the presentation include the different type of mechanism used by cancer cells to protect them from anticancer agents lead to produce resistance. the slide include definition of cancer as per WHO, type of tumors, treatment of cancer, goal of treatment, problem associated with chemotherapeutic agents, need of studing mechanisms of resistance for anticancer agents, resistance, different mechanism of drug resistance, epigenetics, drug efflux, drug inactivation, DNA damage repair, drug target alteration and cell death inhibitiond

1. ANTICANCER AGENT
RESISTANCE
BY: PRIYA SHUKLA

2. CONTENT
INTRODUCTION
TYPE OF TUMOURS
TREATMENT FOR CANCER
GOAL OF TREATMENT

3. PROBLEMS ASSOCIQATED WITH
CHEMOTHERAPY
NEED FOR STUDING ANTICANCER DRUG
RESISTANCE
ANTICANCER AGENT RESISTANCE
TEST TO DETERMINE RESISTANCE
MULTIDRUG RESISTANCE

5. • DEFINITION: Cancer is an abnormal growth of
cells which tend to proliferate in an uncontrolled way
and, in some cases, to metastasize(spread).
• The medical term for tumour(or) cancer is Neoplasm,
which means a relatively autonomous growth (or) un
coordinated cell proliferation of body tissue.

6. TYPES OF TUMOURS
• Not all tumours are cancerous; tumours are of
2 type
• –benign
• - malignant
• Malignant tumours: are cancer cells, cells in
this tumours can damage nearby cells of
tissue and spread to other parts of the body.
The spread of cancer from one part of the
body to another is called metastasis

7. TREATMENT OF CANCER
• 1. CHEMOTHERAPY – rapidly dividing cell
metastasised cancers
• 2. RADIOTHERAPY – in combination with other
therapies iodine-131( thyroid cancer)
• 3. SURGERY
• 4. IMMUNOTHERAPY- immune system made
stronge to fight with cancer
• 5. HORMONE THERAPY- altering hormone level
and killing cancer cells
• 6. GENE THERAPY – replacing defective genes

8. A true cure
requires the
eradication
of every
neoplastic
cell.
control of
the disease,
to extend
survival and
maintain the
best quality
of life.
individual
maintains a
“near-
normal”
existence of
life

9. Problems associated with chemotherapy
Cancer drugs are:
Anticancer agents are nothing but toxins which
are used to kill the cancer cells and therefore,
not surprising that all cells including cancer
cells have an in build defence mechanism
how’s ultimate goal is to protect them self
from toxins.
• This lead to produce resistance for anticancer
agents which are used to treat the cancer
disease.

10. Needs of studing mechanisms of
resistance for anticancer agents:
• Cancer is the 2nd leading cause of death in world,
so it’s important to study the cause, factors,
treatment and also its treatment resistance.
• So that we can overcome all the drawbacks and
get an effective solution to cure the same.
• So, to study the resistance mechanisms of
anticancer agent is important , this will help us to
proceed with rational treatment for cancer with
excluding the maximum chances of treatment
failure of the same.

11. NEED
RATIONAL
THERAPY
DEVELOPMENT
OF NEW DRUG
OVERCOME
FROM
DRAWBACK

13. Resistance
• Resistance is the reduction in effectiveness of
medication due to different means of
mechanisms
• The development of drug resistance is minimized
by short-term, intensive, intermittent therapy
with combinations of drugs.
• Drug combinations are also effective against a
broader range of resistant cells in the tumour
population.

14. Mechanism of drug resistance:

15. ANTI-CANCER DRUG RESISTANCE:-
• Drug resistance is a well-known phenomenon
that results when diseases become tolerant to
pharmaceutical treatments. This concept was first
considered when bacteria became resistant to
certain antibiotics, but since then similar
mechanisms have been found to occur in other
diseases, including cancer.
• Some methods of drug resistance are disease-
specific, while others, such as drug efflux, which
is observed in microbes and human drug-
resistant cancers, are evolutionarily conserved.

