A view about anti-cancer drugs

1. 1

2. 2
Dr. Manisha Saxena
PG 1st year
OMR

3. Contents
•Introduction
•Principles of chemotherapy
•Aims of chemotherapy
•Modalities
•Toxicity
•Classification
3

4. • Cancer
– Uncontrolled multiplication and spread within the
body of abnormal forms of body's own cells
• Neoplasm
– A mass of tissue formed as a result of
• Abnormal
• Excessive
• Uncoordinated
• Autonomous and
• purposeless
Proliferation of cells
4

5. Cancer cells differ from normal cells by
5
• Uncontrolled proliferation
• De-differentiation & loss of function
• Invasiveness
• Metastasis

6. Anticancer Drugs
The anticancer drugs either kill cancer cells or
modify their growth.
Cancer treatment include-
Chemotherapy
Radiotherapy
Immunotherapy
Surgery
6

7. Principles of Chemotherapy
1. The cell kill hypothesis of Skipper
• Survival of animal is inversely related to tumor
burden.
• Tumors are best treated when they are small in
volume.
• Treatment must continue until last cell is eradicated.
• If treatment is discontinued as soon as tumor is no
longer clinically detectable, at least 109 tumor cells
will remain unkilled and relapse is inevitable.
7

8. Principles of chemotherapy
2. Norton Simon Hypothesis
The Norton–Simon hypothesis states that the rate of cancer
cell death in response to treatment is directly proportional
to the tumour growth rate at the time of treatment.
•The rate of regrowth increases as the tumor shrinks with
therapy.
•The level of treatment adequate to initiate a regression
may be insufficient to maintain the regression n cure.
•MDR, radiotherapy and bone marrow transplantation may
be used to intensify the treatment.
8

9. The drug effect is not just the pharmacokinetic
concentration multiplied by time and anticancer effect
is not always linear.
The chance of eradicating the tumour is maximized by
delivering the most effective dose level of drug over as
short a time as possible e. Thereby, tumours given less
time to grow between treatments are more likely to be
eradicated.
Administering high quantities of the drug at the
beginning of the chemotherapy cycle (i.e. front-loading)
is difficult-
1. Levels higher than a certain concentration may not increase
the killing of cancer cells.
2. The toxicity could be intolerable.
9
The Norton–Simon hypothesis: designing more effective and less toxic
chemotherapeutic regimens Richard Simon* and Larry Norton

10. Maximum
dose
Short
interval
Reasonable
quality of life
10

11. Aim of Cancer Therapy
11
Cure
Palliation
Adjuvant CT

12. Cancer chemotherapy not as successful as
antimicrobial chemotherapy
12
• Metabolism in parasite differs qualitatively
from host cells, while metabolism in cancer
cells differ only quantitatively from normal host
cells
Target selectivity is more difficult in cancer
No substantial immune response
Diagnostic complexity: delay
institution of treatment

13. Modalities of treatment in cancer
13
• Surgery
• Radiotherapy
• Chemotherapy: 50 % of the patients can be
treated with chemotherapy contributing to
cure in 15 -20 % of patients
1/3 of patients can be cured, effective
when tumor has not metastasized

14. Pathogenesis of cancer
14
Chemicals, viruses, irradiation, etc
Acquired Mutations
Protooncogenes  oncogenes ↓ expression of tumor
supressor genes (P53, Rb etc)
Promoters,
co-carcinogen,
hormones
Uncontrolled cell
proliferation,
dedifferentiation
↓ apoptosis, alterations
in telomerase
Inherited Mutations
Development of primary tumor

15. Pathogenesis of cancer
15
Development of primary tumor
Production of metalloproteinases
Invasion of nearby tissue by tumor cells
Angiogenesis
Metastasis
Development of secondary tumors

16. Effects of various T/t on cancer cell burden
16

17. Early diagnosis and early T/t why?
17
• Survival time inversely related to initial
number of cells
• Aging cancer cells are less susceptible to
chemotherapy, because there is
– ↑ cell cycle (division) time
– ↓No of actively dividing cells with more resting
cells
– ↑ cell death within tumor
– Overcrowding of cells

18. Combination chemotherapy?
18
• Heterogenicity of cells remaining in different
phase of growth cycle , showing different level
of sensitivity
– Nature of drug (with different biochemical site of
action)
– Avoid emergence of drug resistance
• Monotherapy adequate in Burkitts lymphoma
& choriocarcinoma

