Therapeutics Exam 1 (Wendt and Dykhous) Flashcards
6 essential characteristics of cancer? sustaining \_\_\_\_\_\_\_\_ evading \_\_\_\_\_\_\_ activating \_\_\_\_\_\_ enabling \_\_\_\_\_\_\_ inducing \_\_\_\_\_\_ resisting \_\_\_\_\_\_
sustain: proliferative signaling
evade: growth suppressors
activate: invasion and metastasis
enable: replicative immortality
induce: angiogenesis
resist: cell death
2 newer/emerging hallmarks of cancer
deregulating _______
avoiding ______
deregulate: cellulare energetics
avoid: immune destruction
Terminology:
Cancer?
any malignant neoplasm
Terminology:
Tumor
nonspecific term meaning lump or swelling
Terminology:
Neoplasm
any new growth - benign or malignant
Terminology:
Neoplasia
process of expansion due to defects in the molecular controls that regulate cellular proliferation/cell death
Terminology - the “plasias”:
Hyperplasia
increase in NUMBER of cells
Terminology - the “plasias”:
Metaplasia
SUBSTITUTION of one type of adult tissue to another adult tissue
Terminology - the “plasias”:
Dysplasia
LOSS OF NORMAL architecture/ abnormal cellular proliferation
Terminology - the “plasias”:
Anaplasia
loss of STRUCTURAL DIFFERENTIATION
Terminology - the “plasias”:
Desmoplasia
formation and proliferation of CONNECTIVE TISSUES and cells
Terminology - the “omas”:
Carcinoma
malignant neoplasm of EPITHELIAL cell origin
Terminology - the “omas”:
Adenoma
epithelial neoplasm derived from glandular tissue
Terminology - the “omas”:
Papilloma
surface epithelium in which neoplastic cells grow outward in finger like fibrovascular stalks
Terminology - the “omas”:
Teratoma
germ cell neoplasm –> several different differentiated cell and tissue types
Terminology - the “omas”:
Sarcoma
malignant neoplasm from mesenchymal tissues (aka soft tissues Ex: muscle)
Terminology - the “omas”:
Lymphoma or Leukemia
malignant neoplasms of hematopoietic tissues
Terminology - the “omas”:
Blastoma
more common in children —
caused by malignancies in precursor cells
Terminology - the “omas”:
Melanoma
cancer of pigment producing cells
_____ is the most lethal aspect of cancer
Metastasis
Metastatis is a multi step process:
Normal epithelium –> _____ –> _________ –> ______ –> intravasation/extravasation –> metastatis
dysplasia; carcinoma in situ; invasive carcinoma
Metastatis is highly _____ process
inefficient
unlike carcinomas, sarcomas arise from ______
soft tissues
leukemia is the cancer of _____ cells
white blood
lymphomas arise from cells that populate from _____
lymph nodes
what is a reed-sternberg cell?
a binucleated cell - a part of Hodgkin’s Lymphoma
Staging of Carcinomas
stage 0
in situ carcinoma; no sign of local invasion
Staging of Carcinomas
stage I
microscopic invasion of surrounding tissue
Staging of Carcinomas
stage II
4 - 9 surrounding lymph nodes are involved
Staging of Carcinomas
stage III
10 + surround lymph nodes are involved
Staging of Carcinomas
stage IV
distant metastases are detected
what stage # for carcinoma?
in situ carcinoma - no sign of local invasion
0
what stage # for carcinoma?
microscopic invasion of surrounding tissue
1
what stage # for carcinoma?
4 - 9 surrounding lymph nodes are involved
2
what stage # for carcinoma?
10+ lymph nodes are involved
3
what stage # for carcinoma?
distant metastases are detected
4
what is another specific staging system for tumors?
TNM staging (primary tumor (T); regional lymph nodes (N), distant Metastasis (M) X: cant be evaluated 0: no evidence 1+: present
summary staging for cancer:
in situ?
abnormal cells are present only in the layer of cells in which they develop
summary staging for cancer:
localized?
cancer is ONLY in the organ where it BEGAN
summary staging for cancer:
regional?
spread beyond primary site to NEARBY lymph nodes or tissues and organs
summary staging for cancer:
distant?
aka has metastasized - gone to distant tissues or organs…..
what is tumor grading?
way to grade the tumor based on how abnormal the tumor cells and tissues look under a microscope
is G1 or G4 more concerning for a tumor?
