1. Recent
Advances
in Cancer
Chemotherapy
Dr. Kunal A. Chitnis
1st Year Resident
T.N.M.C., Mumbai
12th March 2011

2. Carcinos means crab
Over 100 different types of cancer & each is classified by the type
of cell that is initially affected
Second leading cause of death worldwide
expected to increase five fold in the next 25 years
India:
Prevalence 2.5 million
over 8,00,000 new cases & 5,50,000 deaths occur each year
Males: Oral Ca
Female: Cervical Ca
six persons die every day from cancer in India
40- 50% directly or indirectly related to tobacco

3. A neoplasm, as defined by Willis,
"an abnormal mass of tissue, the growth of which exceeds & is
uncoordinated with that of the normal tissues, and persists in the
same excessive manner after the cessation of the stimuli which
evoked the change."
Benign, its microscopic and gross characteristics are considered
to be relatively innocent, remain localized, cannot spread to other
sites
Malignant, the lesion can invade and destroy adjacent structures
and spread to distant sites

5. The Cell Cycle

6. Anti-Cancer Chemotherapy
The first efforts…..
Traced back to the observation by Louis Goodman and
Alfred Gilman, of the profound lymphoid and myeloid
suppression produced by sulfur mustard gas – a chemical
warfare agent.

7. Cytotoxic Drugs

8. I. Alkylating Agents
MOA:
• Alkylate nucleophilic group of
DNA bases (N7 Guanine)
• Abnormal base pairing, cross
linking of bases & DNA strand
breakage
• Cell cycle non-specific
Common adverse effects:
1. Gastrointestinal distress
2. Bone marrow supression
3. Alopecia
4. Secondary Leukamias
5. Sterility
6. Veno-occlusive disease of liver (↑dose)

9. Mechanism of Resistance development
• ↓ Permeation of actively transported drug (mechloethamine,
melphalan)
• ↑ intracellular concentrations of nucleophilic substances
• ↑ activity of DNA repair pathways
• ↑ rates of metabolism of the activated forms of
cyclophosphamide and ifosfamide

10. A. Nitrogen Mustards:
Currently used drugs:
Cyclophosphamide,
Ifosfamide
Wegener’s
granulomatosis, ALL, CLL, HL, NHL, Multi
ple myeloma
(MM), breast, ovary, lung, Wilm’s, cervix, t
estis
Mechlorethamine Hodgkin’s disease
Melphalan Multiple myeloma, breast, ovary
Chlorambucil CLL, HL, NHLDrug related side effects:
 Cyclophosphamide, Ifosfamide: Hemorrhagic cystitis, SIADH

11. Newer Agents:
Trofosfamide
• Prodrug of ifosfamide
• Orally active
• Metastatic soft tissue sarcomas
Prednimustine
• Ester of prednisolone and chlorambucil
• Better drug delivery
• CLL, NHL, Ca breast
• S/E: myelosuppression, fluid retension

12. Uramustine
• Derivative of nitrogen mustard and uracil
• Non Hodgkin’s lymphoma
Bendamustine
• Benzimidazole ring and nitrogen mustard
• Inhibits mitotic checkpoints & induces mitosis
• Partial cross resistance to other nitrogen mustards
• Approved for CLL
• Hodgkin’s lymphoma NHL, multiple myeloma, breast Ca
• S/E: myelosuppression, nausea, vomiting, hypersensitivity
reactions

13. B. Alkylsulfonates
Currently used:
Busulfan → CML
S/E: Pulmonary fibrosis, hyperpigmentation, adrenal insufficiency
Newer drugs:
Mannosulfan
• Tried for polycythaemia rubra vera
• Lesser S/E
• Phase 2
Treosulfan
• Evaluated for ovarian cancers
• Lesser S/E compared to busulfan

14. C. Nitrosoureas
• Highly lipid soluble
• Cross blood brain barrier
Currently used agents:
Carmustine, Lomustine, Semustine → Brain tumours like
gliomas
Streptozocin → pancreatic islet cell carcinoma, malignant
carcinoid tumors
A/E: delayed myelosupression, renal failure