19. Why intermittent regimen?
19
• Favours risk –benefit ratio
• Allows time for damaged normal host cells to
recover
• Pulse therapy
– Type of intermittent chemotherapeutic regime
employing highest tolerated dose within a short
administration period
– Based on principle of drug conc. (C) x duration of
exposure (T) = constant

20. Adjuvant & Neoadjuvant chemotherapy
20
Adjuvant chemotherapy:
Neo-adjuvant chemotherapy
CT given after
surgery/radiation to
destroy micro
metastasis
CT given before
surgery to diminish
volume

21. • Nausea & Vomiting
• Bone marrow depression
• Alopecia
• Gonads: Oligospermia, impotence, ↓ ovulation
• Foetus: Abortion, foetal death, teratogenicity
• Carcinogenicity
• Hyperuricemia
• Immunosuppressant
• Hazards to staff
General toxicity of cytotoxic drugs
21

22. Phases of cell cycle
22

23. CLASSIFICATION - I:
23
CELL CYCLE NON SPECIFIC :
Kills resting cells & dividing
cells
• Cyclophosphamide
• Chlorambucil
• Cisplatin
• Actinomycin-D
• L-asparaginase
CELL CYCLE SPECIFIC
Kills actively dividing cells
• G1 – Vinblastine
• S – Methotrexate
6-Mercaptopurine
5-Fluorouracil
• G2 –Bleomycin
Etoposide, Topotecan
Daunorubicin
• M – Vincristine
Vinblastine
Paclitaxel,Docetaxel

24. CLASSIFICATION - II:
Depending on mechanism at cell level
24
• Directly acting cytotoxicdrugs:
1.Alkylating agents
2.Antimetabolites
3.Antibiotics
4. Vinca alkaloids
5. Taxanes
6. Epipodophyllotoxins
7. Campothecins analogs
8. Enzymes
9. Biological response modifier
10. Miscellaneous:
Cisplatin, carboplatin
• Indirectly acting- by
altering the hormonal
milieu :
1. Corticosteroids
2. Estrogens & ERMs
3.5 alpha reductase
inhibitors
4.Gnrh agonists
– Progestins

25. Classification of Anti cancer drugs
25
Anticancer drugs
Taxanes
Antimetabolite
Alkylating agents Vinca alkaloids
Antibiotics
Hormones
antagonist
Campothecins
Epipodophyllotoxins
Miscellaneous
agents
Enzymes

26. 26

27. 27
Anticancer drugs
Campothecins
Topotecans, irinotecan
Vinca alkaloids
Vinblastine, Vincristine
Taxanes
Paclitaxel,Docetaxel
Antibiotic
Actinomycin, Bleomycin
Doxorubicin, Daunorubicin
Mitocyin D
Enzymes
L- asparaginase
Epipodophyllotoxins
• Etopside, tenopside
Miscellaneous agents
Hydroxyurea, imatinib

28. 28
Hormones and antagonist
• Corticosteroids
– Prednisolone
• Estrogens
– Ethinyl Estradiol
• SERM
– Tamoxifen, Toremifene
• SERD
– Fulvestrant
• Aromatase Inhibitors
– Letrozole, Anastrazole,
Exemestane
• Progestins
– Hydroxyprogesterone
• Anti-androgens
– Flutamide,
Bicalutamide
• 5-alpha reductase
inhibitor
– finasteride
dutasteride
• GnRH analogs
– Naferelin, goserelin

29. Alkylating agents
29
• Nitrogen Mustards (MCI)
– Meclorethamine, Melphalan, Chlorambucil,
Cyclophosphamide, Ifosfamide
• Ethyleneimine : Thiotepa
• Alkyl Sulfonate: Busulfan
• Nitrosureas
– Carmustine,lomustine, streptozocin
• Triazines
– Dacarbazine, temozolamide

30. Mechanism of action
30
Alkylating Agents
Form highly reactive carbonium ion
Transfer alkyl groups to nucleophilic sites on DNA bases
Results in
DNA strand breakage
↓ cell proliferation
Cross linkage Abnormal base pairing
Alkylation also damages RNA
and proteins

