Test 3: 51-52 Flashcards
what are some variables that make a person susceptible to cancers
gender and ethnicity, health status, nutrition, young age and genetics
Chemically induced and ___ induced mutations are thought to be causative factor in a large majority of human and animal cancers.
oxidative stress
Most cancers are “___” in origin
clonal
what does it mean when cancer is clonal in nature
cancer begins with genetic and metabolic changes in one or a few cells. These cells then duplicate/ clone rapidly and lead to malignant cells
vogelstein model
how cancer forms:
Mutations in the tumor suppressor genes APC and DCC drive the progression of colon epithelial cancer. K-Ras mutation augments proliferation of cells carrying mutations further increase the chances of accumulating additional mutations. P53 is another important tumor suppressor gene and its mutation culminates in the formation of full blown carcinomas, and metastasizing tumors
steps of chemical carcinogenesis
chemical carcinogens get taking into the body and activated by cytochrome P450 to become activated carcinogens (UCs).
they body tries to stop by carcinogen inhibitors but mutations in Class II drug metoblizing enzymes leads to UCs binding to DNA and causing mutations
tumor promoters cause cell division of bad cells into hyperplastic nodules
tries to block with cis Retinols, diallyl sulfide and perillyl alochol but if unsuccesful will become neoplasia (cancer)
Cancer is a multi-step process and involves a series of mutational events, changes in metabolic profiles, cell cycle ___, and large scale changes in gene ___pattern.
regulation
expression
Simple steps involved in chemically induced cancer:
Tumor initiation (mutations induced by DNA reactive chemicals)
tumor promotion (changes in cell cycle progression rapid cell division and changes in gene expression) leading to the formation of hyperplastic nodules
progression to full blown cancer
metastasis.
Most chemical carcinogens are inert and they need to be ___ by the host enzyme system.
activated
Chemicals activated by ___ enzyme systems contain reactive groups (chemical radicals), or electron deficient group. A majority of them are detoxified by the class II drug metabolizing systems.
cytochrome P450
Binding of activated chemicals to DNA and induction of mutations in the critical genes is regarded as the ___step
initiation
Tumor promotion is essentially amplification of cells carrying mutations by agents that induce ___ and ___
cell cycle progression and cell proliferation
in ___ stage the tumor is still benign and may grow into nodules. At this stage they can be treated surgically, X-ray irradiation or by chemotherapeutic agents
hyperplastic
last step of cancer, tumors are aggressive, resistant to apoptosis, ___into other tissues, and cause tissue or system failure. They can still be treated surgically or by new generation of drugs that target specific molecules or signaling pathways that are either specific or predominate in tumor cells.
metastasize
tumor initiators
broadly classified as chemical carcinogens. They are invariably lipophilic and inert until metabolically activated by cytochrome p450 monooxygenases (class I drug metabolizing enzymes). Activated chemicals physically bind to DNA and induce mutations or chromosomal damage
tumor initiators are invariably ___ and inert until metabolically activated by ___
lipophilic
cytochrome p450 mono-oxygenases (class I drug metabolizing enzymes).
tumor promotors
chemicals, which induce cell proliferation and amplify the mutational damage or help populate the damaged cells. These compounds do not directly bind to or interact with DNA and are not mutagenic. Their action is mostly epigenetic in nature
___ are chemicals, which induce cell proliferation and amplify the mutational damage or help populate the damaged cells.
tumor promoters
Tumor promoters do not directly bind to or interact with DNA and are not ___ . Their action is mostly ___ in nature
mutagenic
epigenetic
tumor inhibitors
A) chemicals which detoxify activated carcinogens by direct binding or by altering the electrophylic property of carcinogens. Examples are GSH and gulcuronic acid and their specific transferases enzymes (class II drug metabolizing enzymes)
Chemicals which cause tumor regression by altering the transcription activity of genes involved in cell cycle regulation and cell proliferation
examples of tumor inhibitors are
GSH and gulcuronic acid and their specific transferases enzymes (class II drug metabolizing enzymes)
___ are chemicals which detoxify activated carcinogens by direct binding or by altering the electrophylic property of carcinogens.