15. Newer Agents:
Fotemustine
• Approved for metastasising melanoma
Nimustine
• Oligodendroglioma, Glioblastoma Multiforme
• Used with cytarabine
Ranimustine
• Approved in Japan
• CML and polycythemia vera

16. D. Other Alkylating agents
Currently used:
Procarbazine→ Hodgkin’s, brain tumors
Dacarbazine→ malignant melanoma, hodgkin’s lymphoma
Temozolomide→ malignant gliomas

17. II. Platinum Compounds
MOA:
• Use platinum to form dimers of DNA
• Intrastrand/ interstrand crosslinks
• CCNS
Currently used agents:
Testicular Ca, Ovarian Ca, Head and neck Ca, bladder Ca,
esophagus & colon Ca
S/E:
N, V, Bone marrow supression, nephrotoxicity,
peripheral neuropathy, ototoxicity
Cisplatin 1st Generation Highly nephrotoxic
Carboplatin 2nd Generation Less nephrotoxic
Oxaliplatin 3rd Generation Cisplatin/ Carboplatin
Resistant

18. Newer Drugs:
Nedaplatin
• 2nd generation analogue of cisplatin
• ↑ Sensitivity gynecological tumors:
Ovarian, Cervical and Endometrial Ca
• ↓ Renal toxicity, nausea & vomiting
• Exclusively approved in Japan since 1995
Triplatin tetranitrate
• Chloride prevents hydrolysis outside the cell
• ↓ diarrhoea, vomiting
• Cancers with cisplatin resistance
• Phase 2 trials: Ovarian Ca, Small cell lung Ca &
Gastro-oesophageal adenocarcinomas

19. Picoplatin
• Retains activity in Cisplatin & Oxaliplatin Resistant cells
• Activity by i.v. & oral routes
• Phase 3 small cell Lung Ca & Colorectal Ca
Aroplatin
• Liposomal oxaliplatin
• Incorporated in multilamellar liposomes
• Good biodistribution
• Well tolerated

20. III. Antimetabolites
• Act on S Phase (i.e. dividing) of cell cycle (CCS)
A. Antifolates
• Tranported intracellularly→ folate transporter
• Inhibit DHFrase→ purine synthesis
• Inhibit thymidylate synthase→ thymidine synthesis
• Intracellular formation of polyglutamate metabolites by FPGS

21. Currently used agents:
Methotrexate→ Choriocarcinoma, ALL, Ca breast,
head & neck Ca, Ca ovary, bladder
Pemetrexed→ Mesothelioma, NSCL Ca
A/E: bone marrow suppression, mucositis, hepatotoxicity;
pulmonary fibrosis (methotrexate), rashes (pemetrexed)

22. Development of resistance:
• ↓ transport via folate carrier
• ↓ formation of polyglutamates
• ↑ formation of DHFRase
• Altered DHFRase with ↓ affinity
Newer Drugs:
Trimetrexate:
• Lipid soluble
• Crosses BBB
• Bypasses membrane transport system→
transport-deficient MTX-resistant tumour cells
• Leiomyosarcoma & Skin Ca

23. Pralatrexate
• Enters cells expressing ↓ folate carrier type 1 (RFC-1)
• Relapsed or Refractory Peripheral T-cell lymphoma
• FDA approval in September 2009
Raltitrexed
• Quinazoline folate analogue
• Selectively inhibits thymidylate synthase (TS)
• Advanced colorectal cancer
Lometrexol
• Inhibits GARFT as well as AICART
• Inhibitor of de novo synthesis of purines
• Phase 2 clinical trials: NSCL cancer

24. B. Purine Analogues
MOA:
• Purine antimetabolites activated by HGPRTase
• Incorporated into DNA & RNA nucleotides
• Inhibits various enzymes of purine synthesis
Currently used agents:
6 Mercaptopurine AML
6 Thioguanine AML , ALL
Cladribine Hairy cell leukamia, CLL,
NHL
Fludarabine CLL, NHL

