anticancer drugs

1. ANTI- CANCER DRUGS
By- Dr. Sushrut Varun Satpathy
3rd year PG
Deptt. Of Clinical Pharmacology
Moderator-
Dr. Chandrakala Sharma
Assoc. Professor
Clinical pharmacology
SMIMS

2. Protocol -
1. Origin of cancer chemotherapy
2. Introduction
3. Goals of therapy
4. Classification
5. General principles of chemotherapy
6. Cell cycle and clinical importance
7. Individual drugs – Alkylating agent- Nitrogen mustards,
triazines, platinum coordination complexes
8. Antimetabolites – Mtx, purine analogues, pyrimidine
analogues
9. Mitotic spindle inhibitor
10. Anti-tumor antibiotics
11. Targeted Drugs
12. Hormones and related agents
13. Resistance to anti-cancer drugs

3. The origin of cancer
chemotherapy.....
WW (I) exposure to mustard gas led to the
observation that alkylating agents caused marrow
and lymphoid hypoplasia which was further studied
during WW(II)
This observation led to the direct application of such
agents to patients with Hodgkin’s disease and
lymphocytic lymphomas at Yale Cancer Center in
1943
Luis Goodman and Alfred Gillmen demonstrated
it for the first time.

4. 1948, Sydney Farber successfully used Antifolates
to induce remission in children with ALL.
1955, National chemotherapy program begins at National
cancer institute, a systematic programme for drug screening.
1958, Roy Hertz and Min Chiu Li demonstrated
Methotrexate as a single best agent for
choriocarcinoma, the first solid tumour that can be cured by
chemotherapy.
1959, FDA approved the alkylating agent,
Cyclophosphamide

5. 1965, The era of combination chemotherapy begins.
# POMP(Methotrexate,Vincristine,6MP,Prednisolone) regimen
was able to induce long term remission in children with ALL
# MOPP(Nitrogen
Mustard,Vincristine,Procarbazine,Prednisolone)
regimen successfully cured HL and NHL used by
Vincent DeVita and collegues in 1970
Currently, nearly all successful cancer
chemotherapy regimens use this paradigm of
multiple drugs given simultaneously,
called combination chemotherapy or
polychemotherapy.

7. Introduction
Cancer (Malignant neoplasm) is a class of
diseases in which a group of cells display
uncontrolled growth, invasion, and sometimes
metastasis
As a single entity, Cancer – biggest cause of
mortality worldwide – estimated 8.2 million
deaths from cancer in 2012 (WHO)
Cancer cases worldwide are forecast to rise by
75% and reach close to 25 million over the next
two decades

8. Types of tumors

9. Goals of Therapy
Cure or induce prolonged ‘remission’ so that all
macroscopic and microscopic features of the cancer
disappear, though disease is known to persist - Acute
Lymphoblastic Leukaemia, Wilm`s tumor, Ewing`s sarcoma etc. in
children, Hodgkin`s lymphoma, testicular teratoma and
choriocarcinoma
Palliation: Shrinkage of evident tumour, alleviation of
symptoms and prolongation of life - Breast cancer, ovarian
cancer, endometrial carcinoma, CLL, CML, small cell cancer of
lung and Non-Hodgkin lymphoma

10. contd.
Adjuvant therapy: One of the main basis of
treatment now
For mopping up of residual cancer cells including
metastases after Surgery, Radiation and immunotherapy
etc.
Routinely used now
Mainly in solid tumours
Insensitive or less sensitive but life may be prolonged - Cancer
esophagus, cancer stomach, sq. cell carcinoma of lung, melanoma, pancreatic
cancer, myeloma, colorectal cancer

11. Classification -
A. Alkylating agents
1. Nitrogen mustards – Mechlorethamine (Mustine HCL),
Cyclophosphamide, Ifosfamide, Melphalan,
Chlorambucil
2. Ethylenimine - Thio-TEPA, hexamethylmelamine
(Altretamine)
3. Alkyl sulfonate – Busulfan
4. Nitrosoureas – Carmustine, Lomustine, Streptozocin
5. Triazines - Procarbazine, Dacarbazine, Temozolomide

12. 2. Platinum coordination complexes –
Cisplatin, Carboplatin,Oxaliplatin
3. Antimetabolites –
Pyrimidine analogs – 5-Fluorouracil , Cytarabine
(cytosine arabinoside), Capecitabine, Gemcitabine
Purine analogs – 6-Mercaptopurine, 6-Thioguanine,
Azathioprine, Fludarabine, Cladribine, Pentostatin
Folic acid analog – Methotrexate, Pemetrexed