18. DRUG INACTIVATION:
• Drug activation is in-vivo process where the agent
interact with different kind of proteins, this
interaction lead to modification, degradation or
complex formation with protein or different
molecule which lead to activation of this agents.
• This anticancer agent may go metabolic
activation which result to acquire clinical
efficiency. But cancer cells produce resistance to
this mechanisms which lead to decrease in
activation of this agent.

19. • Example of this is acute myelogenous
leukemia with cytarabine (AraC), this drug is
activated after multiple phosphorylation
which result to AraC-triphosphate, down
regulation or mutation lead to decrease in the
activation of AraC in this pathway, which lead
to produce AraC resistance.
• The another example which can be include is
cytochrome P450 (CYP450), glutathione-S-
transferase(GST) superfamily. The cytochrome
system is been classified into two class.

20. • Class 1 include CYP1A1, CYP1A2 , CYP2E1, and
CYP3A4, which are well conserved, functional
polymorphisms is not important, and are
active in the metabolism of drugs and
procarcinogens.
• Class II is composed of CYP2B6, CYP2C9,
CYP2C19, and CYP2D6, which are highly
polymorphic and active in drug metabolism.
• class II drugs are more viable then class I drugs
because of that the CYP are more suitable in
drug metabolism because of that it is more
affective towards anticancer drug resistance.

21. • In liver , the CYP1A1 and CYP1A2 from class I
do metabolism of procarcinogens to
carcinogens which is responsible for many
anticancer drug metabolisms, CYP
polymorphism is not associated with
carcinogens then to might be it’s mutation can
affect the drug metabolisms like increasing the
degradation and excretion of the drug by
kidney, which lead to that, that the drug is not
able to maintain the proper level in the body
and therefore the cancer is been considered
to resistance to it.

22. • Metabolic activation is needed by many
anticancer agents and inhibition of this
metabolism process is done by cancer cells,
and thus the drug activation get decrease
which lead to development of anticancer drug
resistance.

23. Inactive agents
Get metabolised in body
(Invivo)
Activated anticancer
agent
Inhibition of
Metabolism process
Anticancer resistance
Produce

25. 2. Alteration of drug target:
• The molecular target is most important factor
for determining the efficiency of the drugs ,
while the alteration of this targets by
modification or mutation leads to failure of
the treatment by anticancer agents. In cancer
this type of alteration can be cause of drug
resistance.

26. • Example : anticancer drugs that target enzyme
known as topoisomerase II, this enzyme is
responsible in prevention of cancer cell DNA
super coiling or under coiling, but the anticancer
agents stabilize it lead to inhibition or damage of
DNA or stopping of mitotic process of the cells.
• The cancer cells can produce drug resistance
because of this circumstances: Mutation of
topoisomerase II lead to resistance of anticancer
agents and inhibition of the same due to
mutation of the topoisomerase II.
• For example, the treatment of breast cancer
tumours with Herceptin.

27. Drug
Recognise and bind
To target site Alteration of target site
Drug
Can’t recognise target
site
Anticancer resistance

29. 3. Efflux pump:
• Drug efflux pump is one of the most important
and well studied mechanism of drug resistance
where the cancer cells do not let the drug to
accumulate in the cell at desire concentration to
its effect which lead to failure of the therapy.
• The ATP- binding casscette protein transporter
(ABC) is responsible for the efflux of the drugs
and is well known studied regulated in human
plasma membrane of healthy cells.

