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1. Dr. Indranil Banerjee
MBBS (Hons), MD, DM(Clinical Pharmacology)
Department of Pharmacology
Lady Hardinge Medical College

2. Introduction
Cancer chemotherapy is treatment that
involves the use of drugs to destroy cancer
cells. Other modalities of cancer treatment
include surgery and radiation.

3. Goal of Cancer Chemotherapy
 Cure:
 Control: If cure is not possible, the goal may be to control
the disease — to shrink any cancerous tumors and/or stop
the cancer from growing and spreading
 Palliation: When the cancer is at an advanced stage,
chemotherapy drugs may be used to relieve symptoms
caused by the cancer.

4. Looking back…..
1940-50 – successful use alkylating agent nitrogen
mustard to treat human cancer
1950-1960 – major alkylating agents and anti-
metabolites currently in use synthesized.
Effective against wide range of cancer types,
particularly rapidly growing leukemias and
lymphomas. Scientific principles of cancer
chemotherapy developed.

5. Looking back…..
1970’s -
Considered "Golden Age” of medical oncology.
Development of effective combination chemotherapy
regimens.
New classes of drug developed - anthracyclines, platinum
compounds
Cure achieved in some forms of cancer (lymphomas,
leukemias, testicular cancer).
Significant responses in some common types of cancer
(breast, stomach, small cell lung cancer)
Effective use of chemotherapy to prevent recurrence in
high risk breast cancer patients

6. Stages of the cell cycle
The cell cycle is composed of four phases during which
the cell prepares for and effects mitosis. Cells that are
committed to divide again enter the G1 phase. Preliminary
synthetic cellular processes occur that prepare the cell to
enter the DNA synthetic (S) phase. Specific protein
signals regulate the cell cycle and allow replication of the
genome where the DNA content becomes tetraploid (4N).
After completion of the S phase, the cell enters a second
resting phase, G2, prior to undergoing mitosis. The cell
progresses to the mitotic (M) phase, in which the
chromosomes condense and separate and the cell divides,
producing two daughter cells.

7. Modes of Chemotherapy
 Primary Chemotherapy - chemotherapy is used as the sole
anti-cancer treatment in a highly sensitive tumor types
 Example – CHOP for Non-Hodgkins lymphoma
 Adjuvant Chemotherapy – treatment is given after surgery
to “mop up” microscopic residual disease
 Example – Adriamycin, cyclophosphamide for breast cancer
 Neoadjuvant chemotherapy – treatment is give before
surgery to shrink tumor and increase chance of successful
resection
 Example – Adriamycin, ifosfamide for osteosarcoma
 Concurrent chemotherapy – treatment is given
simultaneous to radiation to increase sensitivity of cancer
cells to radiation
 Example – Cisplatin, 5-fluourouracil, XRT for head and neck
tumors

8. Stages of the cell cycle

9. MOA of drugs in relation to cell
cycle
 Cell cycle phase nonspecific agents have a
linear dose response curve. Fraction of cells
killed increases with drug dose.
 Cell cycle phase specific drugs have a plateau
beyond which increased dose does not increase
cell kill.

10. Cell-cycle-phase–specific drugs
Phase of
cell cycle
Drugs
S-phase
dependent
Capecitabine, Cytarabine, Doxorubicin, Fludarabine, Floxuridine,
Fluorouracil, Gemcitabine , Hydroxyurea, Mercaptopurine,
Methotrexate
M phase–
dependent
Vinca alkaloids, Vinblastine, Vincristine, Vinorelbine,
Podophyllotoxins
Etoposide,Teniposide, Taxanes, Docetaxel, Paclitaxel
G2 phase–
dependent
Bleomycin, Irinotecan, Mitoxantrone, Topotecan
G1 phase–
dependent
Asparaginase
Corticosteroids

11. Tumor kinetics
The rate of growth of a tumor is a reflection of the
proportion of actively dividing cells (the growth fraction),
the length of the cell cycle (doubling time), and the rate of
cell loss.
Tumors characteristically exhibit a sigmoid-shaped
Gompertzian growth curve, in which tumor doubling time
varies with tumor size. Tumors grow most rapidly at small
tumor volumes. As tumors become larger, growth slows
based on a complex process dependent on cell loss and
tumor blood and oxygen supply.