13. 4. Microtubule damaging agents – Vincristine(
Oncovin), Vinblastine, Vinorelbine, Paclitaxel,
Docitaxel, Estramustine
5. Topoisomerase-2 inhibitors – Etoposide,Teniposide
6.Topoisomerase-1 inhibitors- Topotecan, Irinotecan
7.Antibiotics – Actinomycin D (Dactinomycin),
Doxorubicin, Daunorubicin(Rubidomycin), Epiburicin,
Mitoxantrone,Bleomycins, Mitomycin C

14. 8.Miscellaneous – Hydroxyurea, L-Asparaginase,
Tretinoin, Arsenic trioxide
B. Targeted Drugs –
1.Tyrosine Protein Kinase Inhibitors – Imatinib, nilotinib
2. EGF receptor inhibitors – Geftinib,
Erlotinib,Cetuximab
3. Angiogenesis Inhibitors – Bevacizumab, Sunitinib
4. Proteasome Inhibitor – Bortezomib
5. Unarmed monoclonal antibody – Rituximab,
Trastuzumab

15. C. Hormonal drugs –
1. Glucocorticoids – Prednisolone and others
2. Estrogens – Fosfestrol, Ethinylestradiol
3. Selective estrogen receptor modulators-
Tamoxifen,Toremifene
4. Selective estrogen receptor down regulators –
Fulvestrant
5. Aromatase Inhibitors – Letrozole, Anastrozole ,
Exemestane
6. Antiandrogens – Flutamide,Bicalutamide
7. 5-α reductase Inhibitors – Finasteride, Dutasteride
8. GnRH analogues – Nafarelin,Leuprorelin,triptorelin
9. GnRH antagonists – Cetorelix, Ganirelix, Abarelix
10. Progestins – Hydroxyprogesterone acetate, etc.

17. General Principles of Chemotherapy of
Cancer
1. Analogous with Bacterial chemotherapy – differences are
Selectivity of drugs is limited – because “I may harm you”
No or less defence mechanism – Cytokines adjuvant now
2. All malignant cells must be killed to stop progeny – survival time is
related to no. of cells that escape Chemo attack
3. Subpopulation cells differ in rate of proliferation and susceptibility
to chemotherapy
4. Drug regimens or combined cycle therapy after radiation or surgery
(Basis of treatment now in large tumour burdens)
5. Complete remission should be the goal – but already used in
maximum tolerated dose – so early treatment with intensive
regimens
6. Formerly single drug – now 2-5 drugs in intermittent pulses – Total
tumour cell kill – COMBINATION CHEMOTHERAPY

18. COMBINATION CHEMOTHERAPY
- SYNERGISTIC
Drugs which are effective when used alone
Drugs with different mechanism of action
Drugs with differing toxicities
Drugs with different mechanism of toxicities
Drugs with synergistic biochemical interactions
Optimal schedule by trial and error method
More importantly on cell cycle specificity

19. Cell Cycle and Clinical Importance
• All cells—normal or neoplastic—must
traverse before and during cell division
• Malignant cells spend time in each
phase - longest time at G1, but may
vary
• Many of the effective anticancer drugs
exert their action on cells traversing
the cell cycle - cell cycle-specific
(CCS) drugs
• Cell cycle-nonspecific (CCNS) drugs
- sterilize tumor cells whether they are
cycling or resting in the G0
compartment
• CCNS drugs can kill both G0 and
cycling cells - CCS are more effective
on cycling cells

20. Phases of cell cycle
G1 - primary growth
phase
S – synthesis; DNA
replicated
G2 - secondary growth
phase
collectively these 3
stages are called
interphase
M - mitosis
C - cytokinesis

21. 21
Daughter
Cells
DNA Copied
Cells
Mature
Cells prepare for Division
Cell Divides into Identical cells

22. Control of cell cycle- by special proteins and enzymes
that act as switches
G1 checkpoint- stop, pause or go into S phase some
cells stop permanently
G2 checkpoint- will
cell divide?
M checkpoint-
formation of new
cells

23. Drugs Based on Cell Cycle
CCNS: Nitrogen Mustards-Cyclphosphamide,
chlorambucil, carmustine, dacarbazine, busulfan,
L-asparginase, cisplatin, procarbazine and
actinomycin D etc.
CCS:
G1 – vincristine
S – Mtx, cytarabine, 6-thioguanine, 6-MP, 5-FU,
daunorubicin, doxorubicin
G2 – Daunorubicin, bleomycin
M – Vincristine, vinblastne, paclitaxel etc.