25. Newer Drugs:
Clofarabine:
• Paediatric patients for Relapsed or Refractory ALL
• S/E: Tumour lysis syndrome, bone marrow suppression,
Systemic Inflammatory Response (SIRS)
• FDA approved in 2004

26. C. Pyrimidine Analogues
MOA:
 Cytarabine
activated to arabinoside CTP→ Inhibit DNA polymeraseα/β
 5-FU
converted to 5-dUMP→ Inhibit Thymidylate synthase
 Capecitabine
prodrug of 5-FU
 Gemcitabine
Phosphorylated to GDP→ Inhibit Ribonucleotide Reducatase
GTP→ Inhibit DNA polymerase α/β, incorporated in DNA
 Azacytidine & Decitabine
DNA hypomethylation by inhibiting DNA methyl transferase

27. Cytarabine AML, ALL,CML in blast crises
5-FU Colorectal Ca, Anal Ca, Breast Ca,
Gastro-esophageal Ca, Head & Neck
Ca, hepatocellular Ca
Capecitabine Breast Ca, Colorectal Ca, Gastro-
esophageal Ca, Hepatocellular Ca,
Pancreatic Ca
Gemcitabine Pancreatic Ca, Bladder Ca, NSCL Ca,
Ovary Ca, Soft tissue Sarcoma
Azacytidine &
Decitabine
Pancreatic Ca, lung Ca, ovarian Ca,
Myelodysplasia

28. Newer Drugs:
Tegafur Uracil:
• Tegafur is 5-FU prodrug developed in 1967
• Had unacceptable CNS toxicity & discontinued
• Combination of Tegafur & Uracil (1:4)
• Uracil→ Inhibitor of Dihydropyrimidine Dehydrogenase
• ↑ levels of 5-FU without toxic levels of Tegafur
• Given orally
• Approved in Japan for last 15 years
• Gastric Ca, Colorectal Ca, HCC
Carmofur:
• Oral lipophilic derivativeof 5-FU
• Managable toxicities (hot flushes, urinary frequency)
• Serious toxicity- Leucoencephalopathy
• Adjuvant chemotherapy for curatively resected
Colorectal Ca

29. IV. Mitotic Spindle Inhibitors
A. Vinca Alkaloids:
MOA:
• Bind to microtubule protein-tubulin
• Dissolve the assembly
• Chromosomes cannot align along the division plate
• Cell division arrests in Metaphase
Currently used Agents:
Vinblastine, Vinorelbine Hodgkin’s, NHL, Breast, Lung,
Testis Ca
Vincristine ALL, Neuroblastoma, Wilm’s tumour,
Rhabdomyosarcoma, Hodgkin’s,
NHL

30. Adverse Effects:
• Vinblastine & Vinorelbine→ bone marrow depression (leukopenia)
• Vincristine→ peripheral neuropathy
Resistance:
• ↑ Expression of mdr-1 gene→ ↑ P-glycoprotein (efflux protein)
• Expression of Multidrug Resistant Protein & Breast Ca Related
Protein

31. Newer Agents:
Vinflunine:
• More activity than vinblastine/vinorelbine
• No peripheral neuropathy
• Use: Advanced bladder Ca, advanced Breast Ca
Vindesine:
• ALL, NSCL Ca
• S/E local vescicant, myelosuppression, peripheral neuropathy

32. B. Taxanes
MOA:
• Binds to β tubin subunit of micro-tubules
• Antagonises its disassembly
• Enhancement of tubulin polymerisation
• Metaphase arrest
Currently Used agents:
Paclitaxel, Docetaxel Ovarian, Breast, Prostate, Bladder,
Lung, Head & Neck Ca

33. A/E:
Hypersensitivity reactions, myelosuppression, peripheral
neuropathy
Resistance:
• ↑ Expression of mdr-1 gene→ ↑ P-glycoprotein
• ↑ Survivin→ anti-apoptotic factor
• β tubulin mutations
• Upregulation of β tubulin isoforms