12. Gompertzian kinetics

13. Variation in sensitivity of various
cancers to chemotherapy:
High Intermediate Low
Lymphoma Breast Head and neck
Leukemia Colon Prostate
Small Cell Lung cancer Non-small cell lung
cancer
Gastric
Testicular cancer Pancreatic

14. Role of Drug Combinations
Aims:
1. Maximal cell kill
 2. Wider range of interaction between drugs and tumor
cells
 3. It may prevent or subsequently slow the development of
drug resistance.
Criteria:
 1.Each drug should be active when used against the
particular cancer.
 2.The drugs should have different mechanism of action.
 3. Cross-resistance between drugs should be minimal.
 4.Should have different toxicity profile

15. Cytotoxic agents
Alkylating agents
 As a class, the alkylating agents exert their cytotoxic
effects via transfer of their alkyl groups to various
cellular constituents. Alkylations of DNA within the
nucleus probably accounts for the cell death. The
major site of alkylation within DNA is the N7 position
of guanine.
 Examples: Cyclophosphamide, Chlorambucil,
Mephalan

16. Cyclophosphamide
 Cyclophosphamide It is inactive as such: produces few
acute effects and is not locally damaging. Transformation
into active metabolites. (aldophosphamide,
phosphoramide mustard) occurs in the liver, and a wide
range of antitumour actions is exerted. It has prominent
immunosuppressant property. Thus, it is one of the most
popular alkylating agents useful in many solid tumours.
It is less damaging to platelets, but alopecia and cystitis
(due to another metabolite acrolein) are prominent.
Chloramphenicol retards the metabolism of
cyclophosphamide.

17. Cyclophosphamide
 It has prominent immunosuppressant property. Thus,
it is one of the most popular alkylating agents useful in
many solid tumours. It is less damaging to platelets,
but alopecia and cystitis (due to another metabolite
acrolein) are prominent. Chloramphenicol retards the
metabolism of cyclophosphamide.

18. Ifosfamide
 This congener of cyclophosphamide has a longer and
dose-dependent t½. It has found utility in bronchogenic,
breast, testicular, bladder, head and neck carcinomas,
osteogenic sarcoma and some lymphomas. The dose
limiting toxicity of ifosphamide is haemorrhagic cystitis.
To prevent the same, mesna is routinely given with it.
Mesna is a –SH compound that is excreted in urine—binds
and inactivates the vasicotoxic metabolites of ifosfamide
and cyclophosphamide. Ifosfamide causes less alopecia
and is less emetogenic than cyclophosphamide.

19. MESNA in haemorrhagic cystitis
 Hepatic microsomal cells cause the breakdown of
cyclophosphamide to hydroxycyclophosphamide which is then
converted to aldophosphamide …phosphoramide mustard, the
active antineoplastic metabolite, and acrolein, which has no
significant antitumor activity but is toxic to the urothelium.
Similarly, ifosfamide is metabolized to iphosphamide mustard
and acrolein.
 The bladder being a reservoir for urine is most vulnerable due
to the prolonged exposure of its urothelium to acrolein.
Acrolein causes release of inflammatory mediators such as
tumor necrosis factor-alpha, interleukin-1 beta and
endogenous nitric oxide causing bladder mucosal edema,
vascular dilatation and increased capillary fragility resulting in
hemorrhage. This dose dependent toxicity occurs in 2 to 40%
of patients treated with cyclophosphamide. The onset of
hematuria usually occurs within 48 hours of treatment.

