SONALI JAIN

1. PARUL INSTITUTE OF PHARMACY
Topic – Recent advance in treatment of cancer
PRESENTED BY
SONALI JAIN
MPHARM(PHARMACOLOGY)
DEPARTMENT OF PHARMACY
GUIDED BY
DR. JITENDRA VAGHASIYA
ASSOCIATE PROFESSOR
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2. CONTENT
• What is cancer?
• The cell cycle
• Etiology and pathophysiology of cancer
• Causes and risk factor
• Classification of newer drugs
• References
2

3. What is Cancer?
• Cancer is a disease characterized by
uncontrollable, irreversible, independent,
autonomous, uncoordinated and relatively
unlimited and abnormal over growth of
tissues.
• Cancer spreads by invasion to the
surrounding tissues and by metastasis to
distant sites.
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4. 4

5. 5

6. Causes and risk factors
• Environment
 cigarette smoke
 chemicals
 UV light
 viruses
• Metabolic processes
 free radicals
 DNA copying and repair defects
 Inherited genetic mutations
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7. Classification of newer drugs
1. 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:
 Gastrointestinal distress
 Bone marrow supression
 Alopecia
 Secondary Leukamias
 Sterility
 Veno-occlusive disease of liver (↑dose) 7

8. 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
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9. • A. Nitrogen Mustards:
• Currently used drugs:
 Cyclophosphamide, Ifosfamide Wegener’s
granulomatosis, ALL, CLL, HL, NHL , Multiple myeloma
(MM), breast, ovary, lung, Wilm’s , cervix, testis
 Mechlorethamine : Hodgkin’s disease
 Melphalan: Multiple myeloma, breast, ovary
 Chlorambucil CLL, HL, NHL
• Drug related side effects:
 Cyclophosphamide, Ifosfamide: Hemorrhagic cystitis,
SIADH
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10. • 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
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11.  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
11

12. • 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
12

13. 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
13

14. • Newer Agents:
 Fotemustine
 Approved for metastasising melanoma
 Nimustine
 Oligodendroglioma, Glioblastoma Multiforme
 Used with cytarabine
 Ranimustine
 Approved in Japan
 CML and polycythemia vera
14

15. • D. Other Alkylating agents
• Currently used:
 Procarbazine→ Hodgkin’s, brain tumors
 Dacarbazine→ malignant melanoma, hodgkin’s lymphoma
 Temozolomide→ malignant gliomas
15

16. 2. 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
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17. • 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
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18.  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
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19. 3.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
• 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)
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20. • 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
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21.  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 21

22. • 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
22

23. • 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
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24. • 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
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25.  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, Myelodysplasi
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26. • 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
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27. 4. 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
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28. • 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
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29. • 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
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30. • 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)
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31.  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
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32. 5. 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
• Newer Agents:
 Belotecan : Use ovarian cancer, small cell lung cancer 32

33. • 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
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34. • 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
 Pirarubicin:
 More lipophilic derivative
 Higher uptake rate of cells & better antitumor efficacy
 Lower cardiotoxicity
 Breast cancer, acute leukemias and lymphomas
 Phase 3 34

35.  Zorubicin:
 Four times less cardiotoxic
 Less myelosupression
 Acute leukaemias & breast cancer
 Phase 3
 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 35

36. References
1. Workman, P. Auditing the pharmacological accounts for
Hsp90 molecular chaperone inhibitors: Unfolding the
relationship between pharmacokinetics and pharmacody
namics. Mol Cancer Ther 2003.
2: 131-8. 2. Sawyers, C.L. Opportunities and challengesin the
development of kinase inhibitor therapy for cancer. Genes
Dev 2003, 17:2998-3010.
3. Kamal, A., Thao, L., Sensintaffar, J. et al. A high-affinity
conformation of Hsp90 confers tumour selectivity on Hsp90
inhibitors. Nature 2003, 425: 407-10.
4. Neckers, L. Hsp90 inhibitors as novel cancer
chemotherapeutic agents. Trends Mol Med 2002, 8: S55-61.
36

37. • 5. Elbashir, S.M., Harborth, J., Lendeckel, W.. Yalcin, A., Weber,
K. interference in cultured mammaliancells. Nature 2001, 411:
494-8.
• 6. Brummelkamp. T.R., Nijman. S.M.. Dirac, A.M. and
Bernards, R. Loss of the cylindro matosis tumour suppressor
inhibits apopto sis by activating NF-kappaB. Nature 2003.424:
797-801.
• 7. Subbaramaiah, K. and Dannenberg. A.J. Cyclooxygenase 2:
A molecular target for cancer prevention and treatment.
Trends Pharmacol Sci 2003, 24: 96-102.
8. Harrington, E.A., Bebbinand Tuschl, T. Duplexes of 21
nucleotide RNAs mediateRNA gton, D., Moore, J. et al. VX-680,
a potent and selective small molecule inhibitor of the Aurora
kinases, suppresses tumor growth in vivo. Nat Med 2004, 10:
262-7. 37

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