G4 is more concerning
G4 is undifferentiated = high grade
well differentiated or undifferentiated tumor is worse?
undifferentiated
___ differentiated cells in tumors will look like normal cells and tissues
well - differentiated
_________ receptors can dimerize to each other and drive cell growth
EGF receptor family (HER 2,3,4)
what does RSV stand for?
rous sarcoma virus
why is RSV relevant to tumors?
RSV is a retrovirus and encodes a protein (v-SRC) that is capable of driving proliferation and tumor progression
aka it is like an oncogene
At least 6 viruses are thought to contribute to cancer —-
_____ and _____ viruses
DNA and RNA
proto-oncogenes act as ______ alleles
dominant
____ of function mutations in tumor suppressor genes can lead to cancer
loss
tumor suppressor genes are ______ alleles
recessive
_____ mutations in tumor suppressor genes are more often transmitted as ______ mutations and therefore assoc. w/ heritable forms of cancer
heterozygous;
germ line
HER2 - is an proto oncogene or tumor suppressor?
oncogene —
slide also shows that test a cell with dysplasia with Antibodies - lots of dark spots because antibody binds to lots of HER2 receptors
slide in ppt about DIAGNOSTIC molec. pathology: lung biospies can be tested via PCR for a particular mutation in _____ - if so pts can go on specific anti____ therapies
EGFR; EGFR
PROGNOSTIC Molec pathology example?
oncotypeDX
like 21 genes that will show if a patient is at high or low risk for metastasis in the next five years — if high chance will probably do chemo
OncotypeDx and Mammaprint:
can prevent ______ because predict recurrence
overtreatment
OncotypeDx and Mammaprint:
T or F:
Drive indications for specific therapies
falseeeee
just predicting recurrence
Main cancers that hormones regulate proliferation of
Breast
Endometrial
Prostate
Hormonal Therapies for Cancer:
primarily _____ and ______ is targeted (for breast/endometrial and prostate cancer, respectively)
estradiol
dihydrotestosterone
Androgens and estrogens have ____ effects
opposing
Steroid receptors:
they are ______ hormone dependent ______ factors
cytosolic; transcription
what is the base material for making estradiol and testosterone?
cholesterol
Steroid receptors barely bind to the _____
surface
Steroids diffuse easily or poorly
easily
what are the 2 main classes of anti estrogen therapy
aromatase inhibitors
SERMs (selective estrogen receptor modulators)
aromatase inhibitors will stop estrogen ______
and
SERMs stop estrogen ______
production
function
Steroid Feedback Loop:
Hypothalamus release ____ to work on _____
GnRH
work on pituitary
Steroid Feedback Loop:
Pituitary makes _____ and _____ to work on the _____
FSH and LH;
works on ovaries and testis.
Steroid Feedback Loop:
Estrogen and Progesterone act as a ______ feedback loop on the _____
negative; pituitary
when LH (decrease or increases) estrogen will decrease
increase
_____ is a potent stimulant of breast cancer cell proliferation
estradiol
what are some protective factors against breast cancner
early age of 1st full term pregnancy
lactation
physical activity during reproductive years
Breast Cancer:
Well differentiated tumors - more likely to be ER___
and poorly differentiated tumors are likely to be ER___
+
-
Poorly differentiated tumors - have ____ growth fractions and are generally more _____ to cytotoxic agents
higher growth
more sensitive
_____ correlation b/w presence of estrogen receptor and the likelihood of response to hormone therapy
highly significant
____ in breast cancer risk 5 years after lactation
increased risk
the risk for breast cancer _____ with increasing age
increases
ER+ tumors should be treated with ____ therapy and why
hella estrogen receptors (aka ER+) tumors should get ENDOCRINE therapy - because there is actually receptors are endocrine stuff to affect….
what are the 4 different types of breast cancer
ductal carcinoma in situ (preinvasive)
invasive ductal carcinoma (invasive)
lobular carcinoma in situ (preinvasive)
invasive lobular carcinoma (invasive)
what drugs are SERMs
Tamoxifen
Raloxifene
Toremifene
clomiphene
fulvestrant
which SERM is also used for osteoporosis
raloxifene
how can a SERM be helpful for osteoporosis
it is an ER AGONIST in the bone — estrogen agonist will promote bone growth
tamoxifen wasnt used for awhile because what else was needed?
needed to know if someone is ER+ or ER-
if ER+ – tamoxifen would be effective
Tamoxifen is a _______ that that is metabolized by _____
prodrug; CYP2D6
what is the active form of tamoxifen?
