chemotherapy Flashcards
what is the median age of cancer diagnosis
67
t/f mortality is falling for cancer pts
true; we have gotten better at treating and curing cancer, and fewer environmental factors (smoking, etc.)
def: new growth, may be benign or malignant
neoplasm
def: nonspecific term meaning lump or swelling
tumor
def: any malignant neoplasm
cancer
increase in organ or tissue size due to an increase in # of cells
hyperplasia
adaptive, substitution of 1 type of adult tissue to another type of adult tissue
metaplasia
an abnormal cellular proliferation is which there is loss of normal architecture
dysplasia
loss of structural differentation. cells de-differentiate
anaplasia
normal epithelial tissues are very organized/disorganized?
organized
name 2 synonyms for adenoma
benign & polyp
cancer nomenclature - the “______”
omas
______ origin:
___________: malignant neoplasm of squamous cell (benign is _____)
epithelial
carcinoma; papilloma
______ origin:
___________: malignant neoplasm of glandular tissue (benign is _____)
epithelial
adenocarcinoma; adenoma
malignant neoplasm w origin in mesenchymal tissues or its derivatives (name 3 examples)
sarcoma (bone, muscle, fat
malignant neoplasms of hematopoietic tissues (2)
lymphoma & leukemia
type of cancer of pigment producing cells (melanocytes) in skin or eye (uveal)
melanoma
def: malignances in precursor cells, often call _______, which are more common in ______
blastoma; blasts; children (nephroblastoma, medulloblastoma, retinoblastoma)
germ cell neoplasm made of several diff differentiated cell/tissue types
teratoma
6 yo boy has systemic malignancy orginating from precursor cells of nervous system. what would pathology report say?
a. adenocarcinoma
b. neuroblastoma
c. leukemia
d. metastatic sarcoma
b. neuroblastoma
cancer is a disease of ______
progression
order of cancer progression
cell w mutation > hyperplasia > dysplasia > in situ cancer > invasive cancer
cancer is characterized by what 3 things
uncontrolled cell growth
tissue invasion
metastasis
hallmarks of cancer
-sustaining _______ signaling
-avoiding _______ destruction
-enabling _______ immortality
-activating invasion & ________
-inducing or accessing _________
-genome instability & _______
-resisting cell ________
sustaining proliferative signaling
avoiding immune destruction
enablling replicative immortality
activating invasion & metastasis
inducing or accessing vasculature
genome instability & mutation
resisting cell death
__________ is a cancer of WBC of hematopoietic origin
leukemia
for many tumors the growth of the _______ tumor is not going to be life threatening. these events can take place over periods of ________. metastasized cells are considered a ________ from the _______ site.
primary; years; tumor; primary
t/f a tumor in the brain that originates from the breast is breast cancer not a brain cancer
true
more than ____% of cancer cases can be prevented. what is the primary cause?
40%; smoking (19%)
who was responsible for discovering that cancer could pass through a fine pore filter thus considering it to be a virus (RSV)?
peyton rous; chicken experiment
RSV is a __________virus and integrates into the ________
retrovirus; genome
RSV encodes what protein?
v-SRC
v-SRC is an ___________?
oncogene
any gene in a healthy cell capable of promoting tumor growth is a _________
proto-oncogene
some cancers can result of __________ or __________ of a single potent _______ ________. some of these mutations run in families
mutation; deletion; tumor suppressor
t/f childhood retinal cancer-retinal cells don’t stop dividing during development and form tumors (retinoblastoma)
true
retinoblastoma is an example of Alred Knudsen’s ______ hypothesis
2-hit
RB1 is a ______ _________
tumor suppressor
most tumor suppressors can be expressed from either ________ and thus will need to be __________ deletion/mutation. Because of this, __________ mutations can be inherited and families show _________ susceptibility to cancers. Also called “_________________”
chromosome; homozygous; heterozygous; increased; loss of heterozygosity
t/f often one mutation isn’t sufficient to cause cancer on its own
true
p16 is a ________ __________
tumor suppressor
most players can broadly be classified as _____ ________ or _______ depending on whether they _______ or ________ cancer. This classificiation doesn’t tell you much about molecular mechanisms
tumor suppressors; oncogenes; prevent or promote
cancer classification arrives from the ______ of origin. tumors of the same classification can have a unifying genetic drive but often _____.
-100% of chronic myelogenous luekemia have cr-abl translocation
-non small cell lung cancer (NSCLC) is very heterogeneous collection of cancers
treatments are often determined ___________ and often only affect a subset of patients with the _____ cancer classification
tissue; do not
empirically; same
NSCLC is non smokers median of ________ mutations. in smokers _________.
carcinogen induced cancers have very high mutation rates (bladder, lung, head & neck)
carcinogens include: _____ and ______
888; 15659; smoking & UV exposure
most cancers are __________ & have a variety of gene mutations
heterogeneous
BRCA1 and BRCA2 are _________ _________ that encode for proteins involved in _____ repair. They are inherited as _____ mutations and very prevalent in __________ ancestry
tumor suppressors; DNA; germline; Ashkenazi Jewish
____% of NSCLC patients have an EGFR mutation
These mutations can be identified using sequencing technologies.