20. MESNA in hemorrhagic cystitis
 . The drug sodium 2-mercaptoethane sulfonate (mesna)
has also been used to prevent hemorrhagic cystitis caused
by ifosfamide and less commonly by cyclophosphamide.
Mesna is a sulfhydryl compound that is administered
intravenously and rapidly excreted by the urinary tract
where the sulfhydryl group of mesna complexes with the
terminal methyl group of acrolein forming a nontoxic
thioether. Mesna is best given intravenously and
administered in three doses. A loading dose equivalent to
20% (w/w) of the ifosfamide dose is given 15 minutes
before the drug, followed by two similar doses 4 and 8
hours later. The half-life of mesna is 35 minutes. The side
effects include diarrhea, headaches and limb pain.

21. Cisplatin
 Cisplatin hydrolysed intracellularly to produce a highly
reactive moiety which causes cross linking of DNA. The
favoured site is N7 of guanine residue. It can also react with
–SH groups of cytoplasmic and nuclear proteins.
 Cisplatin is very effective in metastatic testicular and ovarian
carcinoma. It is widely used in many other solid tumours
like lung, bladder, esophageal, gastric, hepatic, head and
neck carcinomas.
 Cisplatin is a highly emetic drug. Antiemetics are routinely
administered before infusing it. The most important toxicity
is renal impairment which is dependent on total dose
administered. Renal toxicity can be reduced by maintaining
good hydration. Tinnitus, deafness, sensory neuropathy and
hyperuricaemia are other problems. A shock like state
sometimes occurs during i.v. infusion.

22. Carboplatin
 Carboplatin It is a less reactive second generation platinum
compound that is better tolerated and has a toxicity profile
different from cisplatin, but mechanism of action and
clinical utility are similar. Nephrotoxicity, ototoxicity and
neurotoxicity are low. Nausea and vomiting is milder and is
delayed: only infrequently limits the dose. The dose-
limiting toxicity is thrombocytopenia and less often
leucopenia. Liver dysfunction may occur.
 It is primarily indicated in ovarian carcinoma of epithelial
origin, and has shown promise in squamous carcinoma of
head and neck, small cell lung cancer, breast cancer and
seminoma.

23. Oxiplatin
 This third generation platinum complex differs
significantly from cisplatin. It appears to target different
biomolecules. Pathways which confer resistance to cisplatin
are not operative in its case. Resistance does not easily
develop to oxaliplatin, and it retains activity against
tumours that have become resistant to cisplatin.
Oxaliplatin is highly effective in colorectal cancer; 5-
fluorouracil markedly synergises with it. Gastroesophageal
and pancreatic cancers also respond.
 The dose limiting toxicity is peripheral neuropathy.
Sensory paresthesias involving arms, legs, mouth and
throat are common. An acute form of neuropathy is usually
triggered by exposure to cold. Myelosuppression is modest,
but diarrhoea and acute allergic reactions are reported.

24. Cytotoxic agents
Antimetabolites
 Act by inhibiting metabolic pathways usually of DNA
synthesis, thus preventing replication & inducing cell
death.
 Examples: Methotrexate, 5-FU, Cytosine arabinoside

25. Cytotoxic agents
Antibiotics
 Example: Adriamycin, Epirubicin, Bleomycin
 Cause linkage of double strands of DNA & prevent
replication

26. Cytotoxic agents
Podophyllotoxins
 Etoposide, Tenoposide
 They are plant derivatives
 They prevent the cell from entering the G1 and S
phase of the cell cycle

27. Cytotoxic agents
Platinum compound
 Cisplatinum, Carboplatin, Oxaliplatin
 They are alkylating agents & they form cross-linking
between DNA strands, thus blocking DNA replication
& transcription.

28. Cytotoxic agents
Plant Alkaloids
 Examples: Vincristine, Vinblastine, Taxanes
(Paclitaxel, Docetaxel)
 They cause mitotic arrest by poisoning the spindles
 Mitotic spindles are vital for cell division

29. Hormones
 Anti-Estrogen: Tamoxifene, Raloxifene
 Aromatase inhibitors: Anatrozole,Letroxole
 Anti-testosterone: Finastride, blocks peripheral
conversion of testosterone to dihydrotestosterone

30. Hormones
 GnRH agonist: Goserelin, produce paradoxical
negative feedback effect followed by inhibition of the
release of FSH & LH when given continuously.
 Steroids: Dexamethaxone, inhibit tumour growth,
reduce inflammation & edema associated with it,
prevent vomiting & cause regression of lymph node
malignancies.

