Final Exam Flashcards
What are the hallmarks of cancer?
-sustaining proliferative staging
-avoiding immune destruction
-enabling replicative immortality
-activating invasion and metastasis
-inducing or accessing vasculature
-genome instability and mutation
-resisting cell death
What are the characteristics of cancer?
-uncontrolled cellular growth
-invasion of tissue
-metastasis
neoplasm
a new growth; may be benign or malignant
tumor
a lump or swelling; may be benign or malignant
cancer
any malignant neoplasm
hyperplasia
an increase in organ or tissue size due to an increase in the number of cells; can be physiologic, compensatory, or pathologic
metaplasia
an adaptive substitution of one type of adult tissue to another type of adult tissue
dysplasia
an abnormal cellular proliferation in which loss of normal architecture occurs
anaplasia
a loss of structural differentiation
carcinoma
malignant neoplasm of squamous epithelial cell origin
adenocarcinoma
malignant neoplasm derived from glandular tissue
sarcoma
malignant neoplasm with origin in mesenchymal tissues or its derivatives
lymphoma and leukemia
malignant neoplasms of hematopoietic tissues
melanoma
a type of cancer of pigment-producing cells (melanocytes) in the skin or eye (uveal melanoma)
blastoma
malignancies in precursor cells
teratoma
a germ cell neoplasm made of several different differentiated cell/tissue types
Is p53 an oncogene or tumor suppressor?
tumor suppressor
Is p16 an oncogene or tumor suppressor?
tumor suppressor
Is Ras an oncogene or tumor suppressor?
oncogene
Is Rbl an oncogene or tumor suppressor?
tumor suppressor
What is a limitation of phase-specific drugs?
number of cells in specific phase at that time
What are dose-limiting toxicities of chemotherapy?
-infections
-hemostasis
-anemia
-GI side effects
-N/V
-loss of appetite
What are mechanisms of drug resistance for chemotherapy?
-altered drug metabolism
-changes in drug target or function
-physiological changes
-cell survival mechanisms
How can drug metabolism be altered?
-increased transport of drugs out of cell through efflux pumps
-reduced transport into cell
-decreased activation of prodrug
-increased detoxification of drug molecule
How can drug target or function be changed?
-increased expression of drug target through gene amplification or expression
-emergence of structurally mutated target
-rewire pathway to bypass need for drug target
What are physiological changes that can lead to drug resistance for chemotherapy?
-refuge of cancer cells in drug-protected anatomical sites
-massive stromalization
-changes in cell state
What are cell survival mechanisms?
-activation of anti-apoptotic regulators
-increased repair of damage caused by chemotherapies
What is the suffix of androgen receptor antagonists?
-lutamide
What are the mechanisms of action of androgen receptor antagonists?
-prevent androgen receptor translocation to nucleus
-inhibits androgen receptor binding to DNA
What is the indication of androgen receptor antagonists?
metastatic and non-metastatic prostate cancer
What is the mechanism of action of abiraterone?
inhibits function of 17α-hydroylase and 17,20 lyase
What is the function of 17α-hydroylase and 17,20 lyase?
convert progestogens to androgens
What is a common side effect of abiraterone?
increased cholesterol
What type of drug is tamoxifen?
selective estrogen receptor modulator (SERM) prodrug
Does tamoxifen have agonist or antagonist activities?
agonist and antagonist
What are tamoxifen antagonist effects?
-blocks estrogen-dependent breast cancer cell proliferation
-hot flashes
What are tamoxifen agonist effects?
-increased incidence of endometrial cancer
-preservation of bone density in postmenopausal women
What population is tamoxifen effective in?
pre- and post-menopausal women
What are the indications for tamoxifen?
resected and metastatic ER+/PR+ breast cancer
What is the recommended duration of use for tamoxifen?
up to 5 years
What type of drug is fulvestrant?
selective estrogen receptor down-modulator (SERD)
Does fulvestrant have agonist or antagonist activities?
antagonist
What is the mechanism of action of fulvestrant?
binds to estrogen receptor and inhibits DNA binding –> rapid receptor degradation
What is the indication of fulvestrant?
ER+ metastatic breast cancer in postmenopausal women who have progressed on other anti-estrogen therapy
What is the route of administration of fulvestrant?