30. • ABC transporters are transmembrane protein
which is present in healthy cells as well in large
extend of cancer cells who’s mechanism is to
transport different type of substance to cross
cellular regions.
• This transporters structure varies from protein to
protein and can exit in different count in different
species ( eg : human has 49 transporters of ABC
family), this transporters are of 2 type based on
distinct domain –
1. Highly conserved nucleotide binding domain and
2. Transmembrane domain

31. • This transporters are mainly substrate specific
and able to efflux many drugs including vinca
alkaloids, epipodophyllotoxins, anthracyclines,
taxanes, and kinase inhibitors out of the cells.
• And thus protect cancer cells and inhibit many
first line therapy and produce anticancer
resistance the MDR1 which produce Pgp is the
very first efflux pump transporter which
produce anticancer agent resistance was been
determined.

32. • This is been largly extended in colon , kidney
and liver when this tissue become cancerous
then MDR1 level increase which try to make
failure of the treatment.
• Tissues which are not associated with it that is
lung, breast and prostate have produced drug
resistance due to MRP 1 and BCRP. BCRP
protect normal cells from the toxine like
xenobiotics and also maintain level of heme
and folate which is expressed in stem cells.

33. • One of the example is estradiol used in the
treatment of breast cancer.
• It is the most effective drug that can be used
in breast cancer but have been resist due to
efflux pump mechanism of cancer cells.

36. 4. DNA Damage repair :
• The DNA damage repair mechanism has the
vital role in anticancer resistance. As the cell
nature or mechanism of the damage DNA
repair lead to produce drug resistance effect
on chemotherapy , and the damage DNA
repair mechanism of the cell can reverse the
damage produce by the drug to the cancer
cells in chemotherapy and lead to produce its
resistance.

37. • Example : platinum containing chemotherapeutic
agents like cisplatin, cause harmfull DNA cross
linked which lead to apoptosis. And resistance of
this can arise due to nucleotide homologous
recombination , this lead to repair the primary
damage of DNA and lead to failure of the
treatment of the anticancer drugs which lead to
produce drug resistance and inhibit the response
of the anticancer agents.
• Increase DNA repair activity lead to increase
resistance , this provide the opportunities to
chemotherapy:

38. • 1. Targeting the overactive damage DNA repair
pathway with chemotherapeutic drugs.
• 2. Another is the knowledge of the
dysfunctional damage DNA repair could allow
proper prescription of a DNA-damage causing
drug, which induces damage only repaired by
the defective pathway.
• In both the cases, it is essential to identify the
over-active and under-active DDR
mechanisms.

39. drug
Act on DNA
Cancer cells DNA
Damage of cancer DNA
Recombination of cancer
Cell DNA
Damage DNA get repaired
Anticancer
resistance

41. 5. Cell death inhibition:
• The cell death is mainly done by two mechanism
i.e. apoptosis and autophagy regulatory events.
While they both are acting antagonistic to each
other but they both act in cell death
mechanisms.
• The apoptosis is consist of 2 distinct pathway:
1. An intrinsic pathway which is associated with
the mitochondria Beta cell lymphoma 2 (BCL2) ,
cascade 9 and Akt.
2. the extrinsic pathway where the death receptors
are involved on the surface of the cell

42. • Both the intrinsic and extrinsic pathways get
activated when there is the increase in the
level of the cascade 3 and Akt which
ultimately lead to apoptosis of the cell and do
cell death.
• In several types of cancers, BCL-2 family
proteins, Akt, and other antiapototic proteins
are highly expressed and decrease
transcription modulators and are highly active,
making these good targets for drug
development.

43. • Example: flurouracil in combination with
chlorouracil has greater effect for cell death
mechanism which is been inhibited by this cell
death inhibition mechanism.

47. 6. Cancer cell Heterogeneity:
• We have seen several mechanisms by which the
cancer cells produce resistance to the anticancer
cells. But here , in this mechanism the cancer
cells do increase in growth of already resistant
cancer cells towards anticancer agents.
• Recent studies has finding that the
heterogeneous cancer cells has the stem cell
properties with which it started producing cells
which are having born anticancer resistance
property.