24. The Log-Kill hypothesis -
The CELL KILL HYPOTHESIS proposes that
actions of CCS drugs follow first order kinetics: a
given dose kills a constant PROPORTION of a tumor
cell population (rather than a constant NUMBER of
cells).

25. Individual Drugs -
ALKYLATING AGENTS –
produce highly reactive carbonium ion intermediates
which transfer alkyl groups to cellular
macromolecules by forming covalent bonds –
position 7 of guanine residues is susceptible
Alkylation results in cross-linking/abnormal base
pairing/scission of DNA strand
Cytotoxic and radiomimetic (like ionizing radiations)
actions
CCNS – dividing + resting cells

26. Nitrogen Mustards
Mechlorethamine (Mustine HCl):
Uses: Hodgkin’s and Non-Hodgkin’s lymphoma
Given IV
Part of MOPP (Mechlorethamine – oncovine-prednisolone and
procarbazine) in Hodgkin`s disease
ADRs: Severe Vomiting, myelo and immunosuppression
Extravasation – severe local toxicity
Dose- 0.1 mg/kg iv daily x 4 days ; courses may be repeated at
suitable intervals
Cyclophosphamide:
Transformed into active aldophosphamide and phospharamide
Administered orally
Used in Hodgkin's lymphoma, breast and ovary cancers

27. Cyclophosphamide Aldophosphamide
Phoshoramide Acrolein
mustard (cytotoxic effect) (toxic metabolite)
Mesna (-SH compound)
Dose – 2-3 mg/kg/day oral , 10-15 mg/kg i.v every 7-
10 days

28. IFOSFAMIDE –
 Congener of cyclophosphamide
 Longer and dose dependent T1/2
used in bronchogenic, breast, testicular,bladder ,head and
neck carcinomas
 Dose limiting toxicity – Haemorrhagic cystitis
Mesna is a SH- compound -- excreted in urine – binds and
inactivates the vesicotoxic metabolites of ifosfamide and
cyclophosphamide
 Causes less alopecia and less emetogenic

29. CHLORAMBUCIL – Slow acting alkylating agent,
esp. active against lymphoid tissues
myeloid tissues – largely spared
(Ch. Lymphatic leukaemia and non-Hodgkin's lymphoma)
Dose – 0.1-0.2 mg/kg daily for 3-6 weeks, then 2 mg daily
for maintenance
 MELPHALAN – very effective in multiple myeloma and
advanced Ovarian cancer , toxicity- BMD
 Thio-TEPA – ethylenimine , High Toxicity
seldom used – Ovarian and Bladder Ca

30. BUSULFAN – alkyl sulfonate , highly selective for
myeloid elements; Granulocyte precursors(most
sensitve) > Platelets and RBC
little effect on lymphoid tissue and GIT
Hyperuricemia(common);
Pulmonary fibrosis and skin pigmentation – specific
adverse effect
 NITROSOUREAS – (Carmustine etc.)
highly lipid soluble, crosses BBB – meningeal
leukemias and brain cancer
N,V - common , CNS effects
BMD –delayed -6 weeks , Visceral fibrosis and
Renal damage

31. Triazines
PROCARBAZINE –
Not a classical alkylating agent, similar properties
After metabolic activation – methylates and depolymerizes
DNA – chromosomal damage
Mutagenic and carcinogenic potential
Component of MOPP regimen – Hodgkin’s Lymphomas
 DACARBAZINE –
after activation in liver – methylating DNA , most imp.
Indication – malignant melanoma, also – hodgkin’s
lymphoma
 TEMOZOLAMIDE-
orally active triazine methylating agent, d.o.c – glioma and
other malignant brain tumours, also melanoma

32. Platinum Coordination Complexes -
CISPLATIN –
Heavy metal complex , CCNS
Hydrolysed intracellularly – highly reactive moiety – cross-
linking DNA ( both intrastrand and interstrand)
Favored site – N7 of guanine residue
Also reacts with –SH groups of cytoplasmic and nuclear
proteins
Effects resemble – alkylating agent and radiation
Plasma protein bound, penetrates tissues
Slowly excreted in urine, T1/2 – 72 hrs
Highly effective – testicular, ovarian, endometrial and
bladder Ca
Also used in Lung and Oesphageal Ca

33. Dose – Cisplatin adm. Slow i.v infusion 50-100
mg/m2 BSA every 3-4 weeks
Adverse effects –
Most emetogenic anticancer drug, controlled by 5HT3
antagonist
Nephrotoxicity – can be minimized by proper hydration
and chloride diuresis
Ototoxicity with hearing loss can occur and is severe
with repeated doses
Electrolyte disturbances : Hypokalemia, Hypocalcemia
and Hypomagnesemia
Rarely Anaphylactic shock ,
Mutagenic , Teratogenic and Carcinogenic properties

