosomal) accelerates the progression by
increasing the likelihood of mutation at each step. Patients with familial polyposis are
already one step into this pathway, since they inherit a germline alteration of the APC
gene. TGF( transforming growth factor).

21. Familial adenomatous polyposis (FAP) is a dominantly
inherited colon cancer syndrome due to germline mutations in
the adenomatous polyposis coli (APC) tumor-suppressor gene
on chromosome 5.
Patients with this syndrome develop hundreds to thousands of
adenomas in the colon. Each of these adenomas has lost the
normal remaining allele of APC but has not yet accumulated
the required additional mutations to generate fully malignant
cells.
However, out of these thousands of benign adenomas, several
will invariably acquire further abnormalities and a subset will
even develop into fully malignant cancers. APC is thus
considered to be a gatekeeper for colon tumorigenesis

22. In contrast to FAP, patients with hereditary nonpolyposis colon cancer
(HNPCC, or Lynch syndrome) do not develop multiple polyposis but instead
develop only one or a small number of adenomas that rapidly progress to
cancer.
HNPCC is commonly defined by family history, with at least three individuals
over at least two generations developing colon or endometrial cancer. Most
HNPCC is due to mutations in one of four DNA mismatch repair genes
which are components of a repair system that is normally responsible for
correcting errors in freshly replicated DNA.
Germline mutations in MSH2 and MLH1 account for >60% of HNPCC
cases, while mutations in MSH6 and PMS2 are much less frequent. When a
somatic mutation inactivates the remaining wild-type allele of a gene, the
cell develops a hypermutable phenotype characterized by profound
genomic instability, especially for the short repeated sequences called
microsatellites.
This microsatellite instability (MIN) favors the development of cancer by
increasing the rate of mutations in many genes, including oncogenes and
tumor-suppressor genes

25. General Classes of Cancer Genes:
There are two major classes of cancer genes.
1.CLASS-I :- This class comprises genes that directly affect
cell growth either positively (oncogenes) or negatively (tumor-
suppressor genes).
These genes exert their effects on tumor growth through
their ability to control cell division (cell birth) or cell death
(apoptosis).
In cancer cells, oncogenes acquire mutations that relieve
this control and lead to increased activity of the gene product.
This mutational event typically occurs in a single allele of the
oncogene and acts in a dominant fashion.

26. In contrast, the normal function of tumor-suppressor genes
is to restrain cell growth, and this function is lost in cancer.
The two-hit hypothesis, which states that both copies of a
tumor-suppressor gene must be inactivated in cancer.
2. CLASS-II :- The second class of cancer genes, the
caretakers, does not directly affect cell growth but rather
affects the ability of the cell to maintain the integrity of its
genome.
Cells with deficiency in these genes have an increased rate
of mutations in all the genes, including oncogenes and
tumor-suppressor genes.

27. Oncogenes in Human Cancer:
Oncogenes are often targets of mutation in human cancer.
Many oncogenes were discovered because of their presence in
retroviruses. Some of these were oncogenes known from
retroviruses like ABL (Acute myelogenous leukemia), and CML
involved in chronic myelogenous leukemia.
The normal growth and differentiation of cells is controlled by
growth factors that bind to receptors on the surface of the cell.
Signaling cascades involving kinases, G proteins, and other
regulatory proteins regulate growth and cell death.
Inappropriate activation of Oncogenes controlled pathways can
lead to carcinogenesis in a particular tissue.

28. Mechanisms of Oncogene Activation:
Mechanisms that upregulate (or activate) cellular oncogenes
fall into three broad categories:
1.Point mutation: It is basically insertion or deletion of single
base pair. Eg Purine base pair with another purine
(Transitional), or purine with pyrimidine or vice versa
(Transversions).
2.DNA amplification: leads to overexpression of the gene
product. Demonstration of amplification of a cellular gene is
often a predictor of poor prognosis. For example,
ERBB2/HER2 and NMYC are often amplified in aggressive
breast cancers and neuroblastoma, respectively.

29. 3. Chromosomal rearrangement: Abnormality caused by
rearrangement of parts between nonhomologus
chromosomes. A gene fusion may be created when
translocation joins two otherwise seperated genes

30. Cancer Cell Biology
The malignant phenotype often requires mutations in several different genes that
regulate cell proliferation, survival, DNA repair, motility, invasion, and angiogenesis

31. Check Points in Cell Cycle:

32. In response to noxious stimuli, p53 and mdm2 are
phosphorylated by the ataxia telangiectasia mutated (ATM) and
related ATR serine/threonine kinases, as well as the
immediated downstream checkpoint kinases, Chk1 and Chk2.
This causes dissociation of p53 from mdm2, leading to
increased p53 protein levels and transcription of genes leading
to cell cycle arrest (p21Cip1/Waf1
) or apoptosis.
Inducers of p53 include hypoxia, DNA damage (caused by
ultraviolet radiation, gamma irradiation, or chemotherapy),
ribonucleotide depletion, and telomere shortening.
A second mechanism of p53 induction is activated by
oncogenes such as Myc, which promote aberrant G1/S
transition.

