Causes of Pancytopenia
Chemical Carcinogenesis (Detailed and Pointwise)
1. Definition and Basis
Chemical Carcinogenesis: Refers to cancer development due to exposure to specific
chemical agents, either directly or through metabolic activation.
Key Mechanisms:
Mutations in DNA caused by interaction with reactive intermediates.
Involves genes like proto-oncogenes (e.g., RAS) and tumor suppressor genes (e.g.,
p53).
2. Classification of Chemical Carcinogens
1. Direct-acting Agents:
Do not require metabolic conversion to become carcinogenic.
Weak carcinogens.
Examples:
Alkylating agents: Found in anticancer drugs like cyclophosphamide and
cisplatin.
Acylating agents: Dimethyl carbamyl chloride.
Cancers Produced:
Solid tumors and hematological malignancies.
2. Indirect-acting Agents (Procarcinogens):
Require metabolic activation to become carcinogenic.
Activated by cytochrome P450 enzymes in the liver.
Examples:
Polycyclic and Heterocyclic Aromatic Hydrocarbons:
Found in cigarette smoke, fossil fuels, and broiled meats.
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Cause lung cancer and soft tissue cancers.
Aromatic Amines and Azo Dyes:
Used in aniline dye industries.
Cause bladder and liver cancers.
Nitrosamines:
Formed in the gut by reactions between dietary nitrites and amines.
Cause gastrointestinal cancers.
Metals: Arsenic, nickel, and chromium lead to lung and skin cancers.
Natural Products:
Aflatoxin B1 from Aspergillus flavus in improperly stored grains and
peanuts.
Causes hepatocellular carcinoma.
3. Mechanism of Action
1. Initiation:
Involves exposure of cells to a carcinogenic agent.
Carcinogens (electrophilic) react with DNA, RNA, or proteins in cells.
Causes permanent, irreversible mutations in DNA, which act as the "first hit."
Non-lethal damage initiates the tumor process.
2. Promotion:
Promoters stimulate the proliferation of initiated cells.
They do not damage DNA directly.
Changes caused are reversible.
Examples of promoters:
Hormones, phorbol esters, phenols, and certain drugs.
3. Progression:
Proliferation of initiated cells continues.
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Secondary mutations accumulate, leading to uncontrolled growth.
Tumors acquire features of malignancy (e.g., invasion, metastasis).
4. Cancer Development:
Final stage involves the formation of a neoplasm.
Involves invasion and metastasis.
4. Examples of Chemical Carcinogens
1. Aflatoxin B1:
Produced by mold Aspergillus flavus.
Causes mutations in the p53 gene.
Leads to hepatocellular carcinoma.
2. Polycyclic Hydrocarbons:
Found in tobacco smoke.
Causes lung cancer.
3. Aromatic Amines:
Source: Dyes and rubber industries.
Causes bladder and liver cancers.
4. Nitrosamines:
Found in preserved meats.
Causes gastrointestinal cancers.
5. Asbestos:
Fibers cause mesothelioma and lung cancers.
5. Testing Carcinogenicity
Ames Test:
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Determines mutagenicity of a chemical.
Uses bacteria to detect DNA mutations caused by the test compound.
A positive test suggests potential carcinogenicity.
This detailed breakdown includes examples, mechanisms, and testing from your source. Let
me know if you need more elaboration!
Oncogenic DNA Viruses (Detailed and Pointwise)
1. Human Papillomavirus (HPV)
General Features:
Infects immature basal squamous epithelial cells or metaplastic cells.
Replication occurs in maturing non-proliferating squamous cells.
HPV genome exists in two forms:
Episomal Form: Found in benign warts and precancerous lesions.
Integrated Form: Associated with malignant transformation.
High and Low-Risk HPV Types:
Low-Risk Types: HPV-6, HPV-11 cause benign warts and condylomas.
High-Risk Types: HPV-16, HPV-18 are implicated in cervical, anal, and oropharyngeal
cancers.
Mechanism of Oncogenesis:
Integration into host DNA disrupts the regulation of E6 and E7 oncogenes:
1. E6 Protein:
Binds and degrades p53, a tumor suppressor.
Activates telomerase, promoting cellular immortalization.
2. E7 Protein:
Binds RB protein, releasing E2F transcription factors.
Stimulates cell cycle progression by inactivating CDK inhibitors (p21 and
p27).
Tumors Caused:
Cervical intraepithelial neoplasia (CIN) and carcinoma.
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Anogenital cancers (vagina, vulva, anus).
Oropharyngeal cancers.
2. Epstein-Barr Virus (EBV)
General Features:
A herpesvirus that infects B lymphocytes via CD21 receptor and epithelial cells.
Can establish both productive (lytic) and latent infections.
Latent infection leads to immortalization of B cells.
Oncogenic Mechanisms:
1. Latent Membrane Protein 1 (LMP1):
Acts as an oncogene by activating NF-κB and JAK/STAT pathways.
Prevents apoptosis by upregulating Bcl-2.
2. EBV Nuclear Antigen 2 (EBNA2):
Activates host genes like cyclin D and proto-oncogenes such as SRC.
3. Viral Cytokine (vIL-10):
Suppresses immune responses, protecting infected cells.
Diseases and Tumors Associated:
Burkitt Lymphoma:
EBV acts as a polyclonal mitogen, promoting translocations (e.g., t(8;14)) that
activate c-MYC.
Nasopharyngeal Carcinoma.
Hodgkin lymphoma.
Gastric carcinomas.
3. Hepatitis Viruses (HBV and HCV)
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Hepatitis B Virus (HBV):
A partially double-stranded DNA virus associated with hepatocellular carcinoma
(HCC).
Mechanisms:
1. HBV genome integration into hepatocyte DNA causes chromosomal deletions.
2. Encodes HBx protein:
Activates transcription factors and signal pathways.
Inhibits p53, promoting genomic instability.
3. Chronic inflammation leads to compensatory hepatocyte proliferation,
enhancing mutagenesis.
Hepatitis C Virus (HCV):
An RNA virus associated with chronic liver damage and HCC.
Mechanisms:
1. Chronic inflammation and oxidative stress promote DNA damage.
2. HCV core protein activates growth-promoting pathways, fostering tumor
development.
Key Tumors Associated:
Hepatocellular carcinoma (HCC).
This detailed overview provides insights into the mechanisms and associations of HPV, EBV,
and hepatitis viruses with cancer. Let me know if additional details are needed!
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