4-OH-Tam
T or F: Tamoxifen has antagonist activity only
False;
agonist and antagonist – it is a SERM (they do both…selective….)
tamoxifen:
binds to ____ receptor and inhibits both _____ and _______
estrogen receptor;
translocation; DNA binding
Tamoxifen:
blocks _______ dependent breast cancer ________
estrogen ; proliferation
Tamoxifen: Estrogen AGONIST effects
increase incidence of _______ cancer
will preserve _________ in postmenopausal women
can cause ________
incidence of endometrial
preserve bone density
blood cots
Tamoxifen: Side effect of hot flashes happens because of..?
estrogen ANTAGonist activity
Tamoxifen:
used in pre or post menopausal women?
both!!!
______ was the first drug approved for breast cancer prevention
tamoxifen
tamoxifen: dosage route?
oral
tamoxifen:
primary use is treatment of ________?
resected ER+/PR+ breast cancer
take tamoxifen for about ______ when treating resected ER+/PR+ breast cancer
3 -5 years
Tamoxifen: antagonist or agonist at these specific parts and its impact?
Brain
antagonist –> hot flashes and thermoregulation
Tamoxifen: antagonist or agonist at these specific parts and its impact?
breast
antagonist — why we use it for ER+ breast cancer
antiproliferative
Tamoxifen: antagonist or agonist at these specific parts and its impact?
blood
agonist – leads to increased coagulability and clots VTE risk
Tamoxifen: antagonist or agonist at these specific parts and its impact?
Uterus
agonist —- endometrial hyperplasia — endometrial cancer increased risk
Tamoxifen: antagonist or agonist at these specific parts and its impact?
bone
partial agonist — blocks bone resorption — yay healthy bones
Raloxifene: antagonist or agonist at these specific parts and its impact?
brain
antagonist —> hot flashes and thermoregulation
Raloxifene: antagonist or agonist at these specific parts and its impact?
breast
antagonist – duh bc treating breast cancer
*not as strong of an antagonist to as tamoxifen in the breast though
Raloxifene: antagonist or agonist at these specific parts and its impact?
blood
agonist —
increased coag/VTE risk
Raloxifene: antagonist or agonist at these specific parts and its impact?
uterus
antagonist !!! aka NO endometrial hyperplasia risk!
difference from tamoxifen
4 strong 2D6 inhibitors? (aka drugs to avoid with contaminant tamoxifen because they will make tamoxifen less effective/not to its active metab…)
fluoxetine
paroxetine
quinidine
bupropion
what drug is a SERD?
fulvestrant
why is a SERD different than a SERM? (structure and MOA)
structure: similar to estradiol but has a long carbon chain: this will lead to a proteosome to break down the estrogen receptor
it is a PURE estrogen antagonist
Fulvetrant: T or F: has agonist and antagonist effects
falseeee
only an antagonist —
Fulvestrant:
binds to ER and inhibits ______ binding — which leads to rapid _____
DNA binding;
receptor degradation
fulvestrant will cause a dramatic loss of cellular ____ levels and reduce ____ expression
cellular ER levels
reduce PR expression
fulvestrant: dosage form route?
IM injection once per month
fulvestrant is approved for who and what condition?
ER+ metastatic breast cancer in POSTMENOPAUSAL women who have progressed on other antiestrogen therpay
aromatase enzyme is important in steroid generation why?
aromatase makes enone A ring of androgen into a aromatic a ring in estrogens
Aromatase inhibitors block synthesis of _______ but not ______ and ______
block: estrogens
not: androgens and progesterone
________ (type of cell) is the principal source of estrogen in postmenopausal women
adipocytes
primary target of aromatase inhibitors is ______ tissue not the ______
peripheral/adipose
not ovary
primary application is estradiol suppression in what group of patients?
POSTmenopausaul women
Aromatase Slide:
Androstenedione is made in the _____ gland and released to circulation:
aromatase takes andorostenedione to _____
adrenal gland
estrone
(estrone will then go to estradiol)
2 main subclasses of aromatase inhibitors?
steroidal and on-steroidal
what drugs are NON-steroidal aromatase inhibitors
anastrozole
letrozole
Anastrozole and letrozole are potent and selective ______ inhibitors for _____ activity
competitive;
aromatase
primary indication for Anastrozole and letrozole ?
tx of breast cancer in POSTmenopausal women
dosage route of anastrozole and letrozole?
orally - everyday
ADEs of letrozole and anastrozole?