34. Newer Agents:
Nab-Paclitaxel:
• Protein bound paclitaxel→ ↓ hypersensitivity reactions
Cabazitaxel:
• Poor substrate for P-glycoprotein efflux pump
• With Prednisolone→ Hormone refractory metastatic Prostate Ca
previously treated with Docetaxel containing regimen
• FDA approved in june 2010
• A/E: Myelosuppression, hypersensitivity reactions, diarrhea
Ortataxel:
• Blocks its own efflux from gpP-overexpressing cells
• Phase 2
• Tried for taxane refractory solid tumours (lung, breast, kidney)

35. Larotaxel:
• Active against taxane-resistant & multidrug-resistant tumors
• Crosses the blood brain barrier
• Advanced Pancreatic Ca & Advanced bladder Ca with
Brain metastasis
• Phase 3
Tesetaxel:
• Orally available
• Eliminates transfusion reactions
• ↓ incidence of peripheral neuropathy
• Tried in Advanced gastric & advanced breast Ca
• Phase 3

36. C. Epothiolones:
MOA:
• Bind to β tubulin
• Stabilise the microtubules
• G2M interphase arrest
Advantages:
• Less susceptible to gpP mediated Multi Drug Resistance
• Superior cytotoxic potential compared to taxanes

37. Ixabepilone
• With Capecitabine
Locally advanced or metastatic Breast Ca not responding to
Anthracyclins & Taxanes
• Monotherapy
Metastatic Breast Ca progressed through treatment with
Anthracyclins, Taxanes & Capecitabine
• A/E: neutropenia, peripheral neuropathy
• Approved in 2007
Sagopilone
• Natural product of epothilone B
• ↑ effective in stabilizing preformed microtubules
• Taxane-resistant settings
• Crosses the blood-brain barrier
• Use: Gastric cancer , NSCLC

38. Patupilone
• Paclitaxel-resistant cancer cells
• Target vasculature of solid tumor→
immature endothelial cells have strong dependence on tubulin
in maintaining their shape
• Phase 2 trials for solid tumours esp Ovarian Ca
KOS 1584/ 21 Aminoepothiolone
• Phase 1 trials

39. V. Topoisomerase Inhibitors
A. Camtothecins:
MOA:
• Inhibit topoisomerase I
• ss breaks
• Collision of replication fork with ss breaks→ ds DNA break
• S phase specific
Currently used Agents
Irinotecan, Topotecan Colon, Lung, Ovary Ca

40. A/E:
• Topotecan→ neutropenia
• Irinotecan→ diarrhoea, cholinergic syndrome
Newer Agents:
Belotecan
• Use ovarian cancer, small cell lung cancer

41. B. Antitumor Antibiotics
MOA:
• Inhibition of topoisomerase II
• Binding to DNA through intercalation→
blockage of DNA & RNA
• Semiquinone & oxygen free radicals
• Bind to cell membrane→ alter fluidity & ion transfer

42. Currently used Agents:
Doxorubicin Breast Ca, HL & NHL, soft tissue sarcoma,
Ovarian Ca, Lung Ca, Wilm’s tumor &
Neuroblastoma
Daunorubicin AML, ALL
Idarubicin AML, ALL, CML in blast crisis
Epirubicin Breast Ca, Gastro-esophageal Ca
Mitoxantrone Hormone Refractory Prostate Ca, NHL, AML
A/E:
Cardiotoxicity, myelosuppression, mucositis, radiation recall
syndrome

43. Newer Drugs:
Aclarubicin
• Inhihibits RNA synthesis more strongly than DNA
• Cardiotoxicity less
• Relapsed/ Resistant AML
Amrubicin:
• Marketed in Japan for Small cell Lung Ca
• Superficial bladder cancer and lymphoma

44. Pirarubicin:
• More lipophilic derivative
• Higher uptake rate of cells & better antitumor efficacy
• Lower cardiotoxicity
• Breast cancer, acute leukemias and lymphomas
• Phase 3
Zorubicin:
• Four times less cardiotoxic
• Less myelosupression
• Acute leukaemias & breast cancer
• Phase 3