33. This pathway is regulated by a second product of the Ink4a
locus, p19ARF
. Levels of ARF are upregulated by Myc and E2F,
and ARF binds to mdm2 and rescues p53 from its inhibitory
effect.
This oncogene checkpoint leads to the death or senescence
(an irreversible arrest in G1 of the cell cycle) of renegade cells
that attempt to enter S phase without appropriate physiologic
signals.

34. Signal Transduction Pathways :

35. Three major signal transduction pathways are activated by
receptor tyrosine kinases (RTK).
1.The protooncogene Ras is activated by the Grb2/mSOS
guanine nucleotide exchange factor, which induces an
association with Raf and activation of downstream kinases (MEK
and ERK1/2).
2.Activated PI3K phosphorylates the membrane lipid PIP2
to
generate PIP3
, which acts as a membrane-docking site for a
number of cellular proteins including the serine/threonine
kinases PDK1 and Akt. PDK1 has numerous cellular targets
including Akt and mTOR. Akt phosphorylates target proteins that
promote resistance to apoptosis and enhance cell cycle
progression, while mTOR and its target p70S6K upregulate
protein synthesis to potentiate cell growth.

36. 3. Activation of PLC-gamma leads the formation of
diacylglycerol (DAG) and increased intracellular calcium,
with activation of multiple isoforms of PKC and other
enzymes regulated by the calcium/calmodulin system.
Other important signaling pathways involve non-RTKs that
are activated by cytokine or integrin receptors. Janus
kinases (JAK) phosphorylate STAT (signal transducer and
activator of transcription) transcription factors, which
translocate to the nucleus and activate target genes.
Integrin receptors mediate cellular interactions with the
extracellular matrix (ECM), inducing activation of FAK (focal
adhesion kinase) and c-Src, which activate multiple
downstream pathways, including modulation of the cell
cytoskeleton.

37. Tumor Angiogenesis
The growth of primary and metastatic tumors to larger than a few
millimeters requires the recruitment of neighboring blood vessels
and vascular endothelial cells to support their metabolic
requirements. The diffusion limit for oxygen in tissues is
~100µm.
A critical element in the growth of primary tumors and formation
of metastatic sites is the angiogenic switch: the ability of the
tumor to promote the formation of new capillaries from
preexisting host vessels.
The angiogenic switch is a phase in tumor development when
the dynamic balance of pro- and antiangiogenic factors is tipped
in favor of vessel formation by the effects of the tumor on its
immediate environment.

38. Stimuli for tumor angiogenesis include hypoxia, inflammation,
and genetic lesions in oncogenes or tumor suppressors that
alter tumor cell gene expression.
Tumor blood vessels are not normal; they have chaotic
architecture and blood flow. Due to an imbalance of angiogenic
regulators such as VEGF and angiopoietins, tumor vessels are
tortuous and dilated with an uneven diameter, excessive
branching, and shunting.
Tumor blood flow is variable, with areas of hypoxia and
acidosis leading to the selection of variants that are resistant to
hypoxia-induced apoptosis (often due to the loss of p53
expression).

40. Tumor angiogenesis is a complex process involving many
different cell types that must proliferate, migrate, invade, and
differentiate in response to signals from the tumor
microenvironment. Endothelial cells (ECs) sprout from host
vessels in response to VEGF, bFGF, Ang2, and other
proangiogenic stimuli. Sprouting is stimulated by
VEGF/VEGFR2, Ang2/Tie-2, and integrin/extracellular matrix
(ECM) interactions
When tumor cells arise in or metastasize to an avascular area,
they grow to a size limited by hypoxia and nutrient deprivation.
Hypoxia, a key regulator of tumor angiogenesis, causes the
transcriptional induction of the gene encoding VEGF by a
process that involves stabilization of HIF-1α .

41. Under normoxic conditions, HIF-1α levels are maintained at a
low level by proteasome-mediated destruction regulated by a
ubiquitin E3-ligase encoded by the VHL tumor-suppressor
locus. However, under hypoxic conditions, HIF-1α is not
hydroxylated and association with VHL does not occur;
therefore HIF-1α levels increase, and target genes including
VEGF, nitric oxide synthetase (NOS), and Ang2 are induced
Loss of the VHL genes, as occurs in familial and sporadic renal
cell carcinomas, results in HIF-1α stabilization and induction of
VEGF. Most tumors have hypoxic regions due to poor blood
flow, and tumor cells in these areas stain positive for HIF-1 α
expression; in renal cancers with VHL deletion, all of the tumor
cells express high levels of HIF-1α , and VEGF-induced
angiogenesis leads to high microvascular density .

42. STEPS IN ANGIOGENESIS:

46. Metastasis
The metastatic potential arise due to genetic and epigenetic
events that characterize tumor progression.
A number of candidate metastasis-suppressor genes have
been identified.
The loss of function of certain genes enhances metastasis
- uncertain molecular mechanism
- enhancing of the ability of the metastatic tumor
cells to overcome the many apoptosis
Gene expression profiling is being used to study the
metastatic process with the goal of identifying signatures
characteristic of primary tumors that have a high propensity
to metastasize, leading to a more rational basis for the use of
adjuvant chemotherapy.

