A comprehensive presentation on cancer biochemistry including biochemical changes,carcinogens,mechanism of chemical carcinogenesis ,oncogenes & activation,monoclonal antibodies for cancer therapy,diet ,prevention &tumor markers

1. CANCER
DR ROHINI C SANE
PROFESSOR
DEPARTMENT OF BIOCHEMISTRY
DR D Y PATIL MEDICAL COLLEGE
EBENE

2. CANCER
• CANCER DISEASE- IN WHICH CELL GROW ABNORMALLY –MALIGNANT NEOPLASM
• (NEW GROWTH )-NEOPLASIA
• A MASS OF TISSUE ---ABNORMAL ,EXCESSIVE,UNCORDINATED ,PURPOSELESS
PROLIFERATION
• ONCOLOGY = ONCOS ( TUMOR ) + LOGY (STUDY )
• BENIGN TUMOR---THAT DOSE NOT INVADE /SPREAD –NON CANCEREROUS
• MALIGNANT TUMOR /CANCER –INVADES DESTROY TISSUE IN WHICH ORIGINATES
–CAN SPREAD IN OTHER TISSUES VIA BLOOD STREAM & LYMPHATIC SYSTEM

3. PROPERTIES OF CANCER CELLS
• UNRESTRAINED GROWTH
• INVANSION OF LOCAL TISSUE
• METASTASIS
MORPHOLOGICAL CHANGES
SHAPE ---ROUNDER
MOTILITY ---LOSS OF CONTACT INHIBITION OF MOVEMENTS
GROWTH --- LOSS OF CONTACT INHIBITION –MULTILAYER /NUMBER OF NUCLEI
BIOCHEMICAL CHANGES
ALTERED GENE REGULATION ---DNA SYNTHESIS ---RNA SYNTHESIS ---PROTEIN
SYNTHESIS---ANABOLISM---GROWTH

4. BIOCHEMICAL CHANGES
ALTERED GENE REGULATION
INCREASED DNA SYNTHESIS
INCREASED RNA SYNTHESIS
 INCREASED PROTEIN SYNTHESIS
ANABOLISM---GROWTH FACTORS &HORMONES
INCREASED AEROBIC & ANAEROBIC GLYCOLYSIS
SYNTHESIS OF LACTIC ACID & LACTIC ACIDOSIS
ALTERATION OF CELL SURFACE DUE CHANGES IN COMPOSITION OF
GLYCOPROTEINS & GLYCOSPHINGOLIPIDS
DECREASED

5. BIOCHEMICAL CHANGES
• CARCINOMAS –CANCER ARISES FROM EPITHELIAL TISSUE
• SARCOMAS –MESENCHYMAL TISSUE
• LEUKAEMIAS-WBC
• LYMPHOMAS
• HEPATOMAS –HEPATOCYTES

6. ETIOLOGY
FAMILIAL GENETIC FACTOR
GEOGRAPHIC FACTORS
• ASIANS-NASOPHARYNGEAL
• JAPNESE –BREAST
• AFRICA –SKIN
• EUROPEANS--COLON
• ENVRIMENTAL FACTORS
• AGE->50YRS
• SEX- MEN >WOMEN

7. ENVIROMENTAL FACOTRS
• CIGARETTE SMOKING
• ALCOHOL ABUSE
• TOBACCO
• BETEL NUT
• ARSENIC
• VINYL CHLORIDE
• ASBESTOS
• BENZENE
• NAPHTHYLOMINE

8. PHYSICAL CARCINOGENS
• RADIENT ENERGY ---UV LIGHT ,IONIZING RADIATIONS
• EXAMPLS –SUNLIGHT ,WELDERS ARC ,UV LAMPS ---SKIN CANCER
• FORMATION OF PYRIMIDINE DIMER IN DNA STRAND
• FORMATION OF APURINIC OR APYRIMIDINE SITE ELIMINATION OF BASES
• BREAKING OF CROSS LINKING OF SINGLE OR DOUBLE STRAND OF DNA
IONIZING RADIATIONS –X RAYS ,ALPHA ,BETA ,GAMMA RAYS ,RADIOACTIVE
ISOTOPES ,PROTONS ,NEUTRONS
• IONIZING RADIATIONS---DAMAGE DNA ,DISLODGE IONS FROM H2O&
BIOMOLECULES ,INTERACT WITH PROTEINS, DNA-----CANCER
(MUTAGENESIS)

9. HORMONAL CARCINOGENESIS
• HORMONE SENSITIVE TISSUE ---BREAST ,ENDOMETRIUM,
MYOMETRIUM,VAGINA THYROID, ,LIVER ,PROSTRATE,TESTIES
• ESTROGENS---OVARIAN,ENDOMETRIUM CARCINOMA
• CONTRACEPTIVE HORMONES ---BREAST CANCER
• ANABOLIC STEROIDS---ATHLETS,LIVER CANCER

