Principles of cancer chemotherapy

1. Sufyan Akram
MBBS PhD
Principles of Cancer
Chemotherapy
National Cancer Institute’s website (an excellent resource):
http://www.cancer.gov/

2. What is Cancer?
 Cancer is a diverse class of diseases which
differ widely in their causes and biology
 Any organism, even plants, can acquire cancer
 Nearly all known cancers arise gradually, as
errors build up in the cancer cell and its
progeny

3. What is Cancer?
 Cancer is a complex disease characterized by
deregulation of cell proliferation and apoptotic
mechanisms, stromal and microenvironmental
changes, angiogenesis and cell metastasis

4. Incidence
According to the American Cancer Society, 7.6 million
people died from cancer in the world during 2007

6. Cell Cycle
 Starting from a single-celled zygote… An adult
human being has approximately 100,000 billion
cells
 Cell division does not stop with formation of
mature organism, but continues throughout its life
 Tens of millions of cells undergo division at any
given moment in an adult human. This amount of
division is needed to replace cells that have aged
or died

7. The Eukaryotic Cell Cycle
 Most eukaryotic cells will
pass through an ordered
series of events in which
the cell duplicates its
contents and then divides
into two cells
 This process of cell
division in multicellular
organisms must be highly
ordered and tightly
regulated

8. G0
G2 Checkpoint
G1 Checkpoint
Metaphase
Checkpoint
Is cell big enough?
Is environment favourable?
Is all DNA replicated?
Is cell big enough?
Is environment favourable?
Are all chromosomes
aligned on spindle?

9. How Cancer Develops?
 Cancer arises from a loss of normal growth control.
In normal tissues, the rates of new cell growth and
old cell death are kept in balance. In cancer, this
balance is disrupted
 This disruption can result from uncontrolled cell
growth or loss of a cell’s ability to undergo cell
suicide by a process called “apoptosis”
 Apoptosis, or “cell suicide,” is the mechanism by
which old or damaged cells normally self-destruct

10. How Cancer Develops?
• Cancer cells do not respond normally to body’s
control mechanisms:
• Ignore density dependent inhibition, cells continue
to multiply until nutrients are exhausted
• Divide excessively and invade other tissues

11. Loss of normal growth control
Cancer
cell division
Fourth or
later mutation
Third
mutation
Second
mutation
First
mutation
Uncontrolled growth
Cell Suicide or Apoptosis
Cell damage that
couldn’t be repaired
Normal
cell division

12. Example of normal growth
Cell migration
Dermis
Dividing cells in
basal layer
Dead cells
shed from
outer surface
Epidermis

13. Cancerous growth
Underlying tissue

14. Benign vs Malignant neoplasms
Malignant (cancer)
cells invade
neighboring tissues,
enter blood vessels,
and metastasize to
different sites
Time
Benign (not cancer)
tumor cells grow
only locally and cannot
spread by invasion or
metastasis

15. Properties of Cancer Cell
 Unchecked growth
 Loss of capacity for apoptosis (growth despite
genetic errors and external anti-growth signals)
 Loss of capacity for senescence (immortality)
 Sustained angiogenesis
 Invasion of neighbouring tissues
 Acquisition of ability to build metastases at distant
sites, the classical property of malignant tumours

16. What causes Cancer?

17. Genes and Cancer
Chromosomes
are DNA
molecules
Heredity
RadiationChemicals
Viruses

18. Tumour Suppressor Genes
Normal
genes
prevent
cancer
Remove or inactivate tumor
suppressor genes
Mutated/inactivated
tumor suppressor genes
Damage to
both genes
leads to
cancer
Cancer cell
Normal cell

19. Oncogenes
Mutated/damaged oncogene
Oncogenes
accelerate
cell growth
and division
Cancer cell
Normal cell Normal
genes
regulate
cell growth

20. Cancer tend to involve multiple mutations
Malignant cells invade
neighboring tissues, enter
blood vessels, and metastasize
to different sites
More mutations,
more genetic
instability,
metastatic
disease
Proto-oncogenes
mutate to oncogenes
Mutations
inactivate
DNA repair
genes
Cells
proliferate
Mutation
inactivates
suppressor
gene
Benign tumor cells
grow only locally and
cannot spread by
invasion or metastasis
Time