IM
What cancers do glucocorticoids have anti-cancer effects in?
-pediatric acute lymphoblastic leukemia
-multiple myeloma
-lymphoma
What are the most commonly used glucocorticoids in cancer treatment?
-methylprednisolone
-prednisolone
-dexamethasone
What is the suffix of non-steroidal aromatase inhibitors?
-trozole
Are non-steroidal aromatase inhibitors competitive or non-competitive?
competitive
What is the indication of non-steroidal aromatase inhibitors?
breast cancer in postmenopausal women
When should non-steroidal aromatase inhibitors be used in treatment?
first-line OR after 3-5 years of tamoxifen treatment
What is a side effect of non-steroidal aromatase inhibitors?
increased bone density loss
What are the two steroidal aromatase inhibitor drugs?
-exemestane
-androstenedione
What is the mechanism of action of exemestane?
-false substrate that aromatase converts to reactive intermediate
-intermediate binds irreversibly at active site and inactivates enzyme
What is the indication of exemestane?
ER+ breast cancer in postmenopausal women who have progressed on anti-estrogen therapy
What are side effects of exemestane?
-hot flashes
-occasional peripheral edema and weight gain
-increased cholesterol
What is the function of aromatase?
convert androgens to estrogens
What are two GnRH analogs?
-leuprolide
-goserelin
What are long-term side effects of GnRH analogs?
-hot flashes
-gynecomastia
-sexual dysfunction
What are the indications of GnRH analogs?
-premenopausal breast cancer
-palliative treatment of advanced prostate cancer
What is a clinical pearl of GnRH analogs?
temporary worsening of symptoms due to initial agonist effects
What drugs are given to premenopausal women with breast cancer?
-GnRH analogs
-tamoxifen
What drugs are given to postmenopausal women with breast cancer?
-tamoxifen
-aromatase inhibitors
-SERDs
What is the suffix of kinase inhibitors?
-nib
What is the mechanism of action of imatinib?
type II small molecule inhibitor of Abl tyrosine kinase
What is the mechanism of action of type II kinase inhibitors?
bind and stabilize inactive conformation of kinase
What is the indication of imatinib?
chronic myeloid leukemia (CML)
What are side effects of imatinib?
-N/V
-fluid retention and edema
-neutropenia and thrombocytopenia
What is the mechanism of action of ponatinib?
BCR-Abl inhibitor
What mutation can ponatinib inhibit that other BCR-Abl inhibitors cannot?
T315I
What is the mechanism of action of type I kinase inhibitors?
bind to active conformation of kinase
What type of FLT3 inhibitor is midostaurin?
first generation
Are first generation FLT3 inhibitors more broad or specific?
broad
What drugs are type I FLT3 inhibitors?
-midostaurin
-crenolanib
What is the indication of FLT3 inhibitors?
acute myeloid leukemia (AML)
What drug is a type II FLT3 inhibitor?
-quizartinib
What mutation are type II FLT3 inhibitors specific for?
internal tandem duplication (ITD)
What type of FLT3 inhibitor is crenolanib?
second generation
Are second generation FLT3 inhibitors more broad or specific?
specific
What is the suffix of rapamycin analogs?
-rolimus
What do rapamycin analogs inhibit the function of?
mTOR
What is the mechanism of action of rapamycin analogs?
inhibit immune response by blocking IL-2 signaling transduction
What is the indication of everolimus?
advanced renal carcinoma in patients who have failed sunitinib or sorafenib
Does everolimus inhibitor mTORC1 or mTORC2?
mTORC1
What is the mechanism of action of alectinib?
specific inhibitor of ALK
What does alectinib require before prescribing?
companion diagnostic test for fusion gene
What is the indication of alectinib?
ALK+ metastatic non-small cell lung cancer (NSCLC) with progression or intolerance to crizotinib
What is the mechanism of action of dabrafenib?
second generation BRAF-V600 inhibitor
What are the indications of dabrafenib?
-BRAF V600E/K-mutant metastatic melanoma
-BRAF-600+ NSCLC
What is the mechanism of action of trametinib?
inhibits kinase activity of MEK1 and MEK2
What type of kinase inhibitor is trametinib?
type III
What is the mechanism of action of type III kinase inhibitors?
occupy allosteric pocket outside ATP-binding pocket
What are side effects of trametinib?