34. Anti-Metabolites
Analogues related to the normal components of DNA
or of coenzymes involved in nucleic acid synthesis
Competitively inhibit utilization of the normal substrate
or get themselves incorporated forming dysfunctional
macromolecules
1. Folic acid analogue – Mtx, Pemetrexed
2. Purine analogue – 6-MP, 6-TG, Fludarabine,
Cytarabine, pentostatin
3. Pyrimidine analogue – 5-Fluorouracil , Cytarabine
(cytosine arabinoside), Capecitabine, Gemcitabine

35. Methotrexate(Mtx) – Folate antagonist
Most commonly and oldest anticancer drug
CCS drug
Acts during S phase of the cell cycle
Antineoplastic , immunosuppresant and anti-inflammatory
effects
Mtx structurally resembles folic acid – competitively
inhibits dihydrofolate reductase enzyme and prevents the
conversion of DHFA to THFA – depletes intracellular
THFA
THFA necessary for synthesis of purines and thymidylate
– DNA and RNA synthesis
Utilizing the folate carrier – enters the cells – transformed
into more active polyglutamate form by enzyme
folypolyglutamate synthase (FPGS)

36. M.O.A
Methotrexate
Dihydrofolate reductase
Dihydrofolic acid Tetrahydrofolic
acid
(DHFA) (DHFR)
(THFA)
Leucovorin synthesis of
purines
Folinic acid and thymidylate
(N5 formyl FH4)

37. Mtx well absorbed after oral adm. , can be given i.m,
i.v or intrathecally
50% bound to plasma proteins
Poorly crosses BBB and most of the drug excreted
unchanged in urine
d.o.c – choriocarcinoma; 15-30 mg/day for 5 days
orally or 20-40 mg/m2 BSA i.m or i.v twice weekly
Also used in Acute leukemias, Burkitt’s Lymphoma
and Breast Ca.
Low dose Mtx ( 7.5-30 mg once weekly) – R.A
Other Uses – Psoriasis, IBD and in Organ
transplantataion

38. Folinic acid rescue/ Leucovorin rescue -
Toxic effects of Mtx on normal cells can be
minimized by giving folinic acid
Availabilty of folinic acid has helped the use of very
high doses of Mtx for better antineoplastic effect
A nearly 100 times higher dose (250-1000 mg/m2
BSA) of Mtx infused i.v over 6 hrs, followed by 3-15
mg i.v calcium leucovorin within 3 hrs, repeated as
required
Can be repeated weekly
Folinic acid (Active CoA) – bypasses the block
produced by Mtx and rapidly reverses the toxicity

39. Resistance:
Reduction of affinity of DHFR to MTX
Diminished entry of MTX into cancer cells
Over production of DHFR enzyme

40. Pemetrexed
Newer congener of Mtx
Primarily targets the enzyme Thymidylate synthase
Though not a DHFRase inhibitor, the pool of THFA is
not markedly reduced
Like Mtx, it utilizes the folate carrier to enter cells
and requires transformation into polyglutamate form
by FPGS for activity enhancement
Adverse effects – Mucositis, Diarrhoea,
Myelosuppression (same as Mtx)
painful, itching erythematous rash, mostly involving
the hands and feet ‘hands foot syndrome’ – common
Dose – 500 mg/m2 i.v every 3 weeks

41. Purine analogues -
6-MERCAPTOPURINE and 6-THIOGUANINE –
Highly effective anti-neoplastic drugs
synthesis in the body into corresponding
Monoribonucleotides – inhibit the conversion of
Inosine monophosphate to adenine and guanine
nucleotides – building blocks for DNA and RNA
Also – feedback inhibition of de novo purine synthesis,
get incorporated into RNA and DNA –
dysfunctional
Esp. useful – childhood acute leukemias,
choriocarcinoma and few solid tumors
Absorbed orally , poor penetration BBB

42. Cont…6-MP and 6-TG
Azathioprine and 6-MP oxidised by xanthine oxidase
Allopurinol
xanthine oxidase
6-Mercaptopurine 6-Thiouric Acid
Dose reduced to 1/4th to 1/2nd if allopurinol is given
concurrently
Thioguanine not a substrate for xanthine oxidase –
(s-methylation)