48. Paraneoplastic Syndromes
•Cushing’s Syndrome
–Adrenal carcinoma (cortisol) more common with benign adrenal processes.
–Small cell undifferentiated lung cancer (ACTH) released through cleavage of
pro-opiomelano-cortin gene product.
•Inappropriate ADH syndrome (Hyponatremia)
–Small cell undifferentiated lung cancer (vassopressin-like hormone.
–Hypothalamic tumors (vasopressin)
•Hypercalcemia Hypercalcemia arises from either osteolysis by primary tumors or
production of PTHrP that may act as PTH at various sites. Hypercalcemia is especially
associated with carcinomas of breast, kidney, ovary, and squamous cell ca of the lung.
--Squamous cell lung cancer (PTH-like peptide)
–Renal cell carcinoma (prostaglandins)
–Parathyroid carcinoma (PTH)
–Multiple myeloma and T-cell lymphoma (IL-1 and perhaps TNF-a)
–Breast carcinoma, usually by bone metastasis

49. Cancer Chemotherapy

50. Rationale approach to
chemotherapy

51. • The goal of cancer treatment is first to
eradicate the cancer.
• The goal of cancer treatment shifts to
palliation, the amelioration of symptoms,
and preservation of quality of life while
striving to extend life.
• Cancer treatments may be undertaken
despite the certainty of severe and
perhaps life-threatening toxicities

52. Diagnosis
• Relies most heavily on invasive tissue
biopsy
• No noninvasive diagnostic test is sufficient
to define a disease process as cancer
• Once diagnonised one should approach
for extent of disease prognosis
• The curability of a tumor usually is
inversely proportional to the tumor burden

53. This process is called staging
1. Clinical staging : physical examination,
radiographs, isotopic scans, CT scans,
and other imaging procedures
2. pathologic staging : histologic
examination
• staging is used to define the extent of
disease either as localized, as exhibiting
spread outside of the organ
• TNM test is carried out to check the
spread of cancer.

54. Stages
• Stage I
The cancer is less than 2 centimeters in size (about 1 inch), and
has not spread
• Stage II
The cancer is more than 2 centimeters in size, but less than 4
centimeters, and has not spread to lymph nodes in the area.
• Stage III
The cancer is more than 4 centimeters in size. The cancer is
any size but has spread to only one lymph node on the same
side of as the cance
r.
• Stage IV
Any of the following may be true: The cancer has spread to
tissues around to any lymph node that measures more than 6
centimeters. The cancer has spread to other parts of the body.
• Recurrent
Recurrent disease means that the cancer has come back
(recurred) after it has been treated.

55. Log kill hypothesis
• According to the log-kill hypothesis, chemotherapeutic
agents kill a constant fraction of cells (first order
kinetics), rather than a specific number of cells, after
each dose
1. Solid cancer tumors - generally have a low growth
fraction thus respond poorly to chemotherapy & in most
cases need to be removed by surgery
2. Disseminated cancers generally have a high growth
fraction & generally respond well to chemotherapy

57. LOG kill hypothesis
• The example shows the effects
of tumor burden, scheduling,
initiation/duration of treatment
on patient survival.
• The tumor burden in an
untreated patient would
progress along the path
described by the RED LINE –
• The tumor is detected (using
conventional techniques) when
the tumor burden reaches 109
cells
• The patient is symptomatic at
1010
-1011
cells
• Dies at 1012
cells.

58. Modalities of treatment:
• 1-local therapy:
• -surgery.
• -radiation therapy.
• 2-systemic treatment:
• chemotherapy.
• Hormonal therapy.
• Monoclonal antibodies.
• Radioactive material.
• 3-supportive care.
• 4-non-conventional therapy.

59. Surgery

60. Surgery:
• Surgery was the first modality used successfully in the
treatment of cancer.
• It is the only curative therapy for many common solid
tumors.
• The most important determinant of a successful surgical
therapy are the absence of distant metastases and no
local infiltration.

61. • Microscopic invasion of surrounding
normal tissue will necessitate multiple
frozen section.
• Resection or sampling of regional lymph
node is usually indicated.
• Surgery may be used for palliation in
patients for whom cure is not possible.
• Has significant role in cancer prevention.
• E.g familial polyposis coli.

62. Surgery for prevention:
• Patients with conditions that predispose them to certain
cancers or with genetic traits
Associated with cancer can have normal life span with
prophylactic surgery.
-colectomy .
-oophorectomy.
-thyroidectomy.
-removal of premalignant skin lesion .

63. Radiation therapy:

64. Radiation therapy:
• Radiation therapy: is a local modality used
in the treatment of cancer .
• Success depend in the difference in the
radio sensitivity between the tumor and
normal tissue.
• It involves the administration of ionizing
radiation in the form of x-ray or gamma
rays to the tumor site.
• Method of delivery:
External beam(teletherapy).
Internal beam therapy(Brachytherapy).