-rash
-diarrhea
-lymphedema
What is the mechanism of action of acalabrutinib?
second generation covalent BTK inhibitor
What is the indication of acalabrutinib?
B-cell lymphoma
What are the EGFR inhibitor drugs?
-gefitinib
-afatinib
-osimertinib
What is the indication of gefitinib and afatinib?
metastatic NSCLC with EGFR exon 19 or 21 mutations
What are the side effects of gefitinib?
-fatigue
-rash
-diarrhea
What mutation is osimertinib effective against?
T790M
What is the mechanism of action of lapatinib?
reversible small molecule tyrosine kinase inhibitor blocking HER2 and EGFR signaling
What is the indication of lapatinib?
advanced metastatic cancer progressive on other therapies
What are side effects of lapatinib?
-diarrhea
-N/V
-reversible decrease in cardiac function
What is the mechanism of action of tucatinib?
small molecule tyrosine kinase inhibitor that preferentially binds HER2
What is the indication of tucatinib?
second-line treatment for advanced metastatic breast cancer progressive on other therapies
Which EGFR inhibitors bind covalently?
-afatinib
-osimertinib
What part of the cell cycle do antimetabolites target?
S phase
What is a dose-limiting toxicity of antimetabolites?
myelosuppression
What drugs are pyrimidine analogs?
-5-FU
-capecitabine
What are the mechanisms of action of 5-FU?
-conversion to FdUMP mimics dUMP –> TMP cannot be produced –> inhibition of DNA synthesis
-conversion to F-UTP –> fluorine interferes with RNA processing and function and with polyadenylation of mRNA
What drug is used as a rescue for 5-FU?
thymidine
What are resistance mechanisms of 5-FU?
-downregulation of activating enzymes that convert 5-FU to FdUMP
-upregulation of thymidylate synthaseW
What polymorphism increases susceptibility to 5-FU?
DPD
What drug is used synergistically with 5-FU?
leucovorin
What drugs are cytidine analogs?
-cytarabine (Ara-C)
-gemcitabine
What is the mechanism of action of cytarabine?
-converted to Ara-CTP intracellularly
-competitive inhibitor of DNA polymerase α
What cancer is cytarabine best at targeting?
meningeal leukemia and lymphoma
What are resistance mechanisms of cytarabine?
-downregulation of activating enzymes and transporter to move drug into cell
-upregulation of cytidine deaminase
What drug is used synergistically with cytarabine?
tetrahydrouridine
How is gemcitabine more beneficial than cytarabine?
higher potency
What drugs are purine analogs?
-6-mercaptopurine
-6-thioguanine
What is a resistance mechanism of 6-mercaptopurine?
loss of HGPRT
What polymorphism causes increased toxicity of 6-mercaptopurine?
TPMT
What is a drug interaction with 6-mercaptopurine but not 6-thioguanine?
allopurinol
What drug is an antifolate?
methotrexate
What is the mechanism of action of methotrexate?
DHFR inhibitor
What are resistance mechanisms of methotrexate?
-amplification of DHFR gene or mutation of DHFR to resistant form
-decreased polyglutamation
What is a side effect of methotrexate?
myelosuppression
What drug is used as a rescue for methotrexate?
leucovorin
What are side effects of alkylating agents?
-myelosuppression
-N/V
What drug class is chlorambucil in?
mechlorethamine derivatives
How are mechlorethamine derivatives more beneficial than mechlorethamine?
reduced reactivity and increased selectivity of nitrogen mustards
Are alkylating agents cell cycle phase specific?
No
What type of drug is cyclophosphamide?
prodrug alkylating agent
What are side effects of cyclophosphamide?
-bone marrow toxicity
-hemorrhagic cystitis
What drug is administered with cyclophosphamide to prevent hemorrhagic cystitis?
mesna
What type of drug is mitomycin C?
alkylating agent
What is a dose-limiting side effect of mitomycin C?
myelosuppression
What is the suffix of platinum drugs?
-platin
What is the mechanism of action of platinum drugs?
covalent crosslinkers
What type of crosslinks are formed by platinum drugs?
intrastrand
What type of tumors are platinum drugs highly effective for?
solid tumors
What are side effects of cisplatin?