43. Cont…6-MP and 6-TG
Methylation by TPMT is an additional pathway of 6-
MP metabolism
Genetic def. of TPMT makes individual more
susceptible to 6-MP induced myelosuppression,
mucositis and gut damage, while overexpression of
TPMT is an important mechanism of 6-MP
resistance in acute leukemia cells
BMD- major adverse effect of 6-MP
Dose – 6-MP - 2.5 mg/kg/day, half dose for
maintenance
6-TG – 100-200 mg/m2/d for 5-20 days

44. Fludarabine -
Newer purine anti-metabolite – phosphorylated
intracellularly – active triphosphate form – inhibits DNA
polymerase and ribonucleotide polymerase – interferes
with DNA repair as well as gets incorporated to form
dysfunctional DNA
Indicated in Chronic Lymphatic Leukemia and Non-
Hodgkin’s lymphoma that have recured after treatment
Adverse effects – chills, fever, myalgia, arthralgia and
vomitting after injection, myelosuppression and
oppurtunistic infections
Dose – 25 mg/m2 BSA daily for 5 days every 28 days by
i.v infusion

45. Pyrimidine analogues -
FLUOROURACIL (5-FU) –
Mechanism of action -
Fluorouracil FdUMP
Thymidylate synthetase
dUMP TMP
DNA synthesis

46. 5-FU cont….
Uses – colorectal , upper GIT, breast and ovarian
Oral absorption of 5-FU is unreliable , primarily used
by i.v infusion
5-FU rapidly metabolized by dihydropyrimidine
dehydrogenase (DPD) resulting in a plasma T1/2 15-
20 mins after i.v infusion
Genetic deficiency of DPD – severe 5-FU toxicity
A/Es – myelosuppression , mucositis, diarrhoea,
nausea and vomitting, peripheral neuropathy (hand-
foot syndrome)

47. Pyrimidine analogues…cont…
CYTARABINE (Cytosine arabinoside) –
Cytidine analogue
Single most effective agent for induction of remission
in AML
Drug is activated by kinases to AraCTP – inhibitor of
Dna polymerases
Of all antimetabolites – Cytarabine is the most specific
for the S phase of the cell cycle
Resistance to cytarabine can occur either due to
decreased uptake or decraesed conversion to
AraCTP
High dose – Neurotoxicity ( Ataxia and peripheral
neuropathy)

48. Pyrimidine analogues…cont…
GEMCITABINE –
Deoxy-Cytidine analogue – converted – active
diphosphate and triphopshate nucleotide form
Gemcitabine diphosphate – inhibits ribonucleotide
reductase – diminish pool of deoxyribonucleoside
triphosphates required for DNA synthesis
Can be incorporated into DNA – chain termination
PK- elimination mainly by metabolism
Clinical use- initially Pancreatic Ca , nowadays widely
– Non-Small Cell Lung Ca, Bladder Ca., and Non-
hodgkin’s lymphoma

49. Mitotic Spindle Inhibitors / Natural Product
Anticancer Drugs -
Most imp. of these plant derived, CCS drugs are
Vinca alkaloids( vinblastine, vincristine, vinorelbine),
podophyllotoxins( etoposide, teniposide), the
camptothecins(topotecan,irinotecan), the
taxanes(paclitaxel, docetaxel)
VINKA ALKALOIDS –
Vinblastine and Vincristine are derived from the
periwinkle plant
CCS agent , act during M phase of the cycle
Block the formation of Mitotic Spindle by preventing
the assembly of tubulin dimers into microtubules

50. M.O.A – Vinblastine and Vincristine
Bind to β-tubulin (drug tubulin complex)
inhibits its polymerization into microtubules
No intact mitotic spindle
cell division arrested in metaphase

51. Vinca alkaloids – cont..
PK- given parenterally, penetrate most tissues except
CSF
cleared mainly via biliary secretions
Clinical use –
Vincristine - Acute leukemias, lymphomas, Wilm’s Tumor
and Neuroblastoma
Vinblastine – Lymphomas,Neuroblastomas,Testicular
ca.and Kaposi’s sarcoma
Vinorelbine – non-small cell lung carcinoma and breast Ca
.
Toxicity – Vinblastine and Vinorelbine cause GI distress,
Alopecia and bone marrow suppression
Vincristine is ‘marrow sparing’ but neurotoxic

52. Natural Product Anticancer Drugs –cont….
ETOPOSIDE and TENIPOSIDE –
Etoposide , a semisynthetic derivative of
podophyllotoxin,induces DNA breakage through its
inhibiton of topoisomerase ІІ
Most active in late S and early G2 phase of the cell
cycle
Teniposide is an analogue with similar properties
PK- orally well absorbed and distributes to most body
tissues
Elimination is mainly via kidneys
Clinical use – Testicular and lung ca. in combination
with cytotoxic agents. Non-hodgkin’s lymphoma and
AIDS related Kaposi’s Sarcoma