31. 1. Cytotoxic action
Depression of bone marrow
• Chlorambucil – more against lymphoid series
• Busulfan – more against myeloid series
2. Skin – dermatitis and alopecia.
3. Gonads –Oligozoospermia and impotence.
4.Fetus – Teratogenic
5. GIT – Nausea and vomiting
6. Hyperuricemia
• Known as radiomimetic drugs(Ionizing rad.)
Pharmacological actions
31

32. • Mechlorethamine
• Melphalan
• Chlorambucil
• Cyclophosphamide
• Ifosfamide
Nitrogen Mustards
32

33. • Very irritant drug
• Given by i.v route only
• Dose = 0.4 mg/kg single or divided
• Uses
– Hematological cancers , lymphomas , solid tumors
– Hodgkin as part of MOPP, CML, CLL
• Adverse effects
– Anorexia, nausea, vomiting
– Bone marrow depression, aplasia
– Menstrual irregularities
• Estramustine
Mechlorethamine (Mustine)
33

34. Melphalan
34
• Very effective in MULTIPLE MYELOMA
• Less irritant locally , less alopecia
• Dose:
10 mg daily for 7 days/6mg per day 2-3
weeks gap of 4 weeks then 2-4mg daily as
maintenance dose.
• Adverse Effects :
– Bone marrow Depression
– Infections , diarrhoea and pancreatitis

35. • Most commonly used Alkylating agent a prodrug
Cyclophosphamide
35

36. Cyclophosphamide
36
Cyclophosphamide
Aldophosphamide
Phosphoramide
mustard
Acrolein
Cytotoxic effect
Hemorrhagic cystitis
Mesna

37. Uses of cyclophosphamide
37
• Neoplastic conditions
– Hodgkins and non hodgkins lymphoma
– ALL, CLL, Multiple myeloma
– Burkits lymphoma
– Neuroblastoma , retinoblastoma
– Ca breast , adenocarcinoma of ovaries
• Non neoplastic conditions
– Control of graft versus host reaction
– Rheumatoid arthritis
– Nephrotic syndrome

38. • Adverse effects:
– Hemorrhagic cystitis,
– alopecia,
– nausea & vomiting,
– SIADH
– hepatic damage
• Dose: 2-3 mg/kg/day oral
10-15 mg/kg IV every 7-10 days
• It can be administered IV, IM, IP,intrapleurally,
Intraarterialy, directly into tumor
Cyclophosphamide
38

39. Ifosfamide
39
• Congener of cyclophosphamide
• Longer half life than cyclophosphamide
• Less alopecia and less emetogenic than
cyclophosphamide.
• Can cause hemorrhagic cystitis and severe
neurological toxicity.
• Used for germ cell testicular tumors and adult
sarcomas.

40. Chlorambucil (Leukeran)
40
• Slowest acting and least toxic Alkylating agent.
• Main action on lymphoid series produces
marked lympholytic action.
• Drug of choice for long term maintenance
therapy of CLL
• Dose: 0.1-0.2 mg/kg daily for 3-6 weeks then 2
mg daily for maintenance

41. ThioTEPA
41
• Triethylene phosphor amide
• Does not require to form active
intermediate.
• Active intravesicular agent can also be used
topicaly in superficial bladder cancer.
• Not well absorbed orally given IV.
• High toxicity, seldom used now
• 0.3 -0 .4mg/kg i.v at 1-4 weeks interval

42. Busulfan (Myleran)
42
• Depresses bone marrow with selective action
on myeloid series.
• Primarily used in Chronic myelogenous
leukemia 2-6 mg/day orally.
• Adverse effect:
– Interstitial pulmonary fibrosis (specific).
– Venoocclusive disease of liver.
– Hyperuricemia.
– Sterility.

