Carcinogenesis

UNDERSTANDING OF CHEMICAL CARCINOGENESIS:�CURRENT AND FUTURE PERSPECTIVES
Carcinogenesis refers to the process by which a normal cell is transformed into a malignant cell and repeatedly divides to become a cancer
Chemicals which initiate this process is called chemical carcinogens
Chemicals which increase the effectiveness of carcinogens is called co-carcinogens
CLASSIFICATION OF CHEMICAL CARCINOGENS
MECHANISM OF ACTION
STAGES OF CARCINOGENESIS
ROLE OF PROTO-ONCOGENES AND TUMOR SUPPRESSOR GENES
ACTIVATION OF PROTO ONCOGENES
INACTIVATION OF TUMOR SUPPRESSOR GENE
OXIDATIVE STRESS IN CARCINOGENESIS
ROS can be produced from both endogenous and exogenous sources
Attack both purine and pyrimidine bases, as well as the deoxyribose backbone
Induces DNA damage which includes single or double-strand breakage, deoxyribose modification, and DNA cross-link
If DNA damage is not properly repaired it may result in mutation which leads to cancer
BIOMARKERS
REGULATORY BACKGROUND
OECD guidelines
451- Carcinogenecity studies
453- Combined chronic toxicity/carcinogenecity
ICH guidelines
S1A- Guideline on the need for carcinogenicity studies of
pharmaceuticals
S1B- Testing for carcinogenicity of pharmaceuticals
S1C- Dose selection for carcinogenicity studies of pharmaceuticals

1. UNDERSTANDING OF CHEMICAL CARCINOGENESIS: CURRENT AND FUTURE PERSPECTIVES Chander K Negi [email protected] 1

2. TABLE OF CONTENTS INTRODUCTION CLASSIFICATION OF CHEMICAL CARCINOGENS MECHANISM OF ACTION ROLE OF OXIDATIVE STRESS CURRENT AND FUTURE PERSPECTIVES REGULATORY BACKGROUND CONCLUSION 2

3. INTRODUCTION Carcinogenesis refers to the process by which a normal cell is transformed into a malignant cell and repeatedly divides to become a cancer Chemicals which initiate this process is called chemical carcinogens Chemicals which increase the effectiveness of carcinogens is called co-carcinogens 3

4. CLASSIFICATION OF CHEMICAL CARCINOGENS 4 CARCINOGENS NON GENOTOXIC GENOTOXIC Direct acting Indirect acting Promoters Cytotoxins Endocrine modifiers Peroxisome proliferators Immune suppressors S. M. Cohen, L. L. Arnold, Chemical carcinogenesis, Toxicol Sci 120 Suppl 1. (2011) S76-92

5. MECHANISM OF ACTION 5 Carcinogen Inactive product Reactive intermediate DNA adduct DNA mutation Cancer Error free DNA DNA repair Phase1 and phase 2 metabolism P. Joseph, Chemical Carcinogenesis; Recent Advances and the Future Directions, Aust - Asian J Cancer. 4(4) (2005) 7

6. STAGES OF CARCINOGENESIS 6 Chemicals Normal cells Initiated cells INITIATION PROMOTION DNA repair Cellular proliferation PROGRESSION CANCER MULTISTEP PROCESS L. A. Loeb, Harris C C , Advances in chemical carcinogenesis: a historical review and prospective, Cancer Res. 68(17) (2008) 6863-6872.

7. ROLE OF PROTO-ONCOGENES AND TUMOR SUPPRESSOR GENES Two classes of genes are mainly involved in carcinogenesis Proto oncogenes Involved in growth and differentiation Activated in cancers Tumor suppressor genes Negative regulators of growth Inactivated in cancers 7

8. ACTIVATION OF PROTO ONCOGENES Point mutation Chromosome translocation Gene amplification Ras oncogene - first activated proto-oncogene detected in a human tumor Permanent activation/over expression lead to neoplastic transformation 8

9. Mutations of the Ras gene lower the GTPase activity of the protein . locks Ras in the permanently active GTP-bound form eventually lead to uncontrolled proliferation and transformation . 9 A. Luch , Nature and nurture - lessons from chemical carcinogenesis, Nat Rev Cancer .5(2) (2005) 113-125

10. INACTIVATION OF TUMOR SUPPRESSOR GENE 10 J. Yang, P. Duerksen -Hughes, A new approach to identifying genotoxic carcinogens: p53 induction as an indicator of genotoxic damage, Carcinogenesis. 19 (1998) 1117-1125 .

11. OXIDATIVE STRESS IN CARCINOGENESIS ROS can be produced from both endogenous and exogenous sources Attack both purine and pyrimidine bases, as well as the deoxyribose backbone Induces DNA damage which includes single or double-strand breakage, deoxyribose modification, and DNA cross-link If DNA damage is not properly repaired it may result in mutation which leads to cancer 11

12. CURRENT PERSPECTIVES 12 Ι . IMPACT OF TECHNOLOGIES P. Joseph, Chemical Carcinogenesis; Recent Advances and the Future Directions, Aust - Asian J Cancer. 4(4) (2005) 7

13. ΙΙ . BIOMARKERS Ι ΙΙ . BIOSENSORS Device that contains two main components including a sensing receptor and a detector Improve the sensitivity and specificity of the biomarker Effective early detection without pain with a noninvasive technique. 13 Z. Altintas, I. Tothill, Biomarkers and biosensors for the early diagnosis of lung cancer, Sensors and Actuators B: Chemical. 188(0) (2013) 988-998

14. FUTURE DIRECTIONS Development of new preclinical models for carcinogenesis Future challenge is to develop and validate biomarkers for non genotoxic chemical carcinogens Understanding chemical carcinogenesis with Inter-individual variation Alteration in gene expression 14

15. REGULATORY BACKGROUND OECD guidelines 451- Carcinogenecity studies 453- Combined chronic toxicity/ carcinogenecity ICH guidelines S1A- Guideline on the need for carcinogenicity studies of pharmaceuticals S1B- Testing for carcinogenicity of pharmaceuticals S1C- Dose selection for carcinogenicity studies of pharmaceuticals 15

16. CONCLUSION Though remarkable progress has been achieved in understanding chemical carcinogenesis, still it remain leading cause for death in world Currently the development in genomics, proteomics and informatics for identification and validation of biomarkers enable us to determine chemical basis of carcinogenesis Understanding at molecular level is perhaps most important step in developing strategies to prevent incidence of chemical carcinogenesis 16

17. THANK YOU 17