65. Cont:
• Fractionated doses :180 to 300 cGy per day,five times a
week for a total course of 5-8 weeks.
• USED :
Hodgkin’s disease,
gynecologic tumors &
CNS tumor .
• Also can use in palliative &emergency setting.

66. Complication of radiation:
• There is two types of toxicity ,acute and
long term toxicity.
• Systemic symptoms
Fatigue,
local skin reaction,
GI toxicity,
oropharyngeal mucositis &
myelosuppression.
• Long-term symptoms:
may occur many months or years after
radiation therapy.

67. Nuclear medicine

68. Radionuclides:
• For decades have been used systemically to treat
malignant disorders.
• Radioactive iodine in the from of 131
I is effective therapy
for well differentiated thyroid carcinoma
• Strontium-89. Is used for the treatment of body
metastasis

69. Chemotherapy:

70. Chemotherapy:
• Systemic chemotherapy is the main treatment available
for disseminated malignant diseases.
• Progress in chemotherapy resulted in cure for several
tumors.
• Chemotherapy usually require multiple cycles.

71. Classification of cytotoxic drug:
• Cytotoxic agent can be roughly categorized based on
their activity in relation to the cell cycle.
p h a s e n o n s p e c i f i c . p h a s e s p e c i f i c
c y t o t o x i c d r u g

73. Cell Cycle Specific (CCS) & Cell Cycle Non-
Specific Agents (CCNS)

74. What are the chemotherapeutic agents?
…..

75. Chemotherapeutic agents:
• Alkylating agents:
• Antimetabolites:
• Antitumor antibiotic:
• Plant alkaloids:
• Other agents
• Hormonal agent:
• Immunotherapy:

76. CHEMOTHERAPEUTIC AGENTS
CLASS TYPE OF
AGENT
NONPROPRIETARY
NAMES (OTHER
NAMES)
DISEASE*
Alkylating
agents
Nitrogen
mustards
Mechlorethamine Hodgkin's disease; non-Hodgkin's
lymphoma
Cyclophosphamide
Ifosfamide
Acute and chronic lymphocytic
leukemia; Hodgkin's disease; non-
Hodgkin's lymphoma; multiple
myeloma; neuroblastoma; breast,
ovary, lung cancer; Wilms' tumor;
cervix, testis cancer; soft-tissue
sarcoma
Melphalan (L-
sarcolysin)
Multiple myeloma; breast, ovarian
cancer
Chlorambucil Chronic lymphocytic leukemia;
primary macroglobulinemia;
Hodgkin's disease; non-Hodgkin's
lymphoma

77. CLASS TYPE OF AGENT NONPROPRIETARY
NAMES (OTHER NAMES)
DISEASE*
Alkylating agents Ethyleneimines
and
methylmelamin
es
Altretamine Ovarian cancer
Thiotepa Bladder, breast, ovarian cancer
Methylhydrazin
e derivative
Procarbazine (N-
methylhydrazine, MIH)
Hodgkin's disease
Alkyl sulfonate Busulfan Chronic myelogenous leukemia
Nitrosoureas Carmustine (BCNU) Hodgkin's disease; non-Hodgkin's
lymphoma; primary brain tumor;
melanoma
Streptozocin
(streptozotocin)
Malignant pancreatic insulinoma;
malignant carcinoid
Triazenes Dacarbazine (DTIC;
dimethyltriazenoimidazo
le carboxamide),
temozolomide
Malignant melanoma; Hodgkin's
disease; soft-tissue sarcomas;
glioma; melanoma
Platinum
coordination
complexes
Cisplatin,
carboplatin,oxaliplatin
Testicular, ovarian, bladder,
esophageal, lung, colon cancer

78. CLASS TYPE OF AGENTS NON PROPRIETRY NAMES DISEASE
Antimetabolites Folic acid analogs Methotrexate
(amethopterin)
Acute lymphocytic
leukemia;
choriocarcinoma; breast,
head, neck, and lung
cancer; osteogenic
sarcoma; bladder cancer
Pemetrexed Mesothelioma, lung
cancer
Pyrimidine analogs Fluorouracil (5-
fluorouracil; 5-FU),
capecitabine
Breast, colon,
esophageal, stomach,
pancreas, head and neck;
premalignant skin lesion
(topical)
Cytarabine (cytosine
arabinoside)
Acute myelogenous and
acute lymphocytic
leukemia; non-Hodgkin's
lymphoma
Gemcitabine Pancreatic, ovarian, lung
cancer
Purine analogs and
related inhibitors
Mercaptopurine (6-
mercaptopurine; 6-MP)
Acute lymphocytic and
myelogenous leukemia
Pentostatin (2'-
deoxycoformycin),
cladribine, fludarabine
Hairy cell leukemia;
chronic lymphocytic
leukemia; small cell non-
Hodgkin's lymphoma