43. Nitrosureas
43
• Highly lipid soluble, Cross BBB
• Uses:
– Meningeal / Brain tumours
• Dose :150-200 mg/m2 BSA
i.v over 1 hr every 6 wks
(Carmustine)
• Adverse Effects:
Delayed bone marrow dep.
Visceral fibrosis, renal
damage

44. Triazenes
44
• Dacarbazine
– Primary inhibitory action on RNA
& protein synthesis
– Used in malignant melanoma
– 3.5mg/kg/day iv for 10 days.
• Temozolamide
– New Alkylating agent
– Approved for malignant glioma
– Rapidly absorbed after oral
absorption & crosses BBB

45. Mechanisms of resistance of Alkylating
agents
45
• ↓ Influx of drug
• ↑ Production of nucleophilic substances like
glutathione that compete with target DNA for
alkylation
• ↑ Activity of DNA repair enzymes
• ↑ metabolic inactivation of drugs

46. Cisplatin
46
• Only active Cytotoxic
agent in cis form.
• Administered IV
• Highly bound to plasma
proteins
• Gets conc in kidney,
intestine, testes
• Poorly penetrates BBB
• Slowly excreted in urine
Pt
NH3
Cl
Cl NH3
Dose:
50-100 mg/m2 for 3-4
weeks.
75 – 100 mg/m2 once in
4 weeks to treat ovarian
cancer

47. Mechanism of action of cisplatin
47
Cisplatin enters cells
Cl-
Forms highly reactive platinum complexes
Intra strand & interstrand cross links
DNA damage
Inhibits cell proliferation

48. Cisplatin uses and adverse effects
48
• Uses
– Testicular cancer (85% - 95 % curative )
– Ovarian cancer
– Other solid tumors: lung, esophagus, gastric
• Adverse effects
– Emesis
– Nephrotoxicity
– Peripheral neuropathy
– Ototoxicity

49. Carboplatin
49
• Better tolerated, iv 400mg/m2 over 15-20min.
• Low nephrotoxicity , ototoxicity , neurotoxicity
• Less emetogenic.
• Dose limiting toxicity thrombocytopenia.
less often leukopenia may occur.
• Less plasma protein binding
• Use:
– primarily in ovarian cancer of epithelial origin
– Squamous cell carcinoma of head and neck

50. Antimetabolites
50
Antimetabolite are analogue of components
of DNA or coenzymes of nucleic acid
synthesis.
• Folate Antagonists
– Methotrexate
• Purine Antagonists
– 6 Mercaptopurine, 6 Thioguanine, Azathioprine
• Pyrimidine antagonists
– 5 Fluorouracil, cytarabine, gemcitabine

51. Methotrexate
51
Adenine, guanine,
thymidine ,
methionine, serine
Folic acid not
useful in toxicity
Folinic acid N5
formyl FH4 should be
given which is
converted to N5,N10-
Methylene –FH4 and
bypasses the
inhibited reductase

52. Pharmacological actions
52
• Cytotoxic actions
– Predominant on bone marrow.
– Ulceration of intestinal mucosa.
– Crosses placenta interferes with embroyogenesis
foetal malformations and death.
• Immunosupressive action
– Prevents clonal expansion of B & T lymphocytes.
• Anti-Inflammatory action
– Interferes with release of inflammatory cytokines
IL-2, IL-6,IL-8 & TNF- , ↓ Rheumatoid Factor
production

53. Pharmacokinetics
53
Prolonged clearance results in
toxicity
Very long
terminal
half
Well
absorbed
orally
Low
doses
i.v, rapid
early half
life of 45
min.

54. Adverse effects
54
• Megaloblastic anemia (low dose)
• Thrombocytopenia, leukopenia, aplasia (high dose)
• Oral, intestinal ulcer , diarrhoea
• Alopecia , liver damage, nephropathy
Treatment of methotrexate toxicity
 Folinic acid (citrovorum factor, N5 Formyl THF)
 IM/IV 8 to 24 hrs after initiation of methotrexate
 120 mg in divided doses in first 24 hrs, then 25
mg oral/IM 6 hrly for next 48 hrs

55. Uses of methotrexate
55
• Antineoplastic
– Choriocarcinoma and tropoblast tumor 15
-30 mg/day orally for 5 days
– Remission maintenance of ALL in children 2.5 to 15
mg/day
– Ca breast, head & neck, bladder, ovarian cancer
• Immuno-supressive agent
– Rheumatoid arthritis, resistant asthma
– Crohns disease, wegeners granulomatosis
– Prevention of graft versus host reaction
• Psoriasis
• Medical termination of pregnancy

56. • 6 Mercaptopurine
• 6 Thioguanine
• Azathioprine
• Fludarabine
Purine antagonists
56

57. 6 Mercaptopurine
57
It inhibits conversion of inosine
monophosphate to adenine and guanine
nucleotides.
It causes bone marrow depression.
Dose- 6-MP 2.5mg/kg/day
6-TG 2mg/kg/day.