21. Causative/ Contributing Factors
Some viruses or bacteria
Heredity
Diet
Hormones
RadiationSome chemicals

23. Examples of Human Cancer Viruses

24. Occupational Carcinogens
Some Carcinogens in the Workplace

25. Types of Cancer
Lung
Breast (women)
Colon
Bladder
Prostate (men)
Some common
sarcomas:
Fat
Bone
Muscle
Lymphomas:
Lymph nodes
Leukemias:
Bloodstream
Some common
carcinomas:

26. Types of Cancer
 Carcinomas, the most common types of cancer, arise
from the cells that cover external and internal body
surfaces. Lung, breast, and colon are the most frequent
cancers of this type
 Sarcomas are cancers arising from cells found in the
supporting tissues of the body such as bone, cartilage,
fat, connective tissue, and muscle
 Lymphomas are cancers that arise in the lymph nodes
and tissues of the body’s immune system
 Leukemias are cancers of the immature blood cells
that grow in the bone marrow and tend to accumulate
in large numbers in the bloodstream

27. Why cancer is dangerous?
Melanoma
cells travel
through
bloodstream
Melanoma
(initial tumor)
Brain
Liver

28. Early cancer is usually symptom-less
 Major problem in detecting and treating cancer is
its late presentation
 Various screening programs has been proposed and
implemented but without much success
 Major emphasis on prevention !!!

29. Symptoms & Complications

30. Local
 Unusual lumps or swelling (tumour)
 Haemorrhage (bleeding)
 Pain and/or ulceration
 Compression of surrounding tissues may cause
pressure symptoms
 Erosion
 Angiogenesis

32. Symptoms of metastasis
 Enlarged lymph nodes
 Cough and haemoptysis
 Hepatomegaly (enlarged liver)
 Bone pain, fracture of affected bones
 Neurological symptoms
 Although advanced cancer may cause pain, it is
often not the first symptom

33. Systemic
 Weight loss
 Poor appetite
 Fatigue and cachexia (wasting)
 Excessive sweating (night sweats)
 Anaemia
 Specific paraneoplastic phenomena, i.e. specific
conditions that are due to an active cancer, such as
ectopic production of hormones by cancer cells

34. Cancer Treatment

35. 3 Major Modalities of Rx

36. Multidisciplinary Approach
 Cancer treatment requires the cooperation of a
multidisciplinary team to coordinate the delivery of the
appropriate treatment (surgery, chemotherapy,
radiotherapy and biological/endocrine therapy), supportive
and symptomatic care, and psychosocial support

37. Chemotherapy
 Conventional chemotherapy kills all rapidly dividing
cells
 High (and sometimes toxic) doses of these drugs
are usually given with the hope that all cancer cells
will be killed
 An unavoidable consequence of this approach is
killing of normal actively dividing cells
 e.g., Hair follicles, Bone Marrow, GI Mucosa

38. Major Side Effects
 This results in the most common side effects of
chemotherapy:
 myelosuppression (decreased production of blood
cells, hence also immunosuppression),
 mucositis (inflammation of the lining of the digestive
tract), and
 alopecia (hair loss)
 Other serious side effects are:
 Severe Nausea and Vomitting
 Infertility
 Secondary Tumors

39. Classes of Drugs
1. Alkylating Agents
2. Antimetabolites
3. Anthracyclins
4. Plant Alkaloids
5. Topoisomerase Inhibitors
6. Cytotoxic Antibiotics

40. 1. Alkylating Agents
 Alkylating agents act by covalently binding alkyl
groups, and their major effect is to cross-link DNA
strands, interfering with DNA synthesis and causing
strand breaks
 Despite being among the earliest cytotoxic drugs
developed, they maintain a central position in the
treatment of cancer
 They work by chemically modifying a cell's DNA

41. 2. Antimetabolites
 Anti-metabolites masquerade as purines or
pyrimidines
 They prevent these substances from becoming
incorporated into DNA during the "S" phase (of the
cell cycle), stopping normal development and
division
 They also affect RNA synthesis
 Due to their efficiency, these drugs are the most
widely used cytostatics