31. Targeted therapy
Targeted therapies
Enzyme inhibitors Farnesyl-transferase Inhibitors: Tipifarnib
in NSCLC
Cyclin Dependent Kinase Inhibitors:
Seliciclib in NSCLC
Alvocidib (Flavopiridol) in AML
Histone deacetylase inhibitor:Vorinostat in
CTCL
Tyrosine kinase inhibitor:Imatinib in CML
Receptor antagonist Retinoid receptor antagonist: Bexarotene
in CTCL
Monoclonal Antibody
Cancer vaccines

32. Monoclonal Antibodies
• Cancer cells express a variety of Antigens
• Target for Monoclonal Antibodies
• Specific Ab’s against specific Ag’s expressed by specific cells
• Mechanism of killing: ADCC, CDC & Direct Induction of
Apoptosis
• Chimerisation/ Humanisation→
↓ immunogenic, ↑ efficient & longer acting

33. Monoclonal Antibodies
• Limitations
 Antigen distribution of malignant cells is highly heterogeneous
 Tumor blood flow is not always optimal
 High interstitial pressure within the tumor

34. mAb Antigen Cancers treated
Rituximab CD20 B Cell Lymphomas
Trastuzumab HER-2 / neu Breast Ca
Gemtuzumab CD33 AML
Alemtuzumab CD52 CLL
Cetuximab EGFR Colorectal, head & neck Ca
Panitumumab EGFR Colorectal Ca
Bevacizumab VEGF Colorectal, breast & NSCL Ca
Ofatumumab CD20 B cell CLL
Monoclonal Antibodies

35. Radioimmuno-Conjugated MonoclonalAbs:
• RICs provide targeted delivery of radioactive particles to tumor cells
Currently Approved:
• Developed with Murine mAbs against CD20 conjugated with 131I –
(131I – tositumomab) & 90Y – (90Y – ibritumomab tiuxetan)
• Both drugs→ Relapsed lymphoma.
• However, reports of secondary leukemias.

37. Monoclonal Ab- Cytotoxic Conjugate
• Enhances its cytotoxicity & drug delivery
Currently used
Gemtuzumab ozogamicin:
mAb against CD33, linked to a semi-synthetic derivative of
Calicheamicin, an enediyne antitumor antibiotic.
Newer Agents
Trastuzumab-maytansinoid
• Trastuzumab linked to DM1
• Trastuzumab → Ab against Her2 receptors
• DM1→ microtubule-depolymerizing agent
• Patients with Her2-positive metastatic breast cancer

38. Cancer Vaccines
• Cancer vaccine contain cancer cells, parts of cells or pure antigens
• ↑ immune response against cancer cells
Autologous
• Made from killed tumor cells taken from the same person
• Whom they will later be used
• Limitations:
Expensive to create a new, unique vaccine for each patient.
Cells tend to mutate over time
Allogeneic
• Use cells from a stock of cancer cells
• Mixture of cells removed from several patients

39. I. Antigen vaccines
• Specific for specific cancer
• Boost immune system by using one antigen (or a few)
• Antigens are usually
 proteins or
pieces of proteins called peptides
• Eg: CDK-4 & β-catenin→ Melanoma
• Prostate cancer vaccine, Sipuleucel-T (Provenge®)
Recently been approved → Advanced prostate cancer
II. Dendritic cell vaccines
• Dendritic cells→ special antigen-presenting cells
• Break down cancer cells & present to T cells
• Exposed to cancer cells or cancer antigens
• Develop cancer antigens on their surface
• Help immune system recognize and destroy cancer cells
that have those antigens on them

40. III.DNA vaccines
• Cells can be injected with bits of DNA
• Code for Cancer cell protein antigens
• Done by DNA vectors→ plasmids
• Integrated into cells
• Altered cells would then make the antigen on an ongoing basis
• Keep the immune response strong