58. 6 Mercaptopurine
58
6 MP
Xanthine oxidase
Allopurinol
TPMT
6 Thiouric acid
Inactive
metabolite

59. • Use:
– Acute leukemia (ALL)
– Choriocarcinoma
• Adverse Effects:
– Bone marrow depression.
– Hepatic necrosis rarely
– Hyperuricaemia
6 Mercaptopurine
59

60. • Phosphorylates intracellularly to form
triphosphate
• Inhibits DNA polymerase and gets incorporated
to form dysfunctional DNA
• Effective in slow growing tumors: (apoptosis)
• Use:
– CLL and non hodgkins recurring after treatment
• Adverse events:
– chills, fever, opportunistic infection,
myelosupression
Fludarabine
60

61. • Like fludarabine converted to triphosphate
• Incorporated into DNA
• Inhibits DNA polymerase and thus inhibits
DNA synthesis and repair
• Used in treatment of Hairy cell leukemia, CLL
and low grade lymphomas
Cladirabine
61

62. Pentostatin
62
Inhibits adenosine deaminase
Accumulation of adenosine & deoxyadenosine
Inhibits ribonucleotide reductase
Blocks DNA synthesis
S adenosyl homocysteine accumulation
Toxic to lymphocytes Used in
Hairy cell leukemia

63. • 5 fluoruracil
• Cytosine arabinoside (Cytarabine)
• Gemcitabine
Pyrimidine antagonists
63

64. 5 fluorouracil
64
5 FU FdUMP
dUMP
Thymidine
Monophosphate
Thymidilate
synthetase
DNA Synthesis
(Selective failure)
Uses : stomach , colon,
breast ovaries , liver, skin
cancers
FdUMP = fluorodeoxyuridine
monophosphate

65. Cytosine arabinoside
65
• Pyrimidine analog considered drug of choice
in inducing remission in AML
• Phosphorylated in body to triphosphate
• Triphosphate of cytarabine inhibits DNA
polymerase &
• Thus inhibit DNA synthesis and repair
Gemcitabine
• Drug of choice in adenocarcinoma of pancreas

66. • Obtained from periwinkle plant ( Vinca Rosea)
• Vincristine, Vinblastine, vindesine, vinorelbine
Vinca alkaloids
66

67. Mechanism of action
67

68. Comparison between
• Marrow sparing effect
• Alopecia more common
• Dose 1.5mg/m2 iv weekly
• Peripheral & autonomic
neuropathy & muscle
weakness (CNS)
• Constipation
• Uses: (Childhood cancers)
• – ALL , Hodgkins, lymphosarcoma,
• Wilms tumor, Ewings sarcoma
68
Vincristine Vinblastine
• Bone marrow supression
• Less common
• .1-.15mg/kg weekly
mental depresssion
• Nausea, vomiting,
diarrhoea
• uses
– Hodgkins disease & other
lymphomas , breast cancer,
testicular cancer

69. Taxanes
69
• Paclitaxel & docetaxel
• Plant product obtained from bark of Pacific
Yew ( Taxus Brevifolia) & European Yew (Taxus
Buccata)

70. Mechanism of action
70
Cell cycle arrested in G2 and M phase

71. • Paclitaxel
– Administered IV 175mg/m2 over3-24 hrs.
– Use: advanced breast & ovarian cancer also lungs,
esophagus, prostrate cancer
– Adverse effects:
• Anaphylactoid reaction because of solvent cremaphor
• Myalgia, myelosupression, peripheral neuropathy
• Docetaxel
– Oral
– Used in refractory breast & ovarian cancer
– Major toxicity neutropenia may cause
aarrhythmias , hypotension
71

72. Epipodophyllotoxins
72
• Etoposide & tenoposide
• Semisynthetic derivatives of podophyllotoxins
podophyllum peltatum (plant glycoside)

73. Etoposide
73
• Act in S & G2 phase
• Inhibit topoisomerase II which results in
breakage of DNA strands & cell death
• Dose 100 mg in 5 ml injection over 30
min.
• Uses:
– Testicular tumors , squamous cell cancer of lungs