hot flashes
bone/join/muscle pain
asthenia (weakness)
increased fracture risk (will increase the extent of bone density loss – because decreasing estrogen…)
Potential fetal damage - avoid in pregnant women!!
what drug is a steroidal aromatase inhbitiors?
exemestane
exemestane has similar structure to _________
androstenedione
Exemestane MOA: is a fake substrate to ______ and gets converted to a reactive intermediate: then this intermediate binds _____ at the ____ site which inactivates the enzyme
aromatase; irreversibly; active
exemestane: dosage route?
orally - daily
primary indication for exemestane?
tx of estrogen responsive breast cancer in POSTmenopausal women – who have progressed on antiestrogen therapy
ADEs of exemestane?
hot flashes
occasional peripheral edema and weight gain
increased cholesterol levels (remember estrogen can help keep ladies’ cholesterol in check
brand of exemestane?
aromasin
Treating with progesterone will inhibit ____ and ____
LH; FSH
Decreased FSH leads to _____ aromatase and _____ estrogen
decreased; decreased
A progesterone _____ will suppress estrogen receptor expression
agonist
progesterone derivs (like medrooxyprogesterone) primary indication?
prevention of endometrial cancer in postmenopausaul women
other effects/uses for medrooxyprogesterone
appetite stimulation/wt gain – good for anorexia/cachexia in cancer/AIDS
antiemetic properties: reduced N/V in cancer patietns
Chronic administration of LHRH analogues will downregulate ______ LHRH receptors and lead to _________
pituitary; pituitary desensititzation
what are examples of LHRH analogs?
GnRH
Leuprolide
Goselerin
Acute admin vs Chronic admin of LHRH agonists
acute: will increase levels of all steroid hormones
chronic: downregulates pituitary LHRH receptors–> pituitary desensititzation
Chronic admin of LHRH agonists will cause a severe _____ of _____ in 3- 4 weeks
estrogen
long term ADEs of LHRH analogs?
since decreased estrogen — hot flashes and sexual dysfunction
what drug class related to steroid hormones will have transient worsening of symptoms
LHRH analogs (because acutely increase all steroid levels)
what hormonal therapy options are for premenopausal women
LHRH agonists (goserelin and luporlide)
Surgical oophorectomy
tamoxifen
what drug can be used as a hormonal therapy option for both pre and post menopausal women
Tamoxifen
what hormonal therapy options are for postmenopausal women
tamoxifen Nonsteroidal aromatase inhibitors steroidal aromatase inhibitors pure anti-estrogens progestin
testosterone is rapidly and irreversibly converted to DHT (dihydrotestosterone) in ____ cells by _______
prostate cells; type 2 5 alpha reductase
DHT binds to what receptor in prostate cells?
androgen receptor (AR)
what are GnRH analogs used in men for prostate cancer?
Leuprolide and goselerin
what are some long term side effects of men being on GnRH agonists
(low testosterone…)
gynecomastia
sexual dysfunction
what is the pro of LHRH receptor antagonists or GnRH agonists for men?
the ANTAGNOISTS will not have the tumor flare
what drugs are GnRH receptor antagonists
abarelix
degarelix
abarelix and degarelix are used for what?
prostate cancer (they are GnRH receptor antagonists)
what drugs are androgen antagonists
enzalutamidide and apalutamide
enzalutamidide and apalutamide are what kind of drugs
androgen receptor antagonists
MOA of androgen receptor antagonists?
prevent AR translocation to the nucleus and inhibits AR from binding to DNA
what are androgen receptor antagonists used for?
prostate cancer (dur - anti testosterone)
what drug inhibits the function of 17-a hydroxylase and C17,20 lyase
Abiraterone
what is the benefit or Abiraterone
it inhibits the enzymes further up in the hormone synthesis process
what is an ADE of Abirtaerone
since it inhibits further up in the hormone synthesis process – it will increase cholesterol
what drugs are 5 alpha reductase inhibitors
finasteride
dutasteride
finasteride or dutasteride?
_____ inhibits only type 2
______ inhibits both type 1 and 2
finasteride
dutasteride
5 alpha reductase inhibitors may delay the growth of ______
benign prostate tumors
what drug was the first kinase inhibitor?
