Carcinogens Flashcards
Neoplasia
heritably altered, relatively autonomous growth of tissue
Benign–tissue of origin + –oma
fibroma, (connective tissue)
lipoma, (fatty lump often situated between skin and underlying muscle layer)
adenoma (starts in gland-like cells of the epithelial tissue (thin layer of tissue that covers organs, glands, and other structures within the body))
common abnormal regulation of gene expression in cancer cells
Increased expression of onco genes and decrease of tumor suppression genes
mesenchymal tissue origin —>sarcoma
fibrosarcoma;
osteosarcoma;
liposarcoma
ectodermal tissue origin (epithelial)–> X + carcinoma;
epdemoid carcinoma;
hepatocellular carcinoma,
gastric adenocarcinoma
Carcinogen
Carcinogen—an agent whose administration to previously untreated animals
leads to a statistically significant increased incidence of neoplasms as compared to control animals.
Sequence of Neoplasia
Initiation
Promotion
Progression
Initiation
a. requires one or more rounds of cell division for the fixation of the process
b. metabolism and regulation of metabolism critical - some populations are therefore more susceptible GSTM1 important for detoxing PAHs
c. DNA interaction can occur spontaneously—promotion/progression are the rate limiting steps (Uv light)
d. activates “oncogenes” or inactivates “tumor suppressor” genes (TP53 is a common tumor suppressor gene)
Promotion
a. no direct interaction with DNA (just ilicest signaling that causes overexpression of cancer genes)
b. metabolism not required for effectiveness
c. Reversible
d. dependent upon continued administration of promoting agent
Progression
transition from early progeny of initiated cells to malignant cell population.
Genotoxicity-
direct interaction with DNA
Problematic when DNA lesions aren’t repaired and are translated into next step
Lesions often get fixed but when they don’t its the problem
But the initiation of lesions is what we base risk calculations on.
Progression characteristics
Induce chromosomal aberrations
chromosomal aberrations through breaks in DNA.
Clastogenic
Progression Mechanisms
- inhibit DNA repair
- topoisomerase activity
- gene amplification
- Altered telomere integrity
complete carcinogen
can promote all three steps.
initiation, Promotion, progression.
nongenetic cancer-causing mechanisms
a. oxidative stress (Oxigen is binding DNA not the chemical but the chemical is increasing the amount of Oxigen near DNA)
b. sustained tissue damage. (increased cell division leads to more spontaneous mutations, which increases cancer potential.)
Epidemiology
findings from observation rather than experimentation
Types of Epidemiology studies
Retrospective Studies
Prospective studies
IARC
International Agency for Research on Cancer
IARC CLASS 1
Agent is carcinogenic
Sufficient human evidence
IARC CLASS 2A
Agent is probably carcinogenic
Sufficient animal evidence
limited human evidence
IARC CLASS 2B
Agent is possibly carcinogenic
Sufficient animal evidence
limited or inadequate human evidence
IARC CLASS 3
agent is not classifiable
IARC CLASS 4
Agent is probably not carcinogenic
inadequate animal evidence
inadequate human evidence
Sufficient evidence
causal relationship with epidemiology data necessary
Limited evidence
causal, but chance bias and confounding variables cannot be excluded
Inadequate evidence
a. few pertinent data
b. studies show association, but did not exclude variables
c. studies did not show evidence of cancer
*QSARs
quantitative structural activity relationships.
(statistical empirical models that relate a quantitative description of chemical structure features of a series of molecules to the responses those molecules show in an experimental system.)
ways to graph predicted cancer risk
Hockey stick regression versus extrapolating back to zero.
overnutrition and high fat diets can…
lead to Promotion of cancer.
Endogenous hormone production
can lead to cancer in 4th decade mothers
common exogenous cause of human cancer?
Tabaco. 85-90% of lung cancer cases and 30% of all cancer deaths.
Chemical Carcinogenesis Resulting from Medical Therapy and Diagnosis
Synthetic Estrogens
8-16 x increase in mammary cancer –post menopausal