74. • Derived from camptotheca accuminata
• Inhibit Topoisomerase I: No resealing of DNA
after strand has untwisted
• Topotecan:
– Used in metastatic ovarian cancer
– Major toxicity is bone marrow depression
• Irinotecan
– Used in metastatic cancer of colon/rectum
– Toxicity: diarrhoea, neutropenia, thrombocytopenia,
cholinergic side effects
Camptothecin analogs
74

75. • Cell cycle non specific drugs.
• Derived from Streptomyces species.
• MOA:
– Intercalation in the DNA between adjoining
nucleotide pairs – blocks DNA & RNA synthesis
– Generation of oxygen radicals which mediate
single strand scission of DNA
– Action on Topoisomerase II
Anticancer antibiotics
75

76. • Uses:
– Wilms tumor,
– gestational choriocarcinoma
• Adverse effects
– bone marrow supression
– Irritant like meclorethamine
– sensitizes to radiation, and
inflammation at sites of prior
radiation therapy may occur
– Gastrointestinal adverse effects
Dactinomycin
76

77. Doxorubicin & Daunorubucin
77

78. • Doxorubicin:
– Used in acute leukemias, malignant lymphoma
and many solid tumors, direct instillation in
bladder cancer.
– Dose 60-75mg/m2 iv every 3 weeks.
• Daunorubicin:
– Use limited to ALL and granulocytic leukemias.
– Dose 30-60mg/m2 iv daily for 3days.
• Toxicity:
– Both cause cardiotoxicity (cardiomyopathy)
– Marrow Depression, Alopecia 78

79. • Mitoxantrone
– Analog of doxorubicin, Lower cardio toxicity
– Dose 12mg/m2 single iv dose repeat at 3 weeks.
– Uses: Acute leukemia, CML, Non Hodgkin's.
• Mitomycin C
– Highly toxic used only in resistant cancers of
stomach, colon, rectum.
– Dose 10 mg/m2 iv according to blood count.
• Mithramycin
– Reduces blood calcium levels by inhibiting
bone calcium release.
– Used in T/t of hypercalcemia with bone metastasis79

80. Bleomycin
80
Reacts with iron,
copper & O2 in
presence of CYP -450
reductase
Also can intercalate
between DNA strands
DNA – Bleomycin – Fe2+
DNA – Bleomycin – Fe3+

81. • Uses :
– Epidermoid cancers of skin, oral cavity,
genitourinary tract, esophagus
– Testicular tumors
– Hodgkins lymphoma
• Adverse effects:
– Pneumonitis
– Fatal pulmonary fibrosis
– Hyper pigmentation
– spares bone marrow
Bleomycin
81

82. L-asparaginase
82

83. L-asparaginase
83
• Isolated from E.coli
• Use: Acute Lymphocytic Leukemia (ALL)
• Dose :
• 50-200KU/kg IV daily for 3-4 weeks
• A/E:
• Hepatic damage
• Hypersensitivity , hemorrhage
• Hyperglycemia, headache, hallucinations ,
confusion, coma

84. Hydroxyurea
84
• Uses: S phase specific
• CML, Polycythemia,
psoriasis
• Dose:
• 20-30 mg/kg /day
orally for 8 weeks
Ribonucleotides
Ribonucleoside diphosphate
reductase
Deoxyribonucleotides
Hydroxyurea
• Adverse effects
• Myelosuppression
(Minimal)
• Hypersensitivity
• Hyperglycemia
• Hypoalbuminemia

85. Procarbazine
85
• MOA: Depolymerizes DNA & causes
chromosomal damage.
• USES: Hodgkin’s disease ( MOPP regimen)
• Non hodgkins lymphoma
• Dose 100-200mg daily orally for 2 weeks.
• MAO inhibitor action, crosses BBB .
• Alcohol causes hot flushing and disulfiram
like reaction.
• Leucopenia, vomiting, thrombocytopenia.