79. CLASS TYPE OF AGENT NONPROPRIETARY NAMES
(OTHER NAMES)
DISEASE*
Natural products Vinca alkaloids Vinblastine, vinorelbine Hodgkin's disease; non-Hodgkin's lymphoma: breast, lung, and testis
cancer
Vincristine Acute lymphocytic leukemia; neuroblastoma; Wilms' tumor;
rhabdomyosarcoma; Hodgkin's disease; non-Hodgkin's lymphoma
Taxanes Paclitaxel, docetaxel Ovarian, breast, lung, bladder, head and neck cancer
Epipodophyllotoxins Etoposide Testis, small-cell lung, and other lung cancer; breast cancer; Hodgkin's
disease; non-Hodgkin's lymphomas; acute myelogenous leukemia;
Kaposi's sarcoma
Teniposide Same as etoposide; also acute lymphoblastic leukemia in children
Camptothecins Topotecan, irinotecan Ovarian cancer; small-cell lung cancer; colon and lung cancer
Antibiotics Dactinomycin (actinomycin D) Choriocarcinoma; Wilms' tumor; rhabdomyosarcoma; testis;
Kaposi's sarcoma
Daunorubicin (daunomycin,
rubidomycin)
Acute myelogenous and acute lymphocytic leukemia
Doxorubicin Soft-tissue, osteogenic, and other sarcoma; Hodgkin's
disease; non-Hodgkin's lymphoma; acute leukemia; breast,
genitourinary, thyroid, lung, stomach cancer;
neuroblastoma and other childhood sarcoma
Anthracenedione Mitoxantrone Acute myelogenous leukemia; breast and prostate cancer
Bleomycin Testis, and cervical cancer; Hodgkin's disease; non-
Hodgkin's lymphoma
Mitomycin (mitomycin C) Stomach, anal, and lung cancer
Enzymes L-Asparaginase Acute lymphocytic leukemia

80. CLASS TYPE OF AGENT NONPROPRIETARY
NAMES (OTHER
NAMES)
DISEASE*
Miscellaneous agents Substituted urea Hydroxyurea Chronic myelogenous
leukemia; polycythemia
vera; essential
thrombocytosis
Differentiating agents Tretinoin, arsenic trioxide Acute promyelocytic
leukemia
Protein tyrosine kinase
inhibitor
Imatinib Chronic myelocytic
leukemia; gastrointestinal
stromal tumors;
hypereosinophilia
syndrome
Gefitinib, erlotinib Non-small-cell lung cancer
Proteasome inhibitor Bortezomib Multiple myeloma
Biological response
modifiers
Interferon-alfa, interleukin
2
Hairy cell leukemia;
Kaposi's sarcoma;
melanoma; carcinoid;
renal cell; ovary; bladder;
non-Hodgkin's lymphoma;
mycosis fungoides;
multiple myeloma; chronic
myelogenous leukemia;
malignant melanoma

81. Classification
Cell Cycle–Specific (CCS) Agents Cell Cycle–Nonspecific (CCNS)
Agents
Antimetabolites (S phase) Alkylating agents
Capecitabine Altretamine
Cladribine Bendamustine
Clofarabine Busulfan
Cytarabine (ara-C) Carmustine
Fludarabine Chlorambucil
5-Fluorouracil (5-FU) Cyclophosphamide
Gemcitabine Dacarbazine
6-Mercaptopurine (6-MP) Lomustine
Methotrexate (MTX) Mechlorethamine
6-Thioguanine (6-TG) Melphalan
TemozolomideEpipodophyllotoxin (topoisomerase II
inhibitor) (G1–S phase) Thiotepa
Etoposide Anthracyclines
Taxanes (M phase) Daunorubicin
Albumin-bound paclitaxel Doxorubicin
Docetaxel Epirubicin
Paclitaxel Idarubicin
Vinca alkaloids (M phase) Mitoxantrone
Vinblastine Antitumor antibiotics
Vincristine Dactinomycin
Vinorelbine Mitomycin
Antimicrotubule inhibitor (M phase) Camptothecins (topoisomerase I
inhibitors)
Ixabepilone Irinotecan
TopotecanAntitumor antibiotics (G2–M phase)
Platinum analogs
Bleomycin Carboplatin
Cisplatin
81

82. MODE OF ACTION

83. Alkylating agents
• Cyclophosphamide
• Cisplatin
• Procarbazine
• Busulfan
• Mechlorethamine
83

84. Alkylating Agents- Used in wide variety of
hematologic and solid tumors
• Thiotepa – ovarian cancer
• Busulfan – DOC in CML (Important ADR-Pulmonary fibrosis).
• Nitrosoureas (Carmustine and lomustine ) - brain tumors
• Highly lipid soluble drugs hence reach high concentration in the brain
and CSF.
• Streptozocin – insulin-secreting islet cell carcinoma of the pancreas
• Mechlorethamine – Prodrug. Component of MOPP regimen for
Hodgkin’s disease. It is a highly irritant drug so care should be taken
to avoid extravasation during IV administration
• Chlorambucil (Leukeran): DOC for CLL. Slow acting and least toxic
nitrogen mustard.
84

85. Cyclophosphamide ( CYTOXAN)
• It is a prodrug and is activated by the P-450 enzymes to
its active form phosphoramide mustard
• The active drug alkylates nucleophilic groups on DNA
bases
• Particularly at the N-7 position of guanine
• This leads to cross linking of bases, abnormal base
pairing and DNA strand breakage
85