-N/V
-bone marrow toxicity
-peripheral neuropathy
-ototoxicity
What is a dose-limiting side effect of cisplatin?
nephrotoxicity
What are resistance mechanisms of alkylating agents and platinum drugs?
-increased expression of DNA repair enzymes
-increased intracellular concentration of non-protein thiones
-increased expression of cellular glutathione S-transferase (GST)
What phase of the cell cycle are cells most susceptible to topoisomerase I inhibitors?
S phase
What are resistance mechanisms of topoisomerase I and II inhibitors?
-PGP overexpression
-MRP overexpression
-glutathione S-transferase overexpression
-topoisomerase downregulation or mutation
What is the suffix of camptothecins?
-otecan
What polymorphism causes increased toxicity of irinotecan?
UGT1A1
How many strands of DNA does topoisomerase I cut?
one
How many strands of DNA dose topoisomerase II cut?
two
Are topoisomerase II inhibitors cell cycle phase specific?
No
What cell cycle phase do topoisomerase II inhibitors have greater activity in?
G2/M
What is the suffix of anthracyclines?
-rubicin
What are side effects of doxorubicin?
-cardiotoxicity
-local tissue damage
What drug mediates cardiotoxicity associated with anthracyclines?
dexrazoxane
How is etoposide different than anthracyclines?
not an intercalator
What cell cycle phase does etoposide target?
G2
What is a resistance mechanism for topoisomerase II inhibitors?
increased DNA damage repair
What cell cycle phases does bleomycin target?
G2/M
What is a side effect of bleomycin?
myelosuppression
What is a dose-limiting side effect of bleomycin?
pulmonary side effects
What is the mechanism of action of vinka alkaloids?
prevent microtubule assembly
What is the mechanism of action of taxanes?
prevent microtubule disassembly
What is a side effect of vinka alkaloids?
peripheral neuropathy
What are side effects of vincristine?
-local inflammation
-myleosuppression
What is a dose-limiting side effect of vincristine?
neurotoxicity
How is eribulin beneficial compared to vincristine?
lower rate of neurotoxicity
What is the suffix of taxanes?
-taxel
What is a side effect of paclitaxel?
neurotoxicity
What is a dose-limiting side effect of paclitaxel?
myelosuppression
What is a clinical pearl of ixabepilone?
not cross-resistant with taxanes
What is the mechanism of action of pembrolizumab?
PD-1 inhibitor
What are the indications for pembrolizumab?
-advanced metastatic melanoma after treatment with ipilimumab and BRAF inhibitor
-PD-L1+ NSCLC
What is the mechanism of action of atezolizumab?
PD-L1 inhibitor
What is the mechanism of action of ipilimumab?
binds to CTLA-4 receptor and reverses CTL inhibition
What is the indication of ipilimumab?
advanced metastatic melanoma
What are side effects of ipilimumab?
-enterocolitis
-hepatitis
-dermatitis
-neuropathy
-endocrinopathy
What is the mechanism of action of trastuzumab and pertuzumab?
recombinant humanized monoclonal antibody specific for HER2
What is the indication of trastuzumab?
HER2+ breast cancer
What are side effects of trastuzumab?
-flu-like symptoms
-risk of cardiomyopathy/CHF
-risk of hypersensitivity reactions
What region of HER2 does trastuzumab bind to?
region IV
What region of HER2 does pertuzumab bind to?
region II
What is the mechanism of action of cetuximab?
recombinant chimeric monoclonal antibody specific for EGFR
What are the indications of cetuximab?
-colorectal cancer
-head and neck cancer
What are side effects of cetuximab?
-infusion reaction
-acneiform rash
-fatigue
-fever
What is the mechanism of action of bevacizumab?
recombinant humanized monoclonal antibody specific for VEGF
What is the indication of bevacizumab?
metastatic colorectal cancer in combination with 5-FU
What does bevacizumab bind?
VEGF ligand
What does ramucirumab bind?
VEGF receptor
What is the mechanism of action of rituximab?
CD20 antibody
What is the indication of rituximab?
B-cell lymphomas
What is the mechanism of action of daratumumab?
CD38 antibody
What is the indication of daratumumab?
multiple myeloma