86. Radio active isotopes
86
• I131 – Emits beta radiation , half life-8.04 days
use:Follicular Ca- Thyroid
• P32 - Emits beta radiation , half life- 14.3 days.
use : Polycythemia vera
• 198Au – gives low energy beta & gamma
radiation, half life- 2.69 days
use :malignant pleural, peritoneal effusion

87. Glucocorticoids
87
• Marked lympholytic effect so used in acute
leukaemias & lymphomas.
• They are also valuable in control of
complication
– Have Anti-inflammatory effect
– Produce sense of well being
– Increase body weight
– Supress hypersensitivity reaction
– Control hypercalcemia & bleeding
– Raised intracranial tension
– Increase antiemetic effect of ondansetron

88. Estrogens
88
• Physiological antagonists of androgens
• Thus used to antagonize the effects of
androgens in androgen dependent prostatic
cancer.
• Fofesterol
– Prodrug , phosphate derivative of stilbesterol
– 600-1200mg IV initially later 120-240 mg orally

89. Selective Estrogen Receptor Modulators
89
(SERMs)
• Tamoxifen : Non steroidal antiestrogen
Agonistic:
Uterus,
bone, liver,
pitutary
Antagonistic:
Breast and
blood vessels

90. Tamoxifen
90
• DOSE:10-20mg bd
• Standard hormonal
treatment in breast cancer
• Adverse effects:
– Hot flushes , vomiting, vaginal
bleeding, menstrual
irregularities, venous
thromboembolism,
dermatitis, rarely endometrial
cancer

91. • Pure estrogen antagonist
• USES: Metastatic ER+ Breast Ca in
postmenopausal women
• MOA:
• Inhibits ER dimerization & prevents interaction of
ER withDNA
• ER is down regulated resulting in more complete
supression of ER responsive gene function
Selective Estrogen Receptor Down
regulator(fulvestrant)
91

92. • FLUTAMIDE & BICALUTAMIDE :
• Androgen Receptor antagonists
• Dose : 250 mg tds, 50mg od resp.
• Palliative effect in metastatic Prostatic Ca
after orchidectomy.
Anti androgens
92

93. 5- reductase inhibitors
93
Finasteride
• Orally active
• DHT levels ↓
• Benign prostatic
hyperplasia
Dose: 5mg/day
Prostate volume
Symptom score
Peak urine flow
rate
DHT level in
prostate
Side effects: Loss of libido & impotence in 5 % pts.
Also used for prevention of hair loss

94. • NAFERELIN : nasal spray / SC inj
• ↓FSH & LH release from pituitary- ↓ the
release of estrogen & testosterone
• USE : Breast Ca, Prostatic Ca
• PROGESTINS:
• Hydroxyprogesterone – used in metastatic
endometrial Ca.
• A/E: bleeding
GnRH agonists
94

95. • Monoclonal antibodies
– Trastuzumab : breast cancer (HER2/neu)
– Bevacizumab: metastatic colon cancer (VEGF)
– Rituximab : non hodgkins lymphoma (CD-20)
– Panitumumab : metastatic colon cancer (EGFR)
– Alemtuzumab : CLL (CD 52 antigen)
– Iodine tositumonab : Non hodgkins (CD-20)
Newer anticancer drugs
95

96. Important drug combinations
96
REGIMEN CANCER DRUGS
MOPP Hodgkins Mechlorethamine, oncovin,
prednisolone, procarbazine
ABVD Hodgkins Doxorubicin, Bleomycin, Vinblastine,
dacarbazine
CMF Breast Cyclophosphamide, methotrexate, 5-FU
CAF Breast Cyclophosphamide, doxorubicin, 5FU
ALL Vincristine, prednisolone, aspargine,
Daunorubicin
AML Cytarabine, methotrexate
CML Hydroxyurea, interferon
Wilms Actinomycin, Vincristine, doxorubicin

97. References
• Medical pharmacology by KDT
•Pharmacology for dental students.
•Textbook of Oral medicine by A G Ghom
97

98. 98

99. 99

100. Newer anticancer drugs
100
• Inhibitors of growth factors receptors
– Imatinib: CML (BCR-ABL gene)
– Gefitinib: Non small cell cancer of lungs (EGFR)
– Nilotinib : CML (Tyrosine kinase inhibitor)
– Dasatinib : CML (Tyrosine kinase inhibitor)
– Lapatinib : metastatic breast cancer (HER2/neu)
– Sunitinib : renal cell carcinoma (VEGF)
– Sorafinib : renal cell carcinoma (VEGF)

101. 101

102. Guiding principles in cancer
chemotherapy
102
• Toachieve cure a TOTAL CELL KILL must be
tried
• Early diagnosis and early institution of
treatment
• Combination chemotherapy
• Intermittent regimens
• Adjuvant and neoadjuvant chemotherapy
occasionally