86. 86

87. 87

88. Mechanism of resistance
• The mechanisms mentioned below are common for all
the alkylyting agents
• Increased DNA repair
• Decreased drug permeability
• Production of “trapping” agents (thiols)
88

89. Uses
• Non-Hodgkin’s lymphoma
• Breast Carcinoma
• Ovarian Carcinoma
• Neuroblastoma
89

90. ADR
• Acrolein is the metabolite
• Responsible for causing hemorrhagic cystitis
• Suprapubic pain
• Hematuria
• This is prevented/treated by MESNA
(mercaptoethanesulfonate)
• Rarely cyclophosphamide can cause pulmonary toxicity
90

91. 91

92. Cisplatin (PLATINOL - AQ)
• Platinum analog
• Same MOA as cyclophosphamide
• Used in testicular carcinoma
• Carboplatin is new drug with better safety profile
ADR
• Nephrotoxicity (prevented by Amifostine)
• Ototoxicity (acoustic nerve damage)
• Peripheral neuritis
• Severe nausea and vomiting
92

93. Procarbazine ( MUTALANE- US
INDICARB – INDIA)
• MOA: forms hydrogen peroxide, which generates free
radicals that cause DNA damage
• Important component of regimens especially for
Hodgkin’s lymphoma
ADR
• Disulfiram like reactions
93

94. 94
Trimetrexate
Pemetrexed
Thioguanine
Fludarabine Phosphate
Cladribine
Cytarabine
Gemcitabine
Capecitabine

95. Antimetabolites
• They are structurally similar to endogenous compounds
• They act as antagonists of:
• Folic acid (methotrexate)
• Purines (Mercaptopurine and thioguanine)
• Pyrimidine (fluorouracil, cytarabine)
95

96. Antimetabolits: sites of drug action
96

97. Methotrexate
97

98. Methotrexate (RHEUMATREX)
• MTX is a folic acid analog that binds with high affinity to
the active catalytic site of dihydrofolate reductase
(DHFR)
• Thus it interferes with the synthesis of tetrahydrofolate
(THF)
• THF serves as the key one-carbon carrier for enzymatic
processes involved in de novo synthesis of thymidylate,
purine nucleotides, and the amino acids serine and
methionine.
• Inhibition of these various metabolic processes thereby
interferes with the formation of DNA, RNA, and key
cellular proteins. 98

99. 99
Mechanism of Resistance
1. Decreased drug
transport
2. Altered DHFR
3. Gene
amplification
4. Increased levels
of DHFR

100. Contd..
• Most commonly used anticancer drug.
• Cell cycle specific (CCS) drug and acts during S phase
of the cell cycle.
• Uses:
• 1. acute lymphoblastic lukemia
2. other non – hodking’s lymphoma
3. immunosuppressant and antiinflammatory
100

101. ADR
• Bone marrow suppression (BMS)
• Mucositis
• Folic acid deficiency
• The toxic effects of MTX on normal cells is reduced by
administering folinic acid (leucovorin)
• This is called leucovorin rescue
• Higher the dose of MTX more the leucovorin you give
101

102. Leucovorin Rescue
102
Mechanism of action of
methotrexate and the
effect of administration of
leucovorin.
• FH2 = dihydrofolate
• FH4 = tetrahydrofolate
• dTMP = deoxythymidine
monophosphate
• dUMP = deoxyuridine
mono phosphate.

103. 6-Mercaptopurine (6-
MP) & Thioguanine
• Both 6-MP and Thioguanine are
activated by HGPRT to toxic
nucleotides that inhibit several
enzymes involved in purine
metabolism
• Resistance is due to cancer cells
having ⇓d activity of HGPRT
• Cancer cells also ⇑es alkaline
phosphatase that inactivate toxic
nucleotides
103

104. 6-MP & Allopurinol
• 6-MP is metabolized in the liver by xanthine oxidase and
the inactive metabolites are excreted in the urine
• Allopurinol is used frequently to treat/prevent
hyperuricemia caused by many anticancer drugs.
• If Allopurinol is used with 6-MP then the dose of 6-MP is
reduced by more than 75%
104

105. Cytarabine (CYTOSAR - U)
• Cytarabine arabinoside is a pyrimidine antimetabolite
• The drug is activated by kinases to AraCTP
• This acts as an inhibitor of DNA polymerase
• of all antimetabolites, this is the most specific for S
phase of tumor cell cycle
105

106. Uses
• It is an important component in acute lukemia regimens
ADR:
at high doses cause neurotoxicity (cerebellar dysfunction
and peripheral neuritis)
Hand & foot syndrome

107. 5-FU
Mechanism of the cytotoxic action of 5-FU
• 5-FU is converted to 5-FdUMP, which
competes with deoxyuridine
monophosphate (dUMP) for the enzyme
thymidylate synthetase.
• 5-FU = 5-fluorouracil
• 5-FUR = 5-fluorouridine
• 5-FUMP = 5-fluorouridine
monophosphate
• 5-FUDP = 5-fluorouridine diphosphate
• 5-FUTP = 5-fluorouridine triphosphate
• dUMP = deoxyuridine monophosphate
• dTMP = deoxythymidine
monophosphate
• 5-FdUMP = 5-fluorodeoxyuridine
monophosphate. 107