41. IV.Telomerase vaccine:
• Loss of telomeric repeats with each cell division cycle→
gradual telomere shortening→ growth arrest
Replicative senescence
• Telomerase→ Reverse transciptase → elongates telomeres
• >90% human cancers express high levels of telomerase
• In vitro studies, inhibition of this telomerase→
leads to tumor cell apoptosis
• Phase I clinical studies

42. Pre-Chemotherapy Assessment
 Physical Examination
 Performance status
Popular instrument used in oncology include
Karnofsky performance index :
Normal – 100%
Death – 0%
Eastern Cooperative Oncology Group (ECOG) :
0 – Asymptomatic
5 - Death

43. Karnofsky performance index
Able to carry on normal activity
and to work; no special care
needed.
100
Normal no complaints; no evidence of
disease.
90
Able to carry on normal activity; minor
signs or symptoms of disease.
80
Normal activity with effort; some signs
or symptoms of disease.
Unable to work; able to live at
home and care for most personal
needs; varying amount of
assistance needed.
70
Cares for self; unable to carry on normal
activity or to do active work.
60
Requires occasional assistance, but is
able to care for most of his personal
needs.
50
Requires considerable assistance and
frequent medical care.
Unable to care for self; requires
equivalent of institutional or
hospital care; disease may be
progressing rapidly.
40
Disabled; requires special care and
assistance.
30
Severely disabled; hospital admission is
indicated although death not imminent.
20
Very sick; hospital admission necessary;
active supportive treatment necessary.
10
Moribund; fatal processes progressing
rapidly.
0 Dead

44. ECOG Performance Status
ECOG PERFORMANCE STATUS*
Grade ECOG
0 Fully active, able to carry on all pre-disease performance without
restriction
1 Restricted in physically strenuous activity but ambulatory and able
to carry out work of a light or sedentary nature, e.g., light house
work, office work
2 Ambulatory and capable of all selfcare but unable to carry out any
work activities. Up and about more than 50% of waking hours
3 Capable of only limited selfcare, confined to bed or chair more than
50% of waking hours
4 Completely disabled. Cannot carry on any selfcare. Totally confined
to bed or chair
5 Dead

45. Pre-Chemotherapy Assessment
Investigations
 Hematologic – CBC, ESR, BM biopsy
 Biochemical – LFT, RFT
 Imaging – CXR, USS, Bone scan, CT, MRI
 Tumour markers – gene products expressed in some
cancers & may be used as diagnostic & monitoring
tools. E.g. a-feto protein, PSA

46. Pre-Chemotherapy Assessment
 Counseling
- Nature & stage
- Rx options
- Side effect
 Optimization
- Fluid & Electrolytes
- Blood if anaemic
- Antibiotics when indicated

47. Planning drug dosage and schedule
 Dose determination
- based on body surface area
- differ between children and adults
- adjusted for people who are elderly, have poor
nutritional status, have already taken or taking
other medications, have already received or are
currently receiving radiation therapy, have low blood
cell counts, or have liver or kidney diseases

48. Planning drug dosage and
schedule
 Schedule (Cycles)
- A cycle = one dose followed by several days or weeks
without treatment for normal tissues to recover from
the drug’s side effects
The number of cycles = based on the type and stage of
cancer, and side effects

49. Planning drug dosage and
schedule
 Recovery of bone marrow
 Supplies mature cells for 8-10 days
 Onset 9-10th days
 Lowest (nadir) 14-18th days
 Recovery by day 21-28.
 Usual schedule is 21-28 days.

50. Planning drug dosage and schedule
It is very important to determine the appropriate dose of
anticancer agents. Individuals have varying abilities to
metabolize and eliminate drugs, and therefore the same
dose of anticancer agents will have different
pharmacokinetics (PK) and pharmacodynamics (PD). In
addition, there is a presumed narrow therapeutic index for
most anticancer agents. Reducing the dose of these agents
not only reduces toxicity but also the effects on the tumor.
In cancer chemotherapy, the doses of chemotherapeutic
agents are generally calculated using the body surface area
(BSA).

