13: Genotoxicity and Carcinogenicity of Drugs Flashcards
new or autonomous growth of tissue (neoplasia) resulting in formation of a lesion named neoplasm
carcinogenesis
abnormal tissue growth
carcinogenesis
malignant neoplasm, disease characterized by mutation, modified gene expression, cell proliferation, and aberrant cell growth
cancer
what is carcinogens
physical or chemical agent that causes of induces neoplasma
what is the process of forming a neoplasm called
carcinogenesis
what is a tumor
lesions characterized by swelling or increase in size, may or may not be neoplastic
agent/ process that interacts with cellular DNA, resulting in alteration of DNA structure
genotoxic
3 cellular basis of cancer
Uncontrolled and inappropriate division of cells
Genetic damage to critical genes that regulate cell growth
Exposure to chemical carcinogens considered important
chemical carcinogenicity is determined by
epidemiological studies- relationship between cancer sus agent and human population
animal studies- at least 2 species with varying dose and time
which stage is reversible
1. initiation
2. promotion
3. progression
4. metastasis
2
which carcinogenesis stages are irreversible
initiation
progression
in proliferation, what is reduced?
apoptosis
what point of the carcinogeneis process do drugs tend to target
promotion
the initiation stage of cancer is _______ and ____
rapid and ireversible
3 steps of initiation include
DNA modification by initiator
single DNA replication without repair
formation of stable, heritable changes in cell DNA
2 classes of mutations
point and frameshift
what is promotion
change in gene expression without change in DNA
promotion is ______
reversible
the promotion stage stimulates __________ in _________ cells
proliferation in both normal and mutated cells
promotion enhances effect of genotoxic initiating agent by
establishing clones of initiated cells
in promotion, a long delay is possible between
admin of initiating agent and promoting agent
what is the final stage of the carcnogenesis process
progression
in the progression stage, there is conversion of
benign preneoplastic lesions into a neoplastic cancer
the conversion of benign preneoplastic lesions into a neoplastic cancer is the result of _______________________________ mediated by __________________
genotoxic events inducing chromosomal damage- aberrations and translocation
Mediated by increase in DNA synthesis and cell proliferation in the preneoplastic lesions (promotion stage)
genotoxic means
Ability to damage DNA = mutations in critical genes = cancer
majority of known human carcinogens are
genotoxic
what is the effect fo nongenotoxic carcinogens
don’t damage DNA but alter balance between proliferation and apoptosis
direct acting chemical carcinogens have ________ that __________
highly reactive electrophile groups
directly attack nucleophilic DNA groups/ proteins
which type of carcinogens are more likely to cause a second form of cancer, usually leukemia
primary carcinogens
what type of carcinogens must be metabolically activated
secondary/ indirect acting
how are indierct acting carcinogens activated
endogenous metabolic pathways like CYP enzymes
what are cocarcinogens
substances that ↑ carcinogenic potential by stimulating biotransformation of a certain substance
what are promoters
suppress apoptosis, stimulate proliferation
list 2 ways chemical carcinogens can mess with DNA
covalent bond formation
intercalation by forming noncovalent bonds
most carcinogens are ___________ acting and _______( genotoxic/ nongenotoxic)
indirect
genotoxic
adduct formation is common on _____ of adenine and _____ of guanine
6, 7 on adenine
2, 7, 8 on guanine
Mutations may be induced by agents that interact with DNA _________ intercalating between 2 base pairs
VDWs forces
insertion of flat planar rings between stacked double helical DNA =
frameshift mutation
alkylated bases in DNA can
mispair with wrong base in DNA replication
modifications on N ___ or ____ of purines can cause cleavage by DNA glycosylase
3, 7
interaction with some carcinogens cause ________________ for better stability, altering transcriptability of certain genes
conformational transition of DNA
what is the tired approach for genotixicity testing
in vitro
short term in vivo tests
long term in vivo carcinogenicity assays