10. Biological carcinogens
• Viruses, parasites ,bacteria
DNA VIRUS
• PAPOVIRUS ---HPV (HUMAN PAPILLOMA VIRUS),SV40B,POLYOMA
VIRUS
• HERPES VIRUS –EPSTEIN BAR VIRUS
• ADENOVIRUS –12,18,31
• HEPITITIS B VIRUS (HBV)

11. RNA VIRUS
ACUTE TRANSFORMING VIRUS :ROUS SARCOMA VIRUS :LEUKEMIA
VIRUS
SLOW TRANSFORMING :MOUSE MAMMARY TUMOR VIRUS
HUMAN T CELL LYMPHOTROPIC VIRUS --- HTLV -1,HTLV II
RNA REVERSE TRANSCRIPATASE
RNA –DNA NEOPLASIA
NOT ALL RETROVIRUSES ARE CARCINOGENIC

12. CARCINOGENESIS &CHEMICAL CARCINOGENS
INITIATORS
DIRECT –DO NOT REQUIRE METABOLIC ACTIVATION
EXAMPLES ---ALKYLATING AGENTS—CYCLOPHOSPAHMIDE
ACYLATING AGENTS-- NITROSOUREA

13. CARCINOGENESIS & CHEMICAL CARCINOGENS
INDIRECT –
AROMATIC HYDROCARBONS---BENZOPYRENES
TOBACO
COAL
TAR
SMOKE
AROMATIC AMINES AZO DYES
BETA NAPHTHYL AMINE
ACETALAMINO FLUORENE
NATURALLY OCCURING ALF TOXIN
BETEL NUT
MISCELLENEOUS ----- VINYL CHLORIDE ,ASBESTOS ,NI, CARBON MONOXIDE

14. PROMOTERS OF CARCINOGENS
• NOT CARCINOGENS BUT INITIATE CARCINOGENESIS
• EXAMPLES –PHENOLS,ESTROGENS,ARTIFICIAL SWEETNER
SACCHARINE,CYCLAMATES
• METABOLIC ACTIVATION

15. Pro-carcinogens
Proximate carcinogens
Ultimate carcinogens
(free radicals)

16. Mechanism of action of chemical carcinogens
DIRECT REACTING CARCINOGEN (WITH NO METABOLIC ACTIVATION
)&INDIRECT (WITH METABOLIC ACTIVATION FORMS REACTIVE
ELECTROPHILES
Electrophiles (free radicals)—deficient in electrons
Interact with DNA Neutrophiles (chiefly DNA,RNA,PROTEINS)
DAMAGE (DNA MUTATION ,DNA repair enzymes fail)
Neoplastic transformation
Development of cancer

17. Apoptosis
• Dropping /falling of the normal programmed destruction of cells
.,during embryogenesis, development of adult life.
• Destruction of apoptosis promote inappropriate cell division ,cell
survival ---development of cancer

19. Proto-oncogenes –normal genes –stimulate cell division
Proto-oncogenes (activated by physical, chemical, biological carcinogens )-----
oncogenes ---growth factor ,growth factor receptors ,signal transduction proteins
Tumor suppressor gene –inhibit cell division
Normal cell –balanced activity of tumor suppressor & protooncogene activator
genes ---normal growth & repair
Neoplasia –uncontrol cell division ---(1)decreased suppressor activity
(2)increased proto-oncogene activity

20. Oncogene expression
proto –oncogenes control normal growth &cell division
Mutated versions of proto-oncogenes act as oncogenes
examples
• Growth factors
• Growth factor receptors
• Protein involved in signal transduction(protein kinase that phosphorylates
tyrosine /serine residue )---GTP binding protein
• Proteins involved in signaling gene expression in nucleus
• some growth factor induce growth but not cell division –cell grows large in size
without ever dividing
• 50 types of growth factors identified –first platelet diving growth factor (PDGF)

21. Mechanisms of activation of proto-oncogenes to oncogenes
• Promoter and enhancer insertion
• Chromosomal translocation
• Gene amplification
• Point mutation
• Effect of oncogene on growth ---putting one foot on accelerator of
automobile
• Tumor suppressor gene ---taking one foot from the break

22. ONCOGENES CHROMOSOMES VIRUS ONCOGENE PRODUCTS
abl 9 Abbleson leukemia in
mouse
Tyrosine kinase
erb B 7 Erythroblastosis in chicken Receptor for E & PR
erb –A 17 Erythroblastosis in chicken Transforming growth factor
receptors
myc 08 Myelocytoma in chicken Platelet derived growth factor
ras 12 Rat sarcoma GTPase

24. ONCOSUPPRESSOR ABBREVATIONS CHROMOSOMES
RETINOBLASTOMA RB 13
FAMILLIAL BREAST
CANCER
BRCA1
BRCA2
17
GENE FOR PROTEIN 53 P53 17