51. Formula for BSA CalculationName of the scientist Year Formula
DuBois and DuBois 1916 BSA = 0.007184 × H0.725 × W0.425
Boyd 1935 BSA = 0.017827 × H0.5 × W0.4838
Gehan and George 1970 BSA = 0.0235 × H0.42246 × W0.51456
Mosteller 1987 BSA = √H × W/3600
Fujimoto 1968 0.008883 × H0.663 × W0.444
Haycock et al 1978 BSA = 0.02465 × H0.39646 × W0.5378

52. Chemotherapy – routes of
administration
 oral
 intravenous
 intramuscular
 intrathecal
 intraperitoneal
 intrapleural
►isolated organ perfusion
 Newer drug delivery
systems

53. Administration of Chemotherapy-
newer drug delivery systems
Enhance delivery of anticancer drug to tumour tissue
 Minimize its distribution & toxicity in healthy tissue
 Effective chemotherapy requires directed action of
drug
 Undirected distribution→ ↓ therapeutic
effectiveness
 ↑ S/E & toxicities

54. Administration of Chemotherapy-newer drug
delivery systems
 Solubilisers
Majority anticancer drugs→ poor solubility
Newer agents→ Sorporol 230, Sorporol 120 Ex,
Aceporol 345-T,
 Self-Emulsifying Drug Delivery Formulations
(SEDDS)
Enhance oral absorption of poorly soluble drugs
 Implantable Carmustine wafer
Biodegradable polymer
Dissolves over several weeks
Releases drug directly to the area of resection
avoiding systemic toxicity
Used in Newly diagnosed high grade malignant
glioma
and Recurrent Glioblastoma multiforme

55. Administration of Chemotherapy-
newer drug delivery systems
 Polymer Drug
Conjugates
Polymer backbone linked
with drug & targeting
ligand Improved
pharmacokinetic profile→
improved organ specific &
tumor specific delivery
Leak through disorganized
vasculature→
accumulates in tumor
Eg: Daunorubicin,
Doxorubicin

56. Administration of Chemotherapy-
newer drug delivery systems
PEGylation
Covalent attachment of polyethylene glycol
polymer chains ↓ immunogenicity, ↑ circulating
half life & ↑ tumor targeting.
Eg: Pegasparginase (PEGylated L- Aspargine;
Oncaspar)
 Liposomes
Spherical vesicle
Phospholipid & cholesterol bilayer
Envelope for active drug particles
Protects drug, ↓ S/E, ↑ duration of action
Drug released intracellularly
A/E: localised in RES→
↓ targetted delivery & RES impairment
Eg: Paclitaxel, teniposide, adriamycin

57. Administration of Chemotherapy-
newer drug delivery systems
 Nanotechnology
Highly targeted therapy with high efficacy & low
toxicity.
Transport of drug across BBB.
 Deliver anticancer drugs into cells without triggering
p- glycoprotein pump
e.g Paclitaxel, Doxorubicin, Dexamethasone 5- FU

58. Administration of Chemotherapy-
newer drug delivery systems
 Carbon nanotubes
Well ordered, hollow
nanotubes ;
Single or multiple
graphene sheets rolled
into a cylinder Single &
multiwalled carbon
nanotubes Consist of
fluorescent marker and a
monoclonal antibody at
non-binding sites
Penetrate cell membranes.
Delivery anticancer drug
 Eg: doxorubicin

59. Criteria used to describe tumor response
Objective tumor response is a common endpoint in
daily practice as well as in clinical trials to evaluate the
efficacy of anti-cancer agents.
Traditionally, the standard World Health Organization
(WHO) criteria has been adopted in these contexts.
However, the recent development of new classes of anti-
cancer agents and progress in imaging technology have
required new methodology to evaluate response to
treatment. Recently, the Response Evaluation Criteria in
Solid Tumors Group (RECIST) proposed new guidelines
using unidimensional measurement.