48. • The anticancer agents are build to treat or
fight with cancer cells which are sensitive to
them, but this heterogeneity in cancer cells
lead to produce cells which are not sensitive
to anticacner treatment, this lead to expand of
cancer in the patient, with the failure of the
treatment.
• Many of this cells are present in the
circulation system of patient which may also
lead to develop cancer in other distinct
organs.

49. • Example: study on acute myeloid leukemia
determined two co-existing dominant clones.
One was the drug sensitive and the other drug
resistant. It is possible that re-occurrence of
this disease in patients after successful
therapy may be the result of cancer cell
growth from the drug resistant clone .
• Example : Taxanes and platinum compound
used in cancer treatment.

52. 7. Role of Epigenetics in Cancer Drug
Resistance :
• Important set of mechanisms that cause
resistance to cancer and which can also do
influence carcinogenesis.
• Certain circumstances in life can cause genes
to be silenced or expressed over time. In other
words, they can be turned off (becoming
dormant) or turned on (becoming active).

53. • The two main types of epigenetic changes are
1. DNA methylation
2. Histone modification via acetylation or
methylation
DNA methylation consists of methyl groups
binding to cytosines at CG-dinucleotides
within regions known as CpG islands,
primarily found in upstream gene promoter
regions.

54. • However, methylation can occur at other
locations also throughout the genome.
• Conversely, histone modifications alter
chromatin conformation. For example, histone
acetylation opens the chromatin, while
deacetylation closes it.
• These mechanisms ultimately regulate the
expression of genes throughout the
chromosome, and in cancer, this normal
regulation is broken.

55. • For example, tumor suppressor genes are
often silenced via hypermethylation, and
oncogenes are over-expressed from
hypomethylation. However, epigenetic
mechanisms are usually reversible, and
researchers may be able to take advantage of
this opportunity to develop treatments that
can counteract drug resistant cancers.

56. • Methylation at the cell promoter controls
MDR1 transcription, increases drug resistance,
and decreases drug accumulation, making it
an excellent target for epigenetic treatment.
Specifically, anti-methylation drugs might be
useful in sensitizing multidrug resistant cancer
cells to other types of drugs.
• Example :treated with nontoxic doses of the
demethylating agent 2-deoxy-5-azacytidine
(DAC).

59. Multidrug resistance:
• This resistance is due to adenosine
triphosphate– dependent pumping of drugs
out of the cell in the presence of P-
glycoprotein.
• . For example, cells that are resistant to the
cytotoxic effects of the Vinca alkaloids are also
resistant to dactinomycin and to the
anthracycline antibiotics, as well as to
colchicine, and vice versa.

60. • These drugs are all naturally occurring
substances, each of which has a hydrophobic
aromatic ring and a positive charge at neutral
pH.
• Certain drugs at high concentrations (for
example, verapamil) can inhibit the pump and,
thus, interfere with the efflux of the
anticancer agent. However, these drugs are
undesirable because of adverse
pharmacologic actions of their own.

62. Drug resistance testing:
• Not all patients are necessarily resistant to
CTX. Some tumors may be highly resistant to
most cytotoxic drugs, while others may be
quite sensitive. Therefore, it would be useful
to have some tests, which could predict
resistance and subsequent clinical failure.
• This would spare patients from the trauma of
ineffective CTX.

63. • A company called IMPATH (Los Angeles, Calif.,
USA) has developed a cell culture drug resistance
assay, which they claim can help in the selection
of chemotherapeutic agents that have the
greatest likelihood of being clinically effective.
• Their method essentially measures 3H-thymidine
uptake into cultured tumour cells, taken from
fresh biopsy specimens, in the presence of
various drugs; an algorithm applied to the data is
used to determine the probability that a patient
will respond to the various therapies tested in the
assay

64. • Kern and Weisenthal reported that this assay
used in clinical trials was highly accurate in
demonstrating that cells extremely resistant in
vitro were also resistant in vivo. The
usefulness of such in vitro testing however
remains a controversial matter.