53. Etoposide and Teniposide
forms complex with DNA and topoisomerase ІІ
prevent resealing of broken DNA strand
Cell death
Toxicity – Etoposide and Teniposide are GI irritants
and cause alopecia and bone marrow suppression

54. Natural Product Anticancer Drugs –cont….
TOPOTECAN and IRINOTECAN –
Obtained from camptotheca acuminata tree
2 camptothecins, Topotecan and Irinotecan, produce DNA
damage by inhibiting Topoisomerase І
PK- Irinotecan – prodrug – converted to active metabolite in
liver , Topotecan is eliminated renally, whereas Irinotecan
and its metabolite eliminated in bile and faeces
Clinical use –Topotecan - 2nd line agent – Advanced Ovarian
Ca and for small cell lung Ca.
Irinotecan – Metastatic Colorectal Ca
Toxicity – Myelosuppression and Diarrhoea

55. Natural Product Anticancer Drugs –cont….
TAXANES – Paclitaxel , docetaxel
Derived from the bark of the western yew tree
Paclitaxel binds to β-tubulin stabilizes
microtubules formation of abnormal
microtubules inhibits mitosis
Prevent microtubule disassembly into tubulin monomers
- Given I.V
- Advanced breast, ovarian, lung, oesophageal and
bladder ca.
- Paclitaxel-neutropenia,thrombocytopenia,high incidence
of peripheral neuropathy and possible hypersensitvity
reaction
- Docetaxel cause neurotoxicity and BMD

56. Antitumor antibiotics -
Made up of several structurally dissimilar microbial
products and includes the anthracyclines, bleomycin
and mitomycin
ANTHRACYCLINES –
Doxorubicin, daunorubicin, idarubicin, epirubicin,
mitoxantrone
Intercalate between base pairs, inhibit Topoisomerase
ІІ , and generate free radicals
Block synthesis of RNA and DNA – cause DNA strand
scission, membrane disruption also occurs
Anthracyclines CCNS drugs

57. Anti-tumor antibiotics…cont…
Doxo and Daunorubicin must be given IV
Metabolized in liver , excreted in bile and urine
Doxorubicin – hodgkin’s and non-hodgkin’s
lymphoma,myelomas, sarcomas, breast, lung,
ovarian and thyroid ca.
Daunorubicin – acute leukemias
Idarubicin – AML
Epirubicin – breast and gastro-esphageal ca
Mitoxantrone –AML, non-hodgkin’s lymphoma,
breast ca and gastro-esophageal ca
Toxicity -
BMD,GI distress and severe alopecia
Distinctive a/e – cardiotoxicity - dexrazoxane (free
radical scavenger) and α-tocopherol

58. Anti-tumor antibiotics…cont…
BLEOMYCIN –
CCS glycopeptide , acts in the G2 phase- generates
free radicals – bind to DNA – DNA strand breaks –
inhibit DNA synthesis
Given parenterally, inactivated by tissue
aminopeptidases mainly
Testicular and Ovarian tumors, Hodgkin’s lymphoma
(ABVP regimen)
Toxicity – Pulmonary dysfunction (pneumonitis,
fibrosis)
cutaneous toxicity
(hyperpigmentation,hyperkeratosis,erythema and
ulcers)

59. Anti-tumor antibiotics…cont…
MITOMYCIN-C
CCNS , metabolized by liver enzymes – forms an
alkylating agent – crosslinks DNA
Mitomycin given intravenously and is rapidly cleared
by hepatic metabolism
Uses- mitomycin act against hypoxic tumor cells and
used in combination regimens for adenocarcinomas
of the cervix, stomach,pancreas and lung
Can be used as intravesical therapy to treat superficial
bladder ca and anal ca (with radiation therapy)
Toxicity – BMD, GI distress and Nephrotoxicity

60. Targeted drugs -
TYROSINE KINASE INHIBITORS – Imatinib,
geftinib,erlotinib,sorafenib,sunitinib,lapatinib etc.
IMATINIB-
Selective anti-cancer drug whose development was
guided by knowledge of specific oncogene
Inhibits tyrosine kinase activity of protein product of
bcr-abl oncogene (t9,22; philadelphia chromosome)
that is commonly expressed in CML