26. Retinoblastoma gene RB gene
• Nucleo phosphoprotein –regulates DNA SYNTHESIS
• SWITCH OF CELL PROLIFERATION—SUPPRESS TUMOR FORMATION

28. MODE OF DNA VIRAL ONCOGENESIS
VIRUS + DNA
ALTERATION IN GENE EXPRESSION
CELL TRANSFORMATION
TYPE OF PROTEIN ALTERED
INACTIVATION OF TUMOR SUPPRESSOR
NEOPLASM

29. MODE OF RNA VIRAL ONCOGENESIS
RNA
DNA (SINGLE STANDED )
C DNA (DOUBLE STRANDED)
C DNA GETS INCORPORATED IN HOST DNA ---PROTEINS /ENZYMES ,
HORMONES SYNTHESIZED
NEOPLASTIC CHANGES

30. IMMUNOLOGIC SURVEILLANCE
• IMMUNE SYSTEM
• RECOGNIZES SPECIFIC ANTIGENS
• DESTROY CANCER CELLS CARRYING ANTIGENS ---STOP ABNORMAL
GROWTH
• IF IMMUNOLOGIC SURVELLIENCE FAILS CANCER GROWS

32. Tumor markers
• DEFINITION –BIOLOGICAL SUBSTANCES SYNTHESIZED OR RELEASED
BY CANCER CELLS AND FOUND IN INCREASED AMOUNT IN BLOOD
,BODY FLUID OR TISSUES INDICATING PRESENCE OF CANCER

33. APPLICATIONS OF TUMOR MARKERS
• DIAGNOSIS (SCREENING )
• DIFFENTIAL DIAGNOSIS
• STAGING OF CANCER
• DETECTION OF RECURRENCE
• MONITORING RESPOSE TO THERAPY (PROGNOSIS)

34. Tumor markers
ENZYMES
PROSTATIC ACID PHOSPHATASE---PROSTRATE CANCER
ALKALINE PHOSPHATASE --- BONE SECONDARIES
PROTEINS
• PROSTRATE SPECIFIC ANTIGEN----PSA--PROSTRATE CANCER
• MULTIPLE MYELOMA----SERUM PROTEIN IMMUNOGLOBULIN/BENCE JONES PROTEINS
• C PEPTIDE ---INSULINOMA
• BETA MICROGLOBULINS –BETA CELL LYMPHOMAS
CARBOHYDRATE
• CARBOHYDRATE ANTIGEN (CA—125)—OVARIAN ,ENDOMETRIUM
• CARBOHYDRATE ANTIGEN (CA—549)—BREAST ,OVARIAN

35. Tumor markers
HORMONES & THEIR METABOLITE
• Beta HCG ---CHORION
CARCINOMA
• CALCITONIN ---
MEDULARYCARCINOMA
• VANILLYL MANDELLIC ACID –
NEUROBLASTOMA
• PROLACTIN –PITUITARY
ADENOMA
• PTH –RENAL,BREAST,LIVER
ONCOFETAL ANTIGENS
• ALPHA FETO PROTEINS ---(AFP)
HEPATOMA
• CARCINOEMBRYONIC ANTIGEN---
(CEA)--COLON ,LUNG ,GIT

36. CANCER & DIET
• INCREASED ANIMAL FAT
• INCREASED BACTERIAL FLORA
• CONVERSION OF ACIDS & STEROLS
• CARCINOGENS
• BENEFIAL ROLE OF VITAMIN C ,E ,SELENIUM ,BETA CAROTENE
• TRACE ELEMENTS ---Manganese ,zinc ,selenium, copper
• Tomatto ,cabbage ,cauliflower

37. Cancer therapy
• Chronic myeloid leukaemia (CML)
• ONCOGENES C—abl (9 ) ,bcr (22)---protein kinase ,tyrosine kinase
• Trnlocation of bcr gene to abl gene --bcr –abl gene –protein kinase
enzyme
• Bcl---abl not regulated
• Increased protein kinase
• Gleevec ---antitumor drug ---STI 571 USED IN TREATMENT OF BCR-
ABL GENE—(tyrosine KINASE) ---90% cancer patients respond to
treatment –rapid growth decreased but side effects

38. MONCLONAL
ANTIBODIES
TARGET USED AGAINST CANCER
Ritutab CD20 ON B CELLS BETA CELL LEUKEMIA
HERCEPTIN HER 2/EGFR 2 BREAST CANCER
BERACIZUMAB VGEF COLORECTAL CANCER
NILITINIB TYROSINE KINASE SOLID CANCER
IMATINIB TYROSINE KINASE NON SMALL CELL LUNG CANCER
GENTFITINIB TYROSINE KINASE CML
PANITUMUMAB EGFR COLORECTAL CANCER

40. IMAGES FROM GOOGLE