Imatinib
what are the 3 main parts of ATP
triphosphate
ribose
adenine base
________ balance the activity of kinases by removing phosphates
phosphotases
Type 1, 2, 3/4 or Covalent kinase Inhibitors?
bind to the active conformation of the kinase
type 1
Type 1, 2, 3/4 or Covalent kinase Inhibitors?
bind to inactive conformation
type 2
Type 1, 2, 3/4 or Covalent kinase Inhibitors?
bind to allosteric pocket
3/4
Type 1, 2, 3/4 or Covalent kinase Inhibitors?
has irreversible inhibition - binds with cysteine residues
covalent!
what drugs are only EGFR kinase inhibitors
Gefitinib Erlotinib Afatinib Neratinib osimertinib
EGFR functions through ______ activity and EGFR signaling induces cell _______
tyrosine kinase; proliferation
Erlotinib and Gefitinib: approved for tx of ______ cancer for tumors that have EGFR _____ and _____ mutations
tx of NSCLC (non small cell lung cancer);
exon 19 and exon 21 mutations
a rash with the drug _____ can be a good thing —- skin rash on chest and back may mean longer survival
Erlotinib
what mutation can cause resistance to Erlotinib and Gefitinib
T790M
what drug is a second gen EGFr inhibitor
Afatinib
what drug was the first approved covalent EGFR inhibitor
afatinib
Afatinib was made to overcome the T790M resistance in EGFR inhibitors — did it work?
Nooooo it didnt - but was a covalent inhibitor
Afatinib - currently approved for?
metastatic NSCLC - where tumors have EGFR exon 19 deletions or exon 21 mutations as detected by an FDA approved test
what drug was made/successfully overcomes the resistance from T790M mutation in the EGFR inhibitor
osimertinib
what EGFR inhibitors are are selective for ErbB/Her2
Lapatinib
Nerabtinib
HER2 inhibitors - all have risk of _____
CHF: it is reversible tho
the HER2 inhibitors: Lapatinib or Nerabtinib
which one is reversible and which one is covalent
lapatinib: reversible
Nerabtinib: covalent
VEGFR is critical for tumor ______
angiogenesis
why are VEGFR inhibitors efficacy limited?
they are not paired with a molecular dianostic
cMET is a the receptor for ______
HGF (hepatocyte growth factor)
what drugs are inhibitors of cMET
Crizotinib and Cabozantinib
out of the cMET inhibitors:
______ can overcome ______ resistance that results to mutations in another receptor ROS1
cabazanitib; crizotinib
explain BCR-ABL gene
BCR normally on chromosome 22; ABL on 9
sometimes they translocate and get near each other and this leads to constitutive growth etc
what drug was the first type 2 inhibitor (kinase inhibitor)
Imatinib
BCR-ABL pathway:
BCR or ABL is a tyrosine kinase?
ABl
Imatibnib will inhibit the _____ kinase, and ______ receptor and the stem cell factor known as _____
ABL tyrosine; PDGFR (platelet derived growth factor receptor); c-Kit
primary indication for imatinib?
and what is the other thing it is effective for?
CML - chronic myelocytic leukemia
GIST - GI stromal tumor
Toxicities of Imatinib
N/V
Fluid retention/edema
Neutropenia/thrombocytopenia
resistance to imatinib results from mutations from kinase domain — can use _____ instead because it can still inhibit BCR-ABL even if there are some mutations
use Nilotinib
what drugs are BCR-Abl inhibitors
imatinib nilotinib ponatinib dasatinib bosutinib
which BCR-Abl inhibitor is the one that is notably able to inhibit all major mutant forms of BCR-Abl even the “gatekeeper mutation” of T3151
Ponatinib
All compounds that bind BCR-Abl (as kinase inhibitors) bind it in the _____ confirmation
“DFG out”
what drugs can be used for the ELM4-ALK translocation?
Crizotinib and Alectinib
EML4 or ALK is the tyrosine kinase?
ALK…
melanoma tends to have ____ mutations
BRAF
Sorafenib can inhibit RAF – but the drug is not effective because it is blocked by the ____ mutation that is very common in melanoma
V600
what drugs are for BRAF and can inhibit when the V600 mutation is present - and which one is the drug of choice
Vemurafenib;
Dabrafenib (this one is DOC)
BRAF inhibitors and wild type enzyme – what is the result
a bad result of where they can actually activate normal B-raf and promote tumor growth
what drugs are RAF inhibitores
Sorafenib
Vemurafenib;
Dabrafenib
what drugs are MEK inhibitors (kinase inhibitors)
trametinib
Cobimetinib
which MEK inhibitor was the 1st approved type 3 (allosteric) inhibitor
trametinib
limitation of Trametinib
not indicated for the tx of pts who have already received BRAF inhibitor therapy
Limitation of Cobimetinib?
not indicated for pts with the wild type BRAF melanoma
PI3K is a ___kinase that leads to the downstream activation of _________ — this pathway is critical for cancer cell survival
lipid; activation of PKB (protein kinase B)
what drug was the first lipid kianse inhibitor
Idelalisib
idelalisib is approved for treating?