61. IMATINIB-
First selectively targeted drug to be introduced
Inhibits a specific tyrosine protein kinase – “Bcr-abl”
tyrosine kinase expressed by CML cells and related
receptor tyrosine kinases including PDGF receptor
that is constitutively active in dermatofibrosarcoma
protuberans, stem cell receptor and c-kit receptor
active in GIST
Very sucessful in chronic phase of CML (remission>
90%) and in metastatic c-kit (+) GIST . Also indicated
in Dermatofibrosarcoma protuberans
Resistance develops mainly due to point mutation in
Bcr-Abl tyrosine kinase

62. IMATINIB- cont…
PK- well absorbed orally , metabolized in liver , one
active metabolite also produced
metabolised mainly by CYP3A4 , metabolites
excreted in faeces through bile
T1/2 – 18 hrs while that of its active metabolite is
double
A/Es- Abdominal pain, vomitting, fluid
retention,periorbital oedema,pleuarl effusion,myalgia
and CHF
Dose – 400 mg/day with meals; accelerated phase
of CML – 600-800 mg/day
Dasatinib and Nilotinib are similar drugs used in
case of Imatinib resistance

63. EGF receptor inhibitors -
GEFTINIB –
EGF – transmembrane receptor-tyrosine-kinase
regulates growth and diffrentiation of epithelial cells
Binding of ligand (EGF) to extracellular domain of
receptor induces dimerization leading to activation of
tyrosine kinase activity of intracellular domain

64. Geftinib …cont…
autophosphorylation of the kinase and
phosphorylation of several cytoplasmic regulatory
proteins which modify gene transcription to regulate
growth
Geftinib – binds to tyrosine kinase domain of EGF
receptor (Erbβ1, or HER1)- prevents phosphorylation
of regulatory proteins
Indicated for Non-small cell lung Ca.(EGFR
activating mutation)
Oral bioavailability – 60% , primarily meatbolized by
CYP3A4
T1/2 – 40 hours
Dose – 250 mg/day orally

65. EGF receptor inhibitors…cont..
Others-
Erlotinib also indicated for Pancreatic Ca with
Gemcitabine
Sorafenib and Sunitinib are small molecules that
inhibit multiple tyrosine kinases – both can be used
for RCC, sorafenib- hepatocellular ca and sunitinib-
GIST , A/e – hypertension
Lapatinib – Breast ca. (-) tyrosine kinase assoc. with
EGFR and her-2/neu receptors
Pazopanib is to form multi targeted tyrosine kinase
inhibitor against VEGF receptors, PDGF receptors
and c-kit, approved for advanced RCC

66. Monoclonal antibodies -
Monoclonal Abs Targeted against Indication Comments
Rituximab CD-20 Non-hodgkin’s
lymphoma
Alemtuzumab CD-52 Low grade
lymphomas and CLL
Trastuzumab HER 2/neu Breast Ca Can cause
cardiotoxicity
Cetuximab and
Panitumumab
EGFR EGFR-positive
metastatic colorectal
carcinoma
Rash,
hypomagnesemia
and interstitial lung
disease
Bevacizumab VEGF Metastatic colorectal
ca
Combined with 5-FU

67. Hormones and related agents -
GLUCORTICOIDS –
Prednisolone - most commonly used glucorticoid in
Ca.chemo. Used for combination chemotherapy in
leukemia and lymphomas
ESTROGEN –
Physiological antagonists of androgens
Antagonizes the effects of androgens in androgen
dependent prostatic tumors- fosfestrol ( prodrug) –
stilboestrol (prostatic tissue)
TAMOXIFEN-
Anti-oestrogen mainly used in the palliative treatment
in hormone dependent breast ca

68. PROGESTINS –
Medroxyprogesterone acetate, hydroxyprogesterone
caproate and megestrol
2nd line hormonal therapy for metastatic hormone
dependent breast ca and endometrial ca
ANTI-ANDROGENS –
Flutamide and bicalutamide – bind to androgen
receptor – inhibit androgen actions
Prostatic ca, used along with GNRH agonist – strategy
known as ‘complete androgen blockade’
Flutamide can cause – hot flushes, hepatic dysfunction
and gynaecomastia

69. GnRH agonists -
Goserelin, Nafarelin and leuprolide act as agonist of
GnRH
used in advanced prostatic ca
A/e- flaring up of disease, hot
flushes,impotence,gynaecomastia and osteoporosis
GnRH antagonist –
Cetrorelix, ganirelix and abarelix are antagonist of GnRH
Decrease the release of gonadotropins without causing
initial stimulation
Can be used in prostatic ca without the risk of flare up
reaction