103. Total cell kill
103
• Aimed at destroying all the malignant cells,
leaving none
• This approach ensures
– Early recovery
– Prevents relapse
– Prolongs survival
• Pharmacological sancturies

104. • Nitrogen Mustards
– Meclorethamine, Melphalan, Chlorambucil,
cyclophosphamide, ifosfamide
• Ethyleneimine : Thiotepa
• Alkyl Sulfonate: Busulfan
• Nitrosureas
– Carmustine,lomustine, streptozocin
• Triazines
– Dacarbazine, temozolamide
Alkylating agents
104

105. • Antibiotics
– Actinomycin D,
Doxorubicin,
Daunorubicin, Bleomycin,
Mitomycin C
• Vinca alkaloids
– Vincristine, Vinblastine,
Vinorelbine
• Taxanes
– Paclitaxel, docetaxel
• Enzymes
– L-Asparginase
Natural Products
105
• Epipodophyllotoxins
– etoposide,
tenoposide
• Camptothecin
analogs
– Topotecan, irinotecan
• Biological response
modifiers
– Interferons,
– Interleukins

106. • Folate Antagonists
– Methotrexate
• Purine Antagonists
– 6 Mercaptopurine, 6 Thioguanine, Azathioprine
• Pyrimidine antagonists
– 5 Fluorouracil, cytarabine, gemcitabine
Antimetabolites
106

107. • Cisplatin
• Carboplatin
• Hydroxurea
• Procarbazine
• Mitotane
• Imatinib
Miscellaneous Agents
107

108. MOA of some anticancer drugs
108
Purine & Pyrimidine synthesis
Ribonucleotides
Deoxy ribonucleotides
DNA
RNA
Proteins
Purine/
Pyrimidine
antagonists Methotrexate
Inhibition of
purine ring &
dTMP
biosynthesis
5 FU inhibits
dTMP synthesis
Dactinomycin ,
Intercalate with DNA
disrupt DNA function
Alkylating agents
Alter structure &
function of DNA
by cross linking
and/or
fragmenting DNA
Cytarabine inhibits
DNA chain elongation

109. Hormones & antagonists
109
• Corticosteroids
– Prednisolone
• Estrogens
– Ethinyl Estradiol
• SERM
– Tamoxifene, Toremifene
• SERD
– Fulvestrant
• Aromatase Inhibitors
– Letrozole, Anastrazole,
Exemestane
• Progestins
– Hydroxyprogesterone
• Anti-androgens
– Flutamide,
Bicalutamide
• 5- reductase
Inhibitors
– finasteride,
dutasteride
• GnRH analogs
– Naferelin, goserelin,
leuoprolide

110. • Letrozole
• Orally active non steroidal compound
• MOA : Inhibits aromatisation of testosterone &
androstenedione to form estrogen.
• Uses : Breast Ca- & adj. to mastectomy
• Dose :2.5mg bd orally
• Anastrozole : more potent
• 1mg OD in ER+ Breast Ca
• A/E : hot flushes
Aromatase Inhibitors
110

111. Hormones & antagonists
111
• Corticosteroids
– Prednisolone
• Estrogens
– Ethinyl Estradiol
• SERM
– Tamoxifene, Toremifene
• SERD
– Fulvestrant
• Aromatase Inhibitors
– Letrozole, Anastrazole,
Exemestane
• Progestins
– Hydroxyprogesterone
• Anti-androgens
– Flutamide,
Bicalutamide
• 5- reductase
Inhibitors
– finasteride,
dutasteride
• GnRH analogs
– Naferelin, goserelin,
leuoprolide

112. Cancer chemotherapy can be curative in
112
• Acute Leukemias
• Wilm’s Tumour
• Ewing’s Sarcoma
• Choriocarcinoma
• Hodgkin’s Disease
• Lymphosarcoma
• Burkitts lymphoma
• Testicular Teratomas
• Seminomas
In children

113. Chemotherapy can have only Palliative effect in
113
• Breast Cancer
• Ovarian Cancer
• Endometrial Cancer
• Prostatic Cancer
• Chronic Lymphatic Leukemia
• Chronic Myeloid Leukemia
• Head & Neck Cancer
• Lung (small cell) Cancer