CLL (chronic lumphocytic leukemia)
Ibrutinib:
is a _____ kinase inhibitor
inhibits ____ which is the downstream of the _____ receptor
indicated for ______
is a BTK
downstream of BCR (b-cell receptor)
b-cell leukemia
what drugs are BTK inhibitors
Ibrutinib
Acalabrutinib
which BTK inhibitor is more selective and potent
Acalabrutinib
Ibrutinib and Acalabrutinib are what type of kinase inhibitor (type 1,2,3,covalent?)
covalent
the BTK inhibitors are covalent
the rapalogs are also known as ______ and inhibit ______
Rapamyacins and inhibit M-TOR
what drugs are Rapalogs
sirolimus
everolimus
Temsirolimus
Deforolimus
m-TOR is a ______ kinase
serine-threonine
PI3K will lead to the stimulation of _____
AKT
what drugs are CDK4/6 inhibitors
palbociclib
ribociclib
abemaciclib
con of CDK inhibitors?
CDK = cyclin dependent kinase
they work down stream of so many of the receptors that it really isnt specific/not really targeted therapy
also the ADEs are neutropenia/N/V/D/fatigue - v similar to chemo
T Cells:
arise in ______ but migrate to the _____ to mature
bone marrow
thymus gland
T Cells:
T or F: T Cells cannot recognize an antigen alone
true
T cell receptors can only recognize an antigen if bound to cell membrane proteins (aka MHC molecule)
2 main kinds ot t Cells?
CD4-TH (helper)
CD8-TC (cytotoxic)
there is also suppressor T cells
Positive vs Negative selection of T Cells?
+: allows T cells to survive if they are capable of recognizing SELF MHC molecules
-: gets rid of T cells that react to strongly to self MHC molecules
Overall goal is Central Tolerance
Antibody production: the _____ arm of the immune system
humoral
B Cell matures to a _____ cell
plasma
idea behind HUMANIZED anitbodies?
can construct a cell line secretes antibodies that are mostly human except for the CDR (complementary determining region)
idea behind fully human antibodies?
transgenic mice have been constructed to express the human VDJ regions of the genome so they make fully human antiboides
Monoclonal antibodies end with _____
-mab
Monoclonal antibodies: substems if its a mouse: \_\_\_\_ chimeric: \_\_\_\_\_ humanized: \_\_\_\_ fully human: \_\_\_\_\_\_
mouse: -o
chimeric: -xi
humanized: -zu
fully human: -u
Antibody production:
from mice — take a antibody forming cells — fuse it with a _____ and this makes a _____
fuse with a tumor cell
makes a hybridoma (hybirdoma will make hella cells that make the same antibody)
why can an antibody binding can lead to several anticancer events?
the antibody binding can lead to CDC (complement dependent cytoxicity) and ADCC (antibody dependent cellular cytotoxicity) and selective elimination of the tumor cell
what 2 antibody drugs are specific for the HER2 receptor
Trastuzumab
Pertuzumab
Trastuzumab and pertuzumab both inhibit HER2 — but why are they be used together at the same time
Tras: blocks internalization/causes ADCC
Pertuz: blocks oligermization/dimerization
what antibody drugs are for EGF receptors
Cetuximab
Panitumumab
why is there a high chance of an infusion reaction with cetuximab?
it is a chimeric antibody!! (aka hella mouse proteins)
what cancers is cetuximab used for?
colorectal, head and neck
NOT LUNG - the drug is for EGFR and the lung cancers will have kinase mutations and the receptor blockage wont do much…
Cetuximab and panitumumab are used for colorectal after _____ status is checked
KRAS mutation
if KRAS mutation is present — antibody won’t be effective —- KRAS is downstream from EGFR
Panitumumab is a ______ type of antibody that binds specifically to ______
fully human antibody
binds to EGF receptor
why do we want to target CD20 for cancer?
CD20 - plays role in B Cell proliferation — important in lymphophomas
what drugs are antibodies for CD20? (which are second gen)
Rituximab
2nd gen:
Ofatumumab
Obinutuzumab
Bevacizumab: binds to _______ not ______
VEGF not VEGFR!!!