60. Criteria used to describe tumor response
WHO RECIST
Measurable, bidimensional Measurable, unidimensional:
Conventional method ≥20 mm;
Spiral CT ≥10 mm; Target
versus non-target lesion
Objective response
Complete response (CR) Disappearance of all known
lesion(s); confirmed at 4 weeks
Disappearance of all known
lesion(s); confirmed at 4 weeks
Partial response (PR) At least 50% decrease;
confirmed at 4 weeks
At least 30% decrease;
confirmed at 4 weeks
Stable disease (SD) Neither PR nor PD criteria met Neither PR nor PD criteria met
Progressive disease (PD) 25% increase; no CR, PR or SD
documented before increased
disease, or new lesion(s)
20% increase; no CR, PR, or SD
documented before increased
disease, or new lesion(s)

61. Resistance to Chemotherapy

62. Resistance to Chemotherapy
 One type of resistance is ‘kinetic resistance’. This term
refers to the reduction in the effectiveness of the drug
which is caused by the cell division cycle. Such resistance
is generally only temporary. Many drugs (such as
methotrexate, vincristine, and citosine arabinoside, to
name a few) are mainly effective during only one specificc
phase of the cell cycle, e.g., during the S phase, when the
DNA is synthesized. Thus, in the case of a short exposure
to the drug, the cell will not be affected if during that time
it is in a different phase. Even more importantly, the cell
will be substantially invulnerable if it is out of the cell
division cycle, i.e., in a resting state" or in the G0 state.

63. Goldie-Coldman Model and Chemotherapy Resistance
 Spontaneous mutations arise in a tumor at some
predictable frequency (i.e. 1:106)
 The likelihood that a drug resistant mutant will arise
in 105 cells is low, in 107 cells is high
 By combining several agents, the statistical chance
that a single cell will develop resistance to each agent
becomes exceedingly low

64. Overcoming Drug Resistance
 Some cellular mechanisms of multidrug resistance (P-
glycoprotein-mediated drug efflux, glutathione
conjugation) can be reversed pharmacologically
 Able to enhance anticancer effects in model systems
 Results in clinical trials disappointing
- probably because of multifactorial nature of drug
resistance

65. Overcoming Drug Resistance
 First multidrug resistance mechanism to be
characterized (Vic Ling, OCI, )
 P-glycoprotein is transmembrane ATP-dependent
efflux pump Actively transports many types of
chemotherapy from cells (anthracyclines, vinca
alkaloids, taxanes)
 Overexpression in cancers causes drug resistance
 P-glycoprotein inhibitors tested in clinical trials

66. Chemotherapy ADR
 Hematologic-
anemia, neutropenia,
thrombocytopenia,
immunosuppression
 Skin/Mucosa-
scaling, mucositis, alopecia
 Cardiac-
decreased myocardial
contractility, arrhythmias
 Renal/GU-
acute tubular necrosis,
chronic renal insufficiency,
hemorrhagic cystitis,
sterility
 Neurologic-
hearing loss, peripheral
neuropathy
 GI-
Nausea/vomiting, diarrhea

67. Chemotherapy in Palliative Care
 Treatment Options for Cancer Pain
i) Surgical intervention: For abscess, pathological fracture, intestinal
obstruction etc.
ii) Radiation therapy: a) External beam radiotherapy: for painful
metastases; superior venacava & spinal cord compression b)
Brachytherapy: Strontium-89 for painful bony metastases in carcinoma
prostate, breast etc.
iii)Pharmacological agents:
(a) Analgesics like NSAIDS, opiates etc. alone or combined.
(b) Bisphosphonates: Pamidronate, clodronate etc to decrease
osteoclastic bone destruction to relieve bony pain of breast cancer and
multiple myeloma.
iv) Anesthesiologic techniques: Sympathetic blocks and neurolytic
agents like ethyl alcohol, phenol etc.
v) Neurosurgical procedures: Neuronal decompression.
vi) Palliative chemotherapy for the underlying aetiology of the pain,
depending upon patient’s tolerability

68. Thank you