Recent advances in Cancer Chemotherapy

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

4. The Cell Cycle

5. 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.

6. Cytotoxic Drugs

7. 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 )

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

9. 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

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

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

12. 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

13. 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

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

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

16. 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 1 st Generation Highly nephrotoxic Carboplatin 2 nd Generation Less nephrotoxic Oxaliplatin 3 rd Generation Cisplatin / Carboplatin Resistant

17. Newer Drugs : Nedaplatin 2 nd 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

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

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

20. 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 )

21. 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

22. 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

23. 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

24. 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

25. Pyrimidine Analogues MOA : Cytarabine activated to arabinoside CTP→ Inhibit DNA polymerase α / 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

26. 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

27. 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

28. Mitotic Spindle Inhibitors 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

29. 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

30. 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

31. 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

32. 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

33. 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)

34. 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

35. 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

36. 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

37. 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

38. Topoisomerase Inhibitors 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

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

40. 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

41. 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

42. 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

43. 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

44. 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

45. Targeted Therapies

46. Enzyme Inhibitors: 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

47. Function of Cyclins & Cyclin Dependent Kinases

48. 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

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

50. 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 Phosphodiesterase Inhibitors

51. 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

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

53. 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

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

55. 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

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

57. Receptor Antagonists: Endothelin Receptor Antagonist (ERA) Endothelin receptors are ET A , ET B1 , ET B2 G-Protein coupled receptors Control vascular tone ET A Vasocontriction , ET B Vasodilation Atrasentan ERA for subtype ET A Vasodilation → ↑ tumor perfusion, ↓ hypoxia ↑ drug delivery, ↑ sensitivity to drug & radiation NSCL Ca Phase 3

58. 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

59. 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

60. 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

61. 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

62. Tyrosine Kinase Inhibitors

63. 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

64. Receptor Tyrosine Kinase Inhibitors 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

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

66. 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

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

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

69. 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

70. 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 t 1/2 30 hrs A/E: hair colour changes, hypertension, hepatotoxicity

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

72. Newer Agents : Dasatinib : Binds of open & closed configurations Approved for CML→ Intolerant/ Resistant to Imatinib Nilotinib : ↑Potency & ↑ Efficacy Long t 1/2 17 hrs Approved for CML→ Intolerant/ Resistant to Imatinib A/E : GI distress→ N, V, diarrhoea Edema & peri -orbital swelling Nilotinib → Prolongs QT interval

73. 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

74. 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

75. 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)

76. 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

77. 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

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

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

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

81. 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

82. 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

83. 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

84. 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

85. 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

86. 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

87. 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

88. 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

89. 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

90. 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

91. 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

92. 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

93. 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

94. 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

95. 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). 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

96. 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

97. 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

98. 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

99. Other Treatment Modalities Hormones Immunomodulators Radioisotopes Complementary System of Medicine

100. 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