Mutations in EGFR catalytic domain __increase/decrease______ the intensity and duration of signaling in response to ligand. Activating mutations also increase the susceptibility to inhibitor almost _____ fold
15-30%; increase; 10
BRCA mutations in breast cancer increase susceptibility to _______ inhibitors
PARP (poly ADP ribose polymerase)
Olaparib is a ______ inhibitor and primarily treats cancers with _______ mutations. Works by trapping _____ to DNA.
Other drugs in class: rucaparib, niraparib, talazoparib, veliparib
PARP; BRCA1/2; PARP
5 year overall cancer survival rate is ____%. Only a few cancers are typically curable by chemotherapy - _______ disease, some childhood leukemias and lymphomas, testicular cancer - 90% of all cancer cures by chemotherapy occur in a small number of total cancer types.
69%; Hodgkin’s disease
What 3 cancer types are typically resistant to chemotherapy?
lung, pancreatic, brain
Describe what happens in each cell cycle phase:
G0/G1:
S:
G2:
G0: cell not in cycle yet, but could be in future
G1: cell is quiescent or accumulating “building blocks” required for division
S: cell replicating DNA
G2: Cell assembling machinery for chromosomal segregation and cytokinesis
The cell cycle clock is driven by _______paired with cyclin-dependent _______.
The ____ point is the critical time point when cells decide whether or not to enter cell cycle
cyclins; kinases; R
List which drug classes target each phase of cell cycle
G1 (mitogenic signaling)
S (DNA replication
G2 (Sister chromatid separation)
M (chromosome segregation)
G1: kinase inhibitors, hormone inhibitors
S: anti-metabolites, anti-folates, topo1 inhibitors
G2: topo2 inhibitors
M: microtubule inhibitors
which drug classes are non cell cycle specific (DNA damaging agents)
Alkylators & intercalaters
Kras, HER2, PI3K are ______
oncogenes
TP53, RB1 and P16 are
tumor suppressors
what tumor suppressor is known as the guardian of the genome?
tp53
Cyclin D and Cdk4,6 are master ________of cell cycle initiation
regulators
Cyclin D can be inhibited by _____ _______, but if it is not, it can find CDK 4/6, which phosphorylates Rb1 which stops rb1 from working, which leads to ______formation
tumor suppressors; cancer
what are the 3 CDK4/6 (cyclin dependent kinases) inhibitors
ribociclib, palbociclib, abemaciclib
palbociclib is a _______ inhibitor
Although they are _____ inhibitors, they aren’t exactly “targeted therapies” because they target all replicating cells
Adverse reactions; ______penia, nausea, fatigue, diarrhea, vomiting (similar to traditional chemotherapies)
Approved for cancers arising due to ________ mutations
Cdk4/6 kinase; kinase; neutro; BRCA1/2
Which of the following is potentially true of a tumor suppressor gene?
A. Allows unrestricted cell growth and proliferation.
B. Promotes different phases of the cell cycle.
C. Produces proteins that block the activity of cyclins.
D. Is often overexpressed in cancer
C
Tumor cells have lost cell cycle control mechanisms which leads to
________cell proliferation.
____________controls are often lost as well
increased;Checkpoint
When NORMAL cells are exposed to certain chemotherapy drugs that cause DNA damage
-Cells halt in ___ until DNA repaired
-Cells then proceed into S
-If cells proceed into S without repairing DNA, they _______ (programmed cell death)
-Preserves genomic integrity of daughter cells
When TUMOR cells that have lost _____ checkpoint control are treated with chemotherapy that causes ____ damage
-Cells don’t halt in G1 and attempt to replicate damaged DNA
-Attempting to replicate damaged DNA can trigger apoptosis
-or, if the apoptotic response has been lost cells replicate damaged DNA and acquire lethal genetic damage that results in _____(cell death that results in lysis and inflammation)
G1; apoptose
DNA; G1/S; necrosis
Drugs that do not require cycling cells. These drugs are effective against cancer cells resting in ____ and cells progressing through the cell cycle.
