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UNDERSTANDING OF CHEMICAL CARCINOGENESIS:

CURRENT AND FUTURE PERSPECTIVES

Chander K Negi

Chandernegi09@gmail.com

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TABLE OF CONTENTS

• INTRODUCTION

• CLASSIFICATION OF CHEMICAL CARCINOGENS

• MECHANISM OF ACTION

• ROLE OF OXIDATIVE STRESS

• CURRENT AND FUTURE PERSPECTIVES

• REGULATORY BACKGROUND

• CONCLUSION

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

CLASSIFICATION OF CHEMICAL CARCINOGENS

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

MECHANISM OF ACTION

Carcinogen

Inactive productReactive intermediate

DNA adduct DNA mutation Cancer

Error free DNA

DNA repair

Phase1 and phase 2metabolism

P. Joseph, Chemical Carcinogenesis; Recent Advances and the Future Directions, Aust- Asian J Cancer. 4(4) (2005) 7

STAGES OF CARCINOGENESIS

Chemicals

Normal cellsInitiated 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.

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ROLE OF PROTO-ONCOGENES AND TUMOR SUPPRESSOR GENES

Two classes of genes are mainly involved in carcinogenesis

1. Proto oncogenes

Involved in growth and differentiation

Activated in cancers

2. Tumor suppressor genes

Negative regulators of growth

Inactivated in cancers

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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

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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.

A. Luch, Nature and nurture - lessons from chemical carcinogenesis, Nat Rev Cancer .5(2) (2005) 113-125

INACTIVATION OF TUMOR SUPPRESSOR GENE

DNA damage DNA damage

p53 activated and binds to DNA

p53 dependent genes not activated

Transcriptional upregulation of target genes

p21(CDK Inhibitor)

GADD45(DNA repair)

Bax Mutant cells

G1 arrest

Succesful repairApoptosis

No cell cyclearrest

No DNArepair

Malignant tumourNormal cell

DNA repairfails

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.

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

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CURRENT PERSPECTIVES

NEW TECHNO-LOGIES

Microarray

DD

SSH

SAGE

Ι. IMPACT OF TECHNOLOGIES

P. Joseph, Chemical Carcinogenesis; Recent Advances and the Future Directions, Aust- Asian J Cancer. 4(4) (2005) 7

ΙΙ. BIOMARKERS

ΙΙΙ. 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.

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• Carcinoembryonic antigen (CEA) - breast cancer

• Neuron specific enolase (NSE) - lung cancer

• α-fetoprotein (AFP) - liver cancer

• Prostate specific antigen (PSA) - prostate cancer

Z. Altintas, I. Tothill, Biomarkers and biosensors for the early diagnosis of lung cancer, Sensors and Actuators B: Chemical. 188(0) (2013) 988-998

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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

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

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

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THANK YOU