108. Contd..
• 5-FU causes, “thymidineless death” of cells
• Resistance is due to ⇓d activation of 5-FU and ⇓d
thymidylate synthase activity
Uses
• Metastatic carcinomas of the breast and the GI tract.
• Carcinomas of the ovary, cervix, urinary bladder,
prostate, pancreas, and oropharyngeal areas
• Combined with levamisole for colon cancer
108

109. ADR
• nausea, mucositis, diarrhea,
• hand and foot syndrome,
• Alopecia,
• hyperpigmentation,
• neurologic deficits,
• bone marrow depression

110. 110
Vinblastine
Vincristine
Vinorelbine
Teniposide Irinotecan Docetaxel

111. Vinka alkaloids
(Vinblastine, vincristine)
• These drugs block the
formation of mitotic spindle by
preventing the assembly of
tubulin dimers into
microtubules
• They act primarily on the M
phase of cancer cell cycle
• Resistance is due to ⇑d efflux
of drugs from tumor cells
111

112. ADR
• Severe neurotoxicity
• Paresthesias : sensation of tingling, pricking, or
numbness
• Loss of reflexes
• Foot drop: inability or difficulty to move ankle/ toes.
Caused by nerve damage
• Ataxia
112

113. 113
VinBlastine VinCristine (oncovan)
Uses ; (ABVD)
Hodgkin’s disease
Lymphomas
Carcinoma Breast
Testicular tumors
Toxicity:
Bone marrow
suppression, anorexia,
nausea, vomiting &
Diarrhea, Alopecia
Uses: (MOPP)
Childhood leukemias
Childhood tumors-Wilm’s
tumor, Neuroblastoma,
Hodgkin’s disease
Toxicity:
Peripheral neuritis with
Paresthesia, Muscle
weakness
Vincristine has marrow
sparing effect

114. Etoposide ( EPOSIN) & Teniposide
( VUMON)
• Acts by inhibiting topoisomerase II
• These drugs are most active in late S and early G2
phase
• Used in combination for carcinoma of lung, prostrate and
testicular carcinomas
Other topoisomerase inhibitors:
• Topotecan, Irinotecan
• Both act by inhibiting topoisomerase-I
114

115. Topoisomerase inhibitors
115

116. Paclitaxel & Docetaxel
• These drugs act by interfering with
mitotic spindle
• They prevent micotubule
disassembly into tubulin
monomers
ADR
• Neutropenia
• Peripheral neuropathy
116

117. Anticancer Antibiotics
• Anthracyclines:
• Doxorubicin (Adriamycin)
• Daunorubicin
• Bleomysin
• Dactinomycin
• Mitomycin
117

118. Doxorubicin ( RUBEX) & Daunorubicin
( DAUNOXOME)
• These drugs intercalate between
base pairs, inhibit topoisomerase
II and also generate free radicals
• They block RNA and DNA
synthesis and cause strand
scission
• Used as a component in ABVD
regimen in Hodgkin’s lymphoma
118

119. ADR
• Cardiac toxicity (due to generation of free radicals)
• Acute form: arrthythmias, ECG changes, pericarditis,
myocarditis
• Chronic form: ***Dilated cardiomyopathy, heart failure
• Rx with dexrazoxane
• This is an inhibitor of iron mediated free radical generation
• Bone marrow depression, Total alopecia
119

120. Bleomycin (BLENOXANE)
• Acts through binding to DNA, which results in
single and double strand breaks following free
radical formation and inhibition of DNA
synthesis
• The DNA fragmentation is due to oxidation of
a DNA-bleomycin-Fe(II) complex and leads to
chromosomal aberrations
• CCS drug that causes accumulation of cells
in G2
Uses
• ABVD regimen for Hodgkin’s
• Intracavitary therapy in ovarian and breast
cancers (Sclerosing agent)
ADR
• Pulmonary fibrosis
120

121. Hormonal agents
• Glucocorticoids
• Sex hormone antagonists
• GnRH analogs
• Aromatase inhibitors
121

122. Glucocorticoids (Prednisone)
• Because of their marked lympholytic action, they are
used in acute leukemias and lymphomas.
• Have anti-inflammatory effect
• Produce euphoria (feeling of well being)
• Suppress hypersensitivity reaction due to certain
anticancer drugs
• Immunomodulatory
122

123. Sex hormone antagonists
123

124. Tamoxifen (ISTUBAL)
• It is a SERM
• Blocks the binding of estrogen to receptors of
estrogen sensitive cancer cells in bresat tissue
• It is used in receptor positive breast carcinoma
• Also useful in progestin resistant endometrial
carcinoma
ADR:
• Hot flushes, vaginal bleeding and venous
thrombosis
Other drugs
• Flutamide: androgen receptor antagonist used in
prostatic carconima
• ADR for flutamide includes: gynecomastia, hot
flushes 124