>DNA alkylating agents can damage DNA __dependent/independent__of cell cycling
G0; independent
Drugs that are more effective against cycling cells at many phases of the cell cycle are called cell cycle __________. These drugs are most effective when the tumor cells are progressing through the cell cycle. However, they are NOT dependent upon the cell being in a specific phase of the cell cycle. Many of these agents have some efficacy against cells resting in G0, but they are more effective against cells progressing through the cell cycle. The two drug classes are:
non-specific; Alkylating agents and DNA intercalation agents
With a phase-specific agent, the number of cells killed by the agent will be limited to the number of cells present in the appropriate (“sensitive”) phase of the cell cycle. ___higher/lower____ drug doses may NOT result in greater tumor cell killing. Rather ___increased/decreased___ cell kill requires prolonged exposure. Two methods of prolonged exposure are:
Higher; repeated administration and continuous infusion
What are the major dose-limiting toxicities associated with chemotherapy?
Hematopoietic- WBC (granulocytes) – infections, Platelets – hemostasis, RBC – anemia
Gastrointestinal, nausea & vomiting, loss of appetite
A chemotherapy that interferes with DNA synthesis is
A S-phase specific
B G1-phase specific
C cell cycle non-specific
D M-phase specific
A S-phase specific
Which phase of the cell cycle do you think is targeted by Palbociclib (the CDK4/6 inhibitor)?
A. G1
B. S
C. G2
D. M
A. G1
CDK4/6 inhibitors target cyclins responsible for cell checkpoints in G1 phase
Cancer chemotherapy kills a constant _____, not a constant ______, of tumor cells
fraction; number
t/f It is impossible to kill all tumor cells with a single dose of drug.
true
Norton-Simon hypothesis
>Give as dose-intensive and early as possible
>Give chemotherapy at __shorter/longer___intervals
>Use combination of drugs with distinct mechanism of action
Explain why
shorter
As tumors grow, their doubling time slows-most anticancer agents work on cycling cells
When tumor burden is decreased, remaining will re-enter exponential growth
Diminishing returns- resistance and/or intolerable side effects
Efficacy of cytotoxic chemotherapy
_____ relationship between tumor size and curability for many tumors.
In order for cancer chemotherapy to be successful, cell killing must be ___> or <___ than cell growth.
inverse, > (greater than)
what are 3 factors that increase success rates of cytotoxic chemotherapy
-small tumors
-early diagnosis!!
-increased drug intensity
t/f a drug that is ineffective when used alone is often NOT approved for combination studies
true, although this is changing
>individual drugs in combination should be used at max dose
>CHOP is a good example of a combo of drugs (cyclophosphamide -alkylating agent, doxorubicin-anthracycline, vincristine-microtubule inhibitor, prednisone-steroid)
Cancer chemotherapy given as single agent results in either:
_________ or ________
Advantages of combination chemotherapy:
>No additive toxicity for drugs with _______________ toxicities
> __decreased/increased__ cell killing
drug resistance or drug toxicity
non overlapping, increased
what are the 4 mechanisms of chemoresistance
- Increased transport of drugs out of the cell through efflux pumps
>P-Glycoprotein (PgP)
>Multi-drug resistance -associated protein (MRP) - Reduced transport into the cell
>Loss of drug importer, decreased membrane permeability - Decreased activation of prodrug
- Increased detoxification of drug molecule
what are 3 ways the drug target or function can change?
1- Increased expression of drug target through gene amplification or expression
>Upregulation of a drug target makes it harder to inhibit
2- Emergence of mutant, structurally altered target
>Mutants that are still active but don’t bind the drug
3- Emergence of cells bearing alterations in genes whose products are functionally redundant with the drug target
>Cells can rewire pathways to bypass the need for the drug target
what are 3 physiological changes that promote resistance
Refuge of cancer cells in drug-protected anatomical sites
>Metastasis to the brain where drugs do not cross blood-brain barrier
Massive stromalization
>Pancreatic carcinomas develop highly desmoplastic stroma that impedes drug transport
Changes in cell state such as EMT (epithelial mesenchymal transition)
>Slows cell cycle, increases drug efflux pumps and increases anti-apoptotic proteins
what are the 2 cell survival mechanisms
1- Activation of anti-apoptotic regulators
>Increase in proteins that help cancer cells bypass cell death
2- Increased repair of damage caused by chemotherapies.
>Most common is the repair of drug-DNA adducts or DNA damage
What is the most common reason for resistance to multiple chemotherapies at once?
A. Decreased activation of prodrugs
B. Drug transport out of cells
C. Cell cycle changes
D. Mutations in drug targets
B. Drug transport out of cells
most chemotherapies are NOT prodrugs
not all target cell cycle
what are the 2 limitations of chemotherapy
resistance & toxicity
Cancer chemotherapy relies on general principle that tumor cells are more sensitive to drugs than normal cells
Therapeutic index: ratio of the dose of a drug that is toxic to normal cells and the dose of a drug that is toxic to cancer cells
t/f BRCA & PARP are tumor suppressor genes
true
if someone already has a BRCA mutation, only PARP works to suppress tumors, so PARP inhibitors can block this, so no repair happens & causes cell death