70. AROMATASE Inhibitors – Anastrozole, letrozole etc
Aromatase is the enzyme responsible for conversion
of androstenedione ( androgen precursor) to estrone
(estrogenic hormone)
1st gen.- aminoglutethimide
2nd gen.- formestane, fadrozole,rogletimide
3rd gen.- exemestane,letrozole,anastrozole
Aromatase inhibitors – useful in advanced breast ca.
Adverse effects – hot flushes, arthralgia and fatigue

71. Other anticancer drugs -
L- Asparaginase –
Enzyme used for treatment of leukemias and
lymphomas
- These tumors require exogenous asparagine for
growth
L-asparaginase acts by depleting this amino acid in
serum
Adm. by IV route
a/e – hypersensitivity reactions, acute pancreatitis and
cortical vein thrombosis
Pentostatin –
Used for treatment of hairy cell leukemia

72. OCTREOTIDE –
Long acting somatostatin analogue
Useful in treatment of islet cell ca (decreases both
insulin and glucagon secretion)
Other uses – secretory diarrhoea, esophageal varices
and acromegaly
PLICAMYCIN –
Used for hypercalcemia of malignancy and metastatic
testicular ca

73. HYDROXYUREA – ( sickle cell anaemia, essential
thrombocytosis and polycythemia vera)
Can also be used in CML –
Acts by inhibiting ribonucleoside reductase (rate
limiting step in synthesis of DNA)
TRETINOIN (ATRA) –
All trans retinoic acid –induces 70% or more rate of
complete remission in acute promyelocytic leukemia
Can cause various types of toxicity – Vit A toxicity,
retinoic acid syndrome, CNS toxicity,
Hyperholesterolemia, hypertriglyceridemia

74. As2O3 –
Used for treatment of acute promyelocytic leukemia
(APML)
May cause hyperglycemia and prolonged QT interval
Bortezomib –
Acts by inhibiting proteasome resulting in down
regulation NF-kB ( involved in cell survival)
used – resistant multiple myeloma

75. Resistance to anticancer drugs -
Drug resistance is a major problem in cancer
chemotherapy. Mechanism of resistance includes the
following –
1. Increased DNA repair – An increased rate of DNA
repair in tumor cells can be responsible for
resistance and is particularly important for
alkylating agents and cisplatin
2. Formation of trapping agents – some tumor cells
increase their production of thiol trapping agents
(eg. glutathione), which interact with anticancer
drugs that form electrophillic species. This
mechanism of resistance is seen with alkylating
agent, bleomycin, cisplatin and anthracyclines

76. 3. Changes in target enzymes – changes in drug
sensitivity of a target enzyme, dihydrofolate
reductase, and increased synthesis of the enzyme
are mechanisms of resistance of tumor cells to
methotrexate
4. Decreased activation of pro-drugs – resistance to
the purine antimetabolites (6-MP,6-TG) and the
pyrimidine anti-metabolite (cytarabine,5-FU) can
result from a decrease in the activity of tumor cell
enzymes needed to convert these prodrugs to their
cytotoxic metabolites

77. 5. Inactivation of anticancer drugs- increased
activity of enzymes capable of inactivating
anticancer drugs is a mechanism of tumor cell
resistance to most of the purine and pyrimidine anti-
metabolites
6.Decreased drug accumulation – this form of multi-
drug resistance involves the increased expression of
a normal gene (MDR1) for a cell surface glycoprotein
(P-glycoprotein). This transport molecule is involved
in the accelerated efflux of many anticancer drugs in
resistant cells

78. References-
WHO Global Health Observatory. Available
at: http://www.who.int/gho/map_gallery/en/
City Mayors. Available
at: http://www.citymayors.com/statistics/largest-
cities-population-125.html
Tripathi KD, Anticancer drugs , Chemotherapy of
neoplastic diseases; 7th ed ; 857-877
Katzung’s and Trevor’s, Pharmacology: Examination
and board review, Cancer chemotherapy, 10th ed.
465-475
Goodman and Gillman’s 12th ed. Images
www.google.com , images

79. THANK YOU FOR YOUR PATIENCE !!
HAVE A GREAT DAY AHEAD !!
Dr.Namgay, Dr. Dhruva and Dr.Ena – lets go
and meet Mr. Debasish Sinha
Dr . Arkojit – WAKE UP !!

80. Chemosensitivity of tumors
► high
ALL
Hodgkin’s
disease
NHL
testicular
cancer
SCLC
Wilms’ tumor
 medium
 ovarian cancer
 breast cancer
 osteosarcoma
 head & neck
cancer
 multiple myeloma
 bladder cancer
 colorectal cancer
 low
 NSCLC
 cervical cancer
 endometrial
cancer
 adult soft
tissue sarcoma
 malignant
melanoma
 liver cancer
 pancreatic
cancer