tumor inhibitors
tumor inhibitors cause tumor regression by altering the ___ of genes involved in cell cycle regulation and cell proliferation
transcription activity
Cytochrome P450 (___ metabolism) enzymes play direct roles in the metabolic activation of carcinogens:
class I drug
Metabolic activation of carcinogens to reactive (electron deficient) forms requires a specific CYP isoenzyme, ___ as an electron donor, and ___ as the source of electrons
cytochrome P450 reductase
NADPH
In the reaction cycle, CYP gets reduced by the transfer of a pair of electrons from ___ and reduced CYP binds to the substrate and O2 and catalyzes the ___ of substrate.
CYP reductase,
oxidation
mechanism of tumor initiation by metabolically activated by a fungal product often contaminates food and feed, ____
aflatoxin B1
Although majority of chemical carcinogens require activation by the CYP monooxygenase system, please note that an important group of environmental/industrial pollutants belonging to the family of ___, are not metabolized by any of the known class I or class II enzymes
polychlorinated biphenyls (PCB)
___ belongs to a large family of polycyclic aromatic hydrocarbons that are found in auto exhaust, industrial combustion, cigarette smoke, byproducts of oil and coal industry.
Benzo(α)pyrene (BaP)
BaP are potent tumor ___
initiators
Activation of Bap requires ___ that are abundantly found in the hepatic and lung ER fraction (widely called as microsomes) and ___ that is also present in the microsomal fraction of most tissues
CYP1A1 (or 1B1)
CYP reductase
The activation of BaP occurs by forming ___ in place of a double bond
epoxides
Epoxides only on certain position of BaP are reactive to ___ residues on DNA
purine
Often epoxides are converted to ___ by the action of epoxide hyrolase.
diols
Since BaP contains many double bonds, it can bind to CYP several times and undergo ___ at different position
epoxidation
Only the ___ epoxide of BaP is highly DNA reactive.
9:10
this formation will bind easily to the N-7 of guanine of DNA
Most mammalian, avian and aquatic species are sensitive to ___ B1 induced liver damage and hepatic cancer.
aflatoxin
The aflatoxin B1 epoxide is detoxified by conjugation to ___.
GSH
where is aflatoxin B1 found
fungal toxin, can be found on contaminated peanuts, grains, beans and animal feeds
mold = aspergillus flavis
___ are agents that induce cell cycle and cell proliferation.
Tumor Promoters
some examples of tumor promoters
phenobarbital and other barbiturates, alcohol, asbestos, cigarette smoke, lipopolysaccharide and other cytokines, phorbol myristate acetate, plant alkaloids, some food additives, and others
. Proliferation of cells carrying mutations in the critical genes associated with oncogenic transformation results in accumulation of population of cells that have ___ regulatory controls
escaped
proliferating mutated cells produce increased ___ because of altered metabolism and accumulate more mutations and become highly ___ even in the absence of any external stimuli.
ROS
proliferative
tumor promotors act like a ___ on cells that have already acquired one or more carcinogenic mutation, causing them to divide and go through ___, increasing the likelihood that they will acquire more mutations
growth factor
S-Phase
___ represent a Large Family of Non-biodegradable Industrial Pollutants and Carcinogens
PCBs
___ are a group of 209 aromatic chemicals formed by the chlorination of biphenyls that were widely used as pesticides, defoliating agents, and in various industrial setting until 1979
Polychlorinated biphenyls PCBs
___ are highly resistant to heat, fire, acids, and they are also non-biodegradable
PCBs
PCB, TCDD, DDT, Arochlor, Phenochlor and various organopesticides including “agent orange”
Unlike other families of carcinogenic compounds listed such as benzo(a)pyrene and aflatoxin B1 above, PCBs are not metabolized by the ___ and once ingested, they remain in the body until ___
CYP enzymes
death
PCBs are associated with many pathological conditions including ___, tissue inflammation and cancer.