45. Valrubicin:
• US FDA approved → BCG refractory bladder Ca insitu
• Administered intravescically
• Systemic absorbtion ↓
• A/E: urinary frequency, urgency, dysuria
Pixantrone:
• Analogue of mitoxantrone
• Less cardiotoxic
• Phase 3
• Relapsed or refractory aggressive NHL

46. Targeted Therapies

47. I. Enzyme Inhibitors:
A. Farnesyl-transferase Inhibitors:
• Ras proteins→ transduction of cell growth
• Ras gene mutation→ constant activation
→uncontrolled cell proliferation
• 30% of all human cancers
• Ras undergoes four steps of modification
• Isoprenylation: Farnesyl-tranferase→
transferring a farnesyl group
• Farnesyl transferase inhibitors (FTIs)
• Blockade of signal transduction pathway→
cessation of cell growth
• Tipifarnib & Lonafarnib

48. Function of Cyclins & Cyclin Dependent Kinases

49. B. Cyclin Dependent Kinase Inhibitors
• Over-expression of Cyclins & CDK’s in Ca
• Inhibitors of cyclindependent kinases (CDKs) restore
cell cycle control or induce apoptosis
Seliciclib:
• Inhibit CDK2→ G1S check point
• Inhibits CDK 7, 9 →inhibits RNA polymerase II dependent
transcription→ inhibits anti-apoptotic proteins
• NSCL Ca
Alvocidib (Flavopiridol):
• Same mechanism
• AML, CLL

50. Bortezomib
• Binds to 20S core of 26S
proteosome & reversibly
inhibits it
• FDA approved for Multiple
Myeloma &
Relapsed/Refractory
Mantle Cell Lymphoma
• A/E:
Thrombocytopenia, neutrop
enia, peripheral neuropathy
Salinosporamide A
• Similar mechanism
• Multiple myeloma
• Preclinical studies
C. Proteosome Inhibtitors

51. Anagrelide:
• Specific inhibition of thrombopoietin-mediated
intracellular signaling
• Reversibly disrupts MegaKaryocyte maturation→
post-mitotic phases of MK development
• Inhibitory effects→ MK ploidy, size and cytoplasmic maturation
• Thrombocythemia, primary/secondary to myeloproliferative
disorders
• Oral→ first-pass hepatic metabolism→ active metabolite
• A/E: Bone marrow fibrosis- reversible, cardiovascular effects
• FDA approved in 2005
D. Phosphodiesterase
Inhibitors

52. E. IMP Dehydrogenase Inhibitor:
• Converted intracellularly into NAD analogue
• Inhibits Inosine Monophosphate dehydrogenase (IMPDH):
IMP to XMP→ de novo guanylate biosynthesis
• Cell proliferation, cell signaling, energy source
• Apoptosis→ neoplastic cell lines & activated T lymphocytes

53. Drugs:
• Tiazofurin: Phase 3 for CML
• Selenazofurin :Phase 2
• Benzamide riboside: Phase 2

54. F. PARP Inhibitors:
• PolyADP-Ribose polymerase (PARP) →
Base excision repair of ss DNA breaks
• Inhibition: accumulation of ss breaks→ collision with DNA
replication forks→ ds breaks
• Ss break repaired by tumour-suppressor genes BRCA1 and
BRCA2→ Homologous Repair
• Mutated BRCA1 & 2→ mechanism defective

55. Iniparib
Phase 3 triple negative Breast Ca
Olaparib
Orally active
Phase 2 breast, ovary, colorectal Ca
Veliparib
Phase 2 breast Ca, melanoma

56. G. Histone Deacetylase Inhibitor
Vorinostat
• DNA warps around histones→ proteosomes
• Acetylation of lysine residues→↑ spatial distance between DNA &
histones→ ↑ transcription activity
• Acetyl group deacetylated by Histone Deacetylases (HDACs)
• Refractory
Cutaneous T-Cell Lymphoma
• A/E- thrombocytopenia,
QT prolongation

57. Romidepsin
• Similar mechanism
• Approved Cutaneous T-Cell Lymphoma &
Peripheral T Cell Lymphoma
Other HDAC Inhibitors in pipeline
Phase 3:
• Panobinostat
Phase 2:
• Belinostat
• Mocetinostat