42. Antimetabolites (cont’d)
 Folic acid antagonist
 methotrexate
 Pyrimidine antagonists
 5-Fluorouracil (5-FU)
 Arabinosides inhibit DNA synthesis by inhibiting DNA
polymerase
 Cytosine arabinoside (cytarabine)
 Purine antagonists
 6-mercaptopurine and 6-tioguanine

43. 3. Anthracyclins
 Anthracyclines (or anthracycline antibiotics) are a
class of drugs derived from Streptomyces bacteria
 The anthracyclines are some of the most effective
anticancer treatments ever developed and are
effective against more types of cancer than any
other class of chemotherapy agents
 Their main adverse effects are heart damage
(cardiotoxicity), which considerably limits their
usefulness

44. Anthracyclins (cont’d)
 Mechanisms of Action:
 1.Inhibit DNA and RNA synthesis by intercalating
between base pairs of the DNA/RNA strand, thus
preventing the replication of rapidly-growing cancer
cells
 2.Inhibit topoiosomerase II enzyme, preventing the
relaxing of supercoiled DNA and thus blocking DNA
transcription and replication
 3.Creates iron-mediated free oxygen radicals that
damage the DNA and cell membranes

45. 4. Plant Alkaloids
 These alkaloids are derived from plants and block
cell division by preventing microtubule function
 The main examples are vinca alkaloids and taxanes
 Vinca alkaloids bind to specific sites on tubulin,
inhibiting the assembly of tubulin into microtubules
(M phase of the cell cycle)
 Taxanes enhance stability of microtubules, preventing
the separation of chromosomes during anaphase

46. 5. Topoisomerase Inhibitors
 Inhibition of type I or type II topoisomerases
interferes with both transcription and replication
of DNA by upsetting proper DNA supercoiling

47. 6. Cytotoxic Antibiotics
 These include doxorubicin, epirubicin, bleomycin
and others
 Have different mechanisms of action:
 Doxorubicin works by intercalating DNA
 Bleomycin works by causing breaks in DNA

48. Chemotherapy Regimen
 Most tumours rapidly develop resistance to single
agents given on their own. For this reason the
principle of intermittent combination
chemotherapy was developed
 Several drugs are combined together
 These drugs are given over a period of a few days
followed by a rest of a few weeks, during which
time the normal tissues have the opportunity for
re-growth

49. Response to Chemotherapy
 As chemotherapy affects cell division, tumors with
high growth fractions (such as acute leukemia and
the aggressive lymphomas, including Hodgkin's
disease) are more sensitive to chemotherapy, as a
larger proportion of the targeted cells are
undergoing cell division at any time
 Malignancies with slower growth rates do not tend
to respond to chemotherapy

50. Targeted Therapy
 Newer anticancer drugs act directly against
abnormal proteins in cancer cells; this is termed
targeted therapy
 Any Examples??

51. Targeted Therapy
 The first molecular target for targeted cancer
therapy was the cellular receptor for the female
sex hormone estrogen, which many breast cancers
require for growth
 When estrogen binds to the estrogen receptor (ER)
inside cells, the resulting hormone-receptor
complex activates the expression of specific genes,
including genes involved in cell growth and
proliferation
 Tamoxifen was the first drug developed as a targeted
therapy

52. Signal Transduction Inhibitors
 Imatinib mesylate (Gleevec®) is approved to treat
gastrointestinal stromal tumor (a rare cancer of the
gastrointestinal tract) and certain kinds of
leukemia
 It targets several members of tyrosine kinase
enzymes that participate in signal transduction

53. In Summary…
 Cancer is a heterogeneous group of diseases, with
wide range of causative factors
 Cancer treatment requires the cooperation of a
multidisciplinary team (surgery, chemotherapy,
radiotherapy and biological/ endocrine therapy)
 The improved understanding of molecular biology
and cellular biology due to cancer research has led
to a number of new and effective treatments

54. References
National Cancer Institute’s website
http://www.cancer.gov/
Lippincott Illustrated Reviews: Pharmacology 5th ed
(2011)