oxidative stress
Due to the high lipid solubility and slow metabolism rate of these chemicals, PCBs accumulate in the ___tissues of almost all organisms
fat rich
PCBs cause:
- Probable human carcinogen (breast, bone, brain and skin cancer)
- Endocrine disrupter (binds to estrogen and thyroid hormone receptor and activates aryl hydrocarbon receptor)
- Reproductive toxicity (induces oxidative stress and protein kinase C cascade)
- Neurotoxicity
- Immune system suppression
PCBs binds to estrogen and thyroid hormone receptor and activates ___ receptor
aryl hydrocarbon
PCBs cause reproductive toxicity by induces oxidative stress and ___ cascade
protein kinase C
hyper active P450 1 A1 and hypo active NAT are common gene mutations in what ethnicity?
african americans
hyper active P4501A1, inactive GSTM1 and slow active epoxide hydrolase are common gene mutations in what ethnicity?
american whites
hyper active P4501A1 and slow glycyronyl transferase are common gene mutations in what ethnicity?
hispanic and asians
___ are chemicals which detoxify activated carcinogens
carcinogen inhibitors
examples of carcinogenic inhibitors
antioxidants
butylated hydoxy anisole
aromatic isothiocyanates
flavones
antioxidants such as __ and __ will neutralize electron __ groups
Vitamin C and Vitamin E
deficient
butylated hydorxy anisole will induce ___ like glutathione S transferase and glucuronide transferase
class II drug metabolizing enzymes
___ come from cruciferous vegtables
aromatic isothiocyantes
isthiocyanates induce __ enzymes.
class II drug metabolizing
(phenethyl isothiocyanates is an inhibitor to lung cancer)
___ found in fruit and vegetables induce class II drug metabolizing enzymes
flavones
one gene targeted by perilly alcohol is ___
IGF BP3 (insulin like growth factor binding protein 3)
which is an extercellular secreted protein
Many tumor cells over express ___ growth factor. Increased extracellular level of ___ essentially blocks the growth factor inducing apoptosis in tumor cells
IGF1
IGF-BP3
Compound MF-tricyclic selectively inhibits ___, the inducible form of enzyme involved in prostanoid biosynthesis.
cycloxygenase2 (COX2)
___ is an important early indicator of tumor development.
COX2
Compound L353381 is selective estrogen modulator (SEM) that inhibits ___ activity in breast cancer cells without affecting estrogenic activities of bone, brain and cardiovascular system.
estrogen receptor
L353381 compound has several advantages over currently used drug Tamoxifen for treatment of breast cancer since it does not induce ___cancers usually associated with Tamoxifen
ovarian or endometrial
Compound LG100268 is a ligand that activates some of the “orphan” retinoic acid receptors called ___, thus helps activation of several of the genes whose expression is lost or subdued in various cancers of epithelial cell origin (lung, breast, intestinal etc.).
RXR
By recruiting or activating ___, LGF100268 helps restore the transcription of important genes (probably some tumor suppressor genes and genes involved in cell cycle control) by activating an otherwise silent transcription factor.
RXR
Most of these cancers typically show the loss (deletion) of an important transcription factor, RARβ.
___ is used to prevent intestinal cancers
MF- tricyclic
___ and ___ are used to prevent breast cancer
L353381
LG100268
___: an isoflavole (3,5,4’ trihydroxy-trans-stilbene) from the roots of Japanese Knotweed, used in herbal medicine in eastern part of Asia is a potent “Aryl Hydrocarbon Receptor, Ahr” antagonist.
Resveratrol
By inhibiting the activation of ___, and thus restricting the expression of CYP 1 family genes, Resveratrol protects against cigarette and environmental toxins induced lung, intestinal and breast cancer.
Aryl Hydrocarbon Receptor,
___: A polyisoprenylated benzophenone and its derivative isogarcinol from Garcinia Indica fruit have potent anticancer activities on multiple tissue cancers.
garcinol
Recent studies show that garcinol are potent inhibitors of ___ and other ___ proteins. The anticancer effects of these compounds are directly related to inhibition of histone modification and chromatin remodeling.
p300
HAT (histone acetyltransferase)
how does BaP become carcinogentic
cytochrome P4501A1 and 1B1 out on reactive epoxide groups on BaP
epoxide hydrolase breaks them down to less toxic form but this causes more problems and creates 9,10 which binds easily to DNA and causes mutations