Bevacizumab:
toxicities?
related to bleeding — since it is block ing VEGF we are blocking vascularization
Minor or Major hemorrhage (nosebleed common)
GI perforations and wound healing complications
Deep vein thrombosis
Ramucirumab: binds to _____ not _____
VEGFR not VEGF
what is an ADC?
antibody drug conjugates
explain the components of the current approved ADC? that wendt mentioned..there might be more of course..)
TDM1 aka Ad-Trastuzumab Emtansine
a cytotoxic agent (mertansine) linked to the antibody trastuzumab
TDM1: the ADC
trastuzumab binds to ________
then
mertansine ______ and inhibits ________
binds to HER2/Neu receptor
enters cell and inhibits microtubule assembly
why do we care to target CD30 in cancer cells?
CD30 is expressed on reed sternberg cells – these are in hodgkins lymphoma
what drug is an anti-CD30 antibody conjugated with MMAE
brentuximab vedotin
what is MMAE
monomethyl auristatin E —is conjugated with teh CD30 antibody to make brentuximab vedotin for hodgkins lymphoma
it is a microtubule destabilizing agent
so toxic — cannot be used by itself
major goal of cancer immunotherapy is getting the immune system recognize and destroy cancer —- this can be done by altering ____ cells
T
Cancer Immunotherapy:
_____ and _____ act as brakes or checkpoints in the immune system — blocking these interactions with antibodies can lead to keep T Cells activated!!
CTLA-4
PD1
what drug can bind to CTlA-4 and reverse the CTL (cytotoxic T lymphocyte) inhibition
(this inhibition is done by dendritic cells via the CTLA-4 receptor)
Ipilimumab
ADE’s of Ipilimumab
MOA: the drug reverses CTL (cytotoxic T lymphocyte) inhibition and thus more T cells are active and doing their thing ==== INFLAMMATION!!
ADE’s Sseen
Enterocolitis/Hepatits (Gi tract inflammation)
Dermatitis, neuropathy, endocrinopathy
How to overcome/help with the inflammation ADE’s seen with Ipilimumab?
high dose corticosteroids
Cancer Immunotherapy: T Cells
PD-1 and PD-L1
one is expressed on macrophages/tumor cells the other on T cells - which is which?
PD-1 = T cells
PD-L1 = macropaghages; tumor cells
Cancer Immunotherapy: T Cells
PD-1 and PD-L1
what does PD stand for
program death!
thus inhibit death of T -cells they can attack the tumor!
what drugs are PD1 antibodies
Pembrolizumab and Nivolumab
will bind to the receptor on T cells
what drugs are PD-L1 antibodies
Atezolizumab; Avelumab
will bind to receptor on macrophages and tumor cells
Cancers with (more or less) mutations will respond better to T cell therapy?
more mutations!
more mutations = less like self = T cells will attack more easily
what types of cancer responds (possibly) best to T cell therapy?
melanoma – because it will have helllla mutations
Colorectal cancer can be very responsive to T cell therapy if the cells are _____ deficient
mismatch repair – if they cant fix their mutations then they will be very unlike self cells –> t cells will wreck them
Cancer immunotherapy /Antitumor immunity is worse or better if it preceded with radiation?
better!
the remaining cells after radiation will be the ones with hella mutations – thus T cell therapy will recognize them easily a
The idea behind bispecific antibodies?
to physically bring an activated T cell into proximity with a tumor cell
what drug is a bispecific antibody (aka BiTE = bi-specific T cell engager)
Blinatumomab
Blinatumomab binds to ____ and _____
CD19 AND CD3
CD3 ON T CELLS
AND CD19 ON B CELLS
Alkylating Agents:
they are electrophilic or nucleophilic?
electrophilic
Alkylating agents tend to react with _____ groups that are found on _____ and _____
nucleophilic; DNA and Proteins
Alkylating agents
major mechanism of action involves alkylation of ______ bases in DNA
purine
Alkylating agents
the most common site of alkylation is?
Guanine N7
Alkylating agents
crosslinking will inhibit DNA ______ and ______
replication; transcription
the cross linking of DNA, done by alkylating agents, is repaired ______
not efficiently!!!
DNA doesn’t encounter this much and thus cant fix it super well
what DNA bases are purines?
