Carcinogenic Agents Flashcards
Desccribe the molecular model for the evolution of colorectal cancers
APC mutation puts mucosa at risk
beta-catenin mutation causes methylation abnormalities and leads to adenoma
K-RAS leads to polyp formation
the lack of p53 leads to additional mutations that cause carcinoma
initiation
an event that causes irreversible DNA damage in a critical target gene
insufficient to give rise to a tumor, but sets the cell up for further mutations
rapidly dividing cells may be more susceptible to initiators
promotion
the process whereby initiated cells are selected for and expanded up into a benign tumor or benign preneoplastic condition
promoters are non-carcinogenic or relatively weak carcinogens such as croton oil and phenobarbital
microsomal enzyme inducers such as TCDD, high fat diets, and bile acids
does not affect DNA directly, reversible
progression
the process by which cells in a benign neoplasm or dysplaisa progress to malignant cells
subpopulations of cells develop additional mutations that give them laignant and metastatic capabilities
interplay between initiation and promotion phases of carcinogenesis in mice
initiators must occur before promoters to give rise to tumors
promoters can occur later in time, does not have to come immediately after initiators
if promoters are spaced out too much, no tumors will develop
direct-acting chemical carcinogens
usually electrophilic and can bind to nucleophilic DNA to form carcinogen-DNA adducts
most are weak carcinogens, some have been used to treat other cancers but resulted in CML
ex. nitrogen mustards, nitrosomethylurea, cyclophosphamide, and benzyl chloride
indirect-acting carcinogens
must be first metabolically activated before they can bind to nucleophilic targets such as DNA, nucleic acids, or proteins
ex. polycyclic aromatic hydrocarbons such as benzo[a]pyrene, cigarette smoke, aflatoxin B1
common converters are cytochrome P450 dependent mixed function mono-oxygenases
general schema of events in chemical carcinogenesis
initiation mutations, if not dealt with will arise in proliferation, additional promoting mutations and finally malignant neoplasms
Ames Test
test that detects mutagens and potential carcinogens
grow salmonella typhimuium with a defective gene that prevents it from making histidine
grow cells on a histidine negative plate in the presence of a chemical, and if cells are mutated so that they can make histidine again, the chemical is likely to be a carcinogen
nitrogen mustards
ex. chlorambucil, melphalan, cyclophosphamide
highly carcinogenic
used in the past as cancer chemotherapeutic agents but high risk of secondary cancers such as leukemia
alkylating agent therapy
associated with loss of chromosomes 5 or 7
prior cytotoxic therapy also associated with ~1-5% lifetime risk of myelodysplastic syndrome and leukemia
alkylating agent mechanism of action
nucleophilic attack of unstable aziridine ring
causes interstrand crosslinks that can cause mutation or block transcription and replication machinery
benzo[a]pyrene
polyccyclic aromatic hydrocarbon produced from incomplete combusion of organic materials, require metabolic activation
acts through a reactive epoxide (BPDE) to create adducts with DNA bases, leading to transversion mutations when polymerase goes through
cigarette smoke
contains polycyclic aromatic hydrocarbons and certain tobacco-specific nitrosamines, more than 60 carcinogens in cigarette smoke
90% of lung cancer caused by cigarette smoking, 8-32 times more relative risk
Aflatoxin B1
indirect-acting chemical carcinogen, produced by some strains of aspergillus (mold)
major cause of hepatocellular carcinoma in Africa and Asia
G:C to T:A transversion in serine codon 249
the role of p53
maintains genome integrity and stability
role of Rb in regulating cell cycle
G1/S checkpoint regulation
HPV proteins E6 and E7
binds Rb, p53, and p21 to inhibit growth arrest and apoptosis
inflammation and carcinogenesis
cytokines produced by inflammation leads to recruitment of lymphocytes and macrophages
production of ROS and RNS as a part of chronic inflammation
cause DNA damage in nearby cells and induce cancer
Burkitt’s lymphoma
tumor cells with viral DNA present, translocation of chromosome 8 with a c-myc oncogene to near the immunoglobulin gene on chromosome 14, which leads to overexpression of c-myc
helicobacter pylori
first bacteria classified as a carcinogen
implicated in the genesis of both gastric adenocarcinomas and gastric lymphomas which are of B-cell origin
infection leads to chronic gastritis and gastric cancer