125. MOA of drugs
125

126. GnRH analogs
• Leuprolide, gosarelin and naferelin
• Effective in management of Prostatic
carcinomas
• When given in constant doses they inhibit
release of pituitary LH and FSH
• These drugs suppress gonadal function due to down
regulation and desensitization of Gn-RH receptors
ADR
• Leuprolide may cause gynecomastia, hematuria,
impotence and testicular atrophy
126

127. Aromatase inhibitors
• The aromatase reaction is responsible for the
extra-adrenal synthesis of estrogen from
androstenedione
• This takes place in liver, fat, muscle, skin, and
breast tissue, including breast malignancies.
• Peripheral aromatization is an important source
of estrogen in postmenopausal women.
• Aromatase inhibitors decrease the production of
estrogen in these women.
127

128. Contd..
128

129. Contd..
• Anastrozole and Letrozole
• These drugs inhibit the aromatase enzyme
• ****Used in postmenopausal women with metastatic
breast cancer (1st
line drug)
• ADR includes:
bone pain
peripheral edema
129

130. Advanced treatment
Asparaginase,
imatinib,
interferons,
monoclonal antibodies
130

131. Asparaginase
• L-Asparaginase catalyzes the deamination of asparagine
to aspartic acid and ammonia.
• L-Asparaginase is used in combination therapy to treat
childhood acute lymphocytic leukemia
• MOA: neoplastic cells require an external source of
asparagine because of their limited capacity to
synthesize sufficient amounts of that amino acid to
support growth and function.
•
• L-Asparaginase hydrolyzes blood asparagine and, thus,
deprives the tumor cells of this amino acid, which is
needed for protein synthesis
ADR
• Acute pancreatitis 131

132. Contd..
132

133. Imatinib ( GLEEVAC)
• Example of a drug, whose development was guided by
knowledge of a specific oncogene
• Used for the treatment of chronic myeloid leukemia
• Acts by inhibiting tyrosine kinase activity of the protein
product of the Bcr-Abl (break point cluster region)
oncogene
• This gene is expressed in CML- chronic myealogenous
leukemia
133

134. MOA of imatinib
134

135. Interferons
• Human interferons have been classified into three types
—α, β, and γ—on the basis of their antigenicity.
• α interferons: leukocytic,
• β interferons: produced by connective tissue fibroblasts
∀ γ interferons: T lymphocytes
• Recombinant DNA techniques in bacteria have made it
possible to produce two species designated interferon-α-
2a and -2b used in Tx of neoplastic diseases.
• .
135

136. • interferon-α-2a( pigasys) :
hairy-cell leukemia,
chronic myeloid leukemia, and
acquired immunodeficiency syndrome (AIDS)–related
Kaposi sarcoma.
• Interferon-α-2b (pigantron):
hairy-cell leukemia,
melanoma,
AIDS-related Kaposi's sarcoma, and
follicular lymphoma

137. Monoclonal Antibodies
• They are created from B lymphocytes (from immunized
mice or hamsters) fused with “immortal” B-lymphocyte
tumor cells.
• The resulting hybrid cells can be individually cloned, and
each clone will produce antibodies directed against a
single antigen type.
• Currently, several monoclonal antibodies are available in
the United States for the treatment of cancer.
• Trastuzumab, rituximab, bevacizumab, and cetuximab
137

138. Trastuzumab (HERCEPTIN)
• In patients with metastatic breast cancer, overexpression
of transmembrane human epidermal growth factor–
receptor protein 2 (HER2) is seen in 25 to 30 % of
patients.
• Trastuzumab is a recombinant DNA–produced,
humanized monoclonal antibody, specifically targets the
extracellular domain of the HER2 growth receptor that
has intrinsic tyrosine kinase activity.
• Trastuzumab binds to HER2 sites in breast cancer tissue
and inhibits the proliferation of cells that overexpress the
HER2 protein, thereby decreasing the number of cells in
the S phase.
138

139. FDA approved MAb
139

140. MARKERS

141. Treatment of Specific cancers
Hodgkin’s disease :
• ABVD regimen
(doxorubicin,bleomycin,vinblastine,dacarbazine)
• MOPP regimen
(mechorethamine,vincristine,procarbazine,prednisone)
Non hodgkin’s disease :
• CHOP regimen
(cyclophosphamide,doxorubicin,vincristine,prednisone)
141

142. Multiple myeloma :
• MP protocol (melphalan and prednisone)
Breast carcinoma:
• CMF protocol (cyclophosphamide-MTX-fluorouracil)
• Tamoxifen
• Anastrozole, letrozole

143. Prevention/management of Cancer
Chemotherapy induced ADR
• Nausea and vomiting : 5-Ht3 antagonist (ondansetron)
• Bone marrow suppression : Filgrastim, Sargromastim
(colony stimulating factors)
• MTX toxicity : Leucovorin
• Cyclophosphamide toxicity : MESNA
• Cisplatin toxicity : Amifostine
• Anthracycline toxicity ; Dexaroxazone
143

144. THANK YOU