Adenine and Guanine
Ag – “pur”e as gold
What other nucloephiles can Alkylating agents react with?
thiols, Cysteine/lysine, and GLUTATHIONE
Alkylating agents:
cells are more susceptible in which phase?
late G1 - S (aka replication prep time) - is most effective
buuut alkylating agents are effective all the time - non cell cycle specific
Alkylating agents
normal cell populations rapidly proliferate and therefore are more sensitive to DNA alkylation/cross linking: those areas are _______ and _____
bone marrow; gut mucosa
especially with very strong Alkylating agents — there is a measurable incidence of second ______
malignancies
what are some other names for mustard gas
Mechlorethamine!!
mustargen
mustine
what are some mechloethamine derivs
Bendamustine
Chlorambucil
Melphalan
Mustard gas (mechloethamine) facts:
EXTREMELY reactive compound
half life in plasma is about ____
1 minute
what are side effects of all Alkylating agents
myleosuppression
N/V
carcinogenic/teratogenic
since mechloethamine is reactive and wild — what are the strategies to make them less wild
- decrease the nucleophilicity by ADDING ARYL GROUPS
2. prodrug strategy
the mechloethamine deriv drugs are made by doing what
adding an aryl group to decrease the nucleophilicity of nitrogen
this lets the have a long half life!!!
for akylating agents it is best for the conjugate acid pKa to be basic or acidic?
acidic!!
stronger acid = weaker conjugate base = resonance stabilzed (done with aromatic ring)
what is an example of a prodrug Alkylating agents of the mustard family
Cyclophosphamide
Cyclophosphamide:
is a PRODRUG needs hydroxylation from _____
its metabolite is ______ and it will cross link DNA
hepatic P450
metabolite: phosphoramide mustard (PMM)
Cyclophosphamide:
the metabolite, PM, will be made in _____ cells
PM is highly (polar or non polar)
PM has a (short or long) half life
made in tumor cells
highly polar — does NOT readily dissuse into cells
short half life! (why good thing it is a prodrug)
Cyclophosphamide:
its PM metabolite is inactivated by ?
aldehydrogenase dehydrogenase
what is the by product made when Cyclophosamide is made into PM
acrolein
what are the two most current/useful alkylating agents
cyclophosphamide and ifosfamide
cyclophosphamide and ifosfamide are the preferred alkylating agents why?
side effects are most mild compared to other alkylating agents
MILD bone marrow toxicity !
cyclophosphamide and ifosfamide will lead to ______ cystitis and why?
hemorrhagic cystitis;
acrolein is toxic to bladder mucosa
acrolein is toxic to ________
bladder mucosa
what drug is used in combo with cyclophosphamide to prevent hemorrhagic cystitis
mesna
how does mesna help prevent hemorrhagic cystitis
this drug accumulates in the urine because it is a charged molecule and does not penetrate cells
it is a reactive thiol with a charged sulfonate group — will react with/inactivate cyclophosphamide metabolites in the urine
alkylating agents are strongeraliphatic or aromatic
aliphatic
(remember use aromatic ones to to “calm” them down”
what drugs are nitrosoureas
carmustine
lomustine
Nitrosoureas:
chemically stable or unstable?
unstable
Nitrosoureas are converted to _____ by a non enzymatic reaction (just chemically unstable)
diazonium ion
the diazonium ion comes from ______
carmustine or
lomustine
diazonium ion is highly (nucleo or electro - phillic) and has a _____ half life
electrophilic! (duh diazonium ions are from alkylating agents and those are electrophillic)
extremely short half life
Nitrosoureas:
are hydro or lipo phillic?
lipo!!!
they will cross blood brain barrier!!!
what alkylating agents are used for glioblastoma
nitrosoureas (they are lipophillic)
what is different about the dosing of nitrosoureas?
since myleosuppression is DELAYED and prolonged — longer interval b/w doses is needed compared to other agents
what drug is an alkyl sulfonate
busulfan
busulfan has what notable toxicity
pulmonary fibrosis “ busulfan drug”
when is busulfan used? (per dykhousen notes)
given with cyclophosphanide before bone marrow transplant to eradicate all hematopoetic cells —
this drug is v toxic
Mitomycin C:
can form _________ adducts
bifunctional (aka crosslinks…)
Mitomycin C:
similarities to _______ compounds
______ containing natural product
_______ is dose limiting
nitrogen mustard;
aziridine
myleosuppression
what drugs are monoalkylating agents
DTIC and TMZ
DTIC: is a monoalkylating agent that needs to be activated by ________
N demethylation by P450 enzyme
both DTIC and TMZ get converted to _______
MTIC
but DTIC - is done by P450 enzyme
TMZ is chemically converted
DTIC or TMZ:
cross blood brain barrier?
TMZ
DTIC or TMZ