58. II. Receptor Antagonists:
A. Endothelin Receptor Antagonist (ERA)
• Endothelin receptors are ETA, ETB1, ETB2
• G-Protein coupled receptors
• Control vascular tone
• ETA Vasocontriction, ETB Vasodilation
Atrasentan
• ERA for subtype ETA
• Vasodilation→ ↑ tumor perfusion, ↓ hypoxia
• ↑ drug delivery, ↑ sensitivity to drug & radiation
• NSCL Ca
• Phase 3

59. B. Retinoid Receptor Agonist
• Retinoids modulate cell proliferation, differentiation, apoptosis
• Retinoid acid receptors (RARs) α,β,Ɣ
• Retinoid X receptors (RXR) α,β,Ɣ
• RXRs heterodimers with RAR’s, vitamin D receptor, thyroid
hormone receptor & PPAR
• Heterodimer binds DNA→ expression of retinoid regulated
genes

60. Bexarotene
• Synthetic retinoid
• Specifically binds to RXRs
• Anticancer action→ blocks cell cycle progression,
induce apoptosis & differentiation, anti-angiogenesis
• FDA approved for the Cutaneous T-cell lymphoma
refractory to at least one prior systemic therapy
• Gel & oral

61. C. Miscellaneous
Amsacrine
• Intercalates into DNA of tumor cells→
altering major & minor groove proportions→
ds DNA breaks
• Inhibits topoisomerase II→ S phase and G2 arrest
• Acute adult leukemia refractory to conventional treatment

62. Trabectedin (Yondelis)
• Marine tunicate
• Binds to minor groove of DNA→
alkylates guanine at N2 position→
bend DNA towards the major groove→
large ternary complexes ds DNA break
• Production of superoxide near DNA strand→
DNA backbone cleavage
• EU- Relapsed Soft tissue sarcomas, Recurrent ovarian Ca

63. Tyrosine Kinase
Inhibitors

64. Protein kinase phosphorylate proteins
Functional change of target protein→
change enzyme activity, cellular location or association with other
proteins
Tyrosine kinases→ subgroup of protein kinases
Phosphorylation of proteins→ Gene trancription &/or DNA
synthesis
Functions as "on" or "off" switch
Mutated, stuck in the "on" position→
unregulated growth of the cell→ Cancer

65. I. Receptor Tyrosine Kinase Inhibitors
A. Epidermal Growth Factor Receptor Inhibitor/
HER 1 Inhibitor
Geftinib:
• Inhibits EGFR tyrosine
kinase activity
• Blocks ATP binding site
• Oral administration
• Approved for NSCLC pts.
who have failed with
std. chemotherapy
• A/E: diarrhoea, pustular/papular
rash

66. Erlotinib
• Similar mechanism of action
• Locally advanced or metastatic NSCL & Pancreatic Ca
• A/E: same

67. B. EGFR/HER1 & HER2/neu Inhibitor
Lapatinib
• Inhibits EGFR & HER2/neu
Kinase activity
• ATP binding pocket
• Approved for Trastuzumab
Refractory breast Ca with
Capecitabine
• Small molecule→ Crosses BBB→
Brain mets (Phase 3)
• A/E: acneform rash, GERD,
diarrhea

68. Afatinib:
• Similar mechanism
• Phase 3: NSCL Ca
Neratinib:
• Phase 2: Breast Ca

69. Angiogenesis of Tumour
• Angiogenesis→ essential property of Ca
• Angiogenic factors→ VEGF, FGF, TGFβ & PDGF
• Turn on angiogenic switch→ tumor growth & mets
• Leaky capillaries→ ↑ permeability→ ↑ interstitial pressure
•↓ drug delivery, ↓ oxygenation
• Anti-angiogenic factors antagonise these actions

70. C. Multiple Receptors Inhibitor
Sunitinib:
• Inhibits multiple tyrosine kinases
VEGFR 2, FLT3, PDGFR α & β (angiogenesis)
RET, CSF1-R & c-KIT (cell proliferation)
• Metastatising RCC & GIST resistant to Imatinib
• A/E: hypertension, proteinuria, arterial thrombotic events
Sorafenib
• Inhibits multiple tyrosine kinases
VEGFR 1, 2 & 3, PDGFR β (angiogenesis);
c-KIT, b-RAF (cell proliferation)
• Hepatocellular Ca & metastatising RCC
• A/E: same

71. Pazopanib
• Multi-targeted receptor tyrosine kinase inhibitor
VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit
• Blocks tumour growth & inhibits angiogenesis
• FDA approved for renal cell carcinoma
• Long t1/2 30 hrs
• A/E: hair colour changes, hypertension, hepatotoxicity

72. II. Non Receptor Tyrosine Kinase
Inhibitors
A. bcr-abl Inhibitor
Has activity against:
• bcr-abl Tk→ CML
• Mutant c-KIT Tk→ GIST
• Mutant PDGFR→ CMML,
hypereosinophilia $,
dermatofibrosarcoma protuberans
Currently used:
• Imatinib

73. Newer Agents:
Dasatinib:
• Binds of open & closed configurations
• Approved for CML→ Intolerant/ Resistant to Imatinib
Nilotinib:
• ↑Potency & ↑ Efficacy
• Long t1/2 17 hrs
• Approved for CML→ Intolerant/ Resistant to Imatinib
A/E:
• GI distress→ N, V, diarrhoea
• Edema & peri-orbital swelling
• Nilotinib→ Prolongs QT interval

74. B. Src tyrosine kinase inhibitor
Bosutinib:
• Inhibits the autophosphorylation of
bcr-abl & Src kinases
• Src→ Transmit integrin dependent signals for cell proliferation
• 30 times more potent → inhibition of bcr-abl
• Against imatinib-resistant mutants of bcr-abl
• Resistant CML failed first-line imatinib and second-line dasatinib

75. C. Janus Kinase 2 Inhibitors
Lestaurtinib
• JAK enzymes→ signaling of cytokine & growth factor receptors
• JAK/STAT signaling exaggerated in MPNs
• Polycythemia vera, essential thrombocythemia & primary
myelofibrosis
• Mutant JAK2 activity
• Inhibits wild type JAK2 kinase activity→
JAK2/STAT5 signaling in cells
• Inhibits proliferation MPD cells
• Phase II AML & Myeloproliferative disorders

76. D. EML4-ALK Fusion Inhibitor
Crizotinib
• Non–small-cell lung cancers→
echinoderm microtubule-associated like-protein 4
anaplastic lymphoma kinase (EML4-ALK) fusion gene
• Protein product→ kinase activity
• Inhibits anaplastic lymphoma kinase (ALK) tyrosine kinase
• Competes with ATP for kinase domain
• Modulation of the growth, migration & invasion of malignant cells
• Phase 3→ ALK-positive NSCLC (non smokers)

77. E. Fusion Protein Against VEGF
Aflibercept
• Fusion protein: VEGFR1 and VEGFR2 , fused to the constant
region of human IgG1
• VEGF → angiogenic factors includes VEGF-A, VEGF-B, and
placental growth factor (PIGF)
• PIGF→ important regulator of angiogenesis
• Binds to VEGF & PIGF in bloodstream & extravascular space
• VEGF Trap
• Inhibits Angiogenesis
• Phase 3 Prostate & Colorectal Ca

78. 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

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

80. 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
I. Monoclonal Antibodies

81. II. Radioimmuno- Conjugated Monoclonal Abs:
• 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.

83. III. 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

84. Gemtuzumab zogamicin
• Humanized anti-CD33 monoclonal antibody conjugated with
Calicheamicin
CD33→ Myeloid lineage
• Calicheamicin → enediyne antitumor antibiotic
• Binds to the minor groove of DNA→ ds breaks
• FDA approval AML
Others in Pipeline:
• Methotrexate (MTX) conjugated with murine monoclonal
antibody (aMM46) mouse mammary tumor antigen (MM
antigen)
• Paclitaxel-antibody conjugates
• Antibody Linked To Ricin Toxin

85. Newer Drug Carrier 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

86. Solubilisers
• Majority anticancer drugs→ poor solubility
• Newer agents→ Sorporol 230, Sorporol 120 Ex,
Aceporol 345-T, Riciporol 335
Self-Emulsifying Drug Delivery Formulations (SEDDS)
• Enhance oral absorption of poorly soluble drugs
Implantable Carmustine wafer
• Gliadel→ adjunct to surgery & radiation
• Newly diagnosed high grade malignant glioma
• Recurrent Glioblastoma multiforme
• Biodegradable polymer
• Dissolves over several weeks
• Releases drug directly to the area of resection
• Avoiding systemic toxicity

87. 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

88. 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

89. Immunoliposomes
• Antibodies or ligands are attached to the liposome surface
• ↑ binding to specific epitopes/receptors on target cells
Stealth liposomes
• Formulated to escape RES
• ↑ the circulation time→ Depot preparations
• Coat→ Polymers, polyethylene glycols, synthetic phospholipids
• Hematological malignancies

90. Proteins & Amino acids as Carrier system
• D-alanine with nitrogen mustard→ good bioavailability
• Serum albumin of human, bovine or rat origin
Cyclodextrins
• Carbohydrate macrocycles
• Form molecular inclusion complexes
with hydrophobic molecules
• A/E renal toxicity
• Eg: melphalan & carmustine
Dendrimers
• Repeatedly branched,
roughly spherical large molecules
• Drug can be coupled to
the core or surface of dendrimer
• Polyamidoamine→ targeted drug carrier
• Eg: Dendrimer platinate→ ↓ toxic than cisplatin

91. Antibody Dependent Enzyme Prodrug Therapy (ADEPT)
• Initial→ Antibody Enzyme Conjugate against tumor
• f/b prodrug
• Activated at tumor site by the enzyme
• Eg: Etoposide, taxol, camptothecin

92. Nanotechnology
• Highly targeted therapy with high efficacy & low toxicity.
• Transport of drug across BBB.
• Deliver anticancer drugs into cells
without triggering p- glycoprotein pump
• Paclitaxel, Doxorubicin, Dexamethasone 5- FU

93. 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

94. Superparamagnetic nanoparticles
• Iron oxide magnetic nanoparticles
• Functionalized with recombinant single chain Fv antibody
fragments
• Target cancer cells
• Injected into the tumor and then heated in an alternating
magnetic field

95. Oncolytic Viruses
• Viruses that replicate selectively in tumor cells with defined
genetic lesions, causing cell death
• Include adenoviruses & RSV
• Designed to replicate in tumor cells that lack functional p53
• Lysis→ Release inflammatory mediators (GM-CSF & TSA)→
Dendritic cells→ Immune response throughout the body

96. 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

97. 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
Prostatic acid phosphatase (PAP).
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

98. 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
• Skeletal muscle cells & adipose cells
• Altered cells would then make the antigen on an ongoing basis
• Keep the immune response strong

99. 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

100. Chemoprevention
• Adjuvant Isotretinoin→ ↓incidence of second primary tumors in
pts. treated with local therapy for H & N cancer
• Oropharyngeal premalignant lesions responded to
β- carotene, retinol, Vit E, Selenium
• Diets high in calcium, lower colon cancer risk
• Men taking Selenium to prevent skin cancer→ ↓ incidence of
prostate cancer.
• Potential of COX- 2 inhibitors to prevent colorectal cancer
continues to remain a subject of study

101. Other Treatment Modalities
1. Hormones
2. Immunomodulators
3. Radioisotopes
4. Complementary System of Medicine

102. Conclusion
The period from 1980 to the present has seen a remarkable
growth in the understanding of many of the cellular and
molecular mechanisms underlying malignant transformation of
a cell.
Given our increasing knowledge about the biology of cancer,
it is clear that no single therapy will serve as a panacea & it is
most likely that in the near future, agents directed against the
molecular events will have to be combined with the existing
standard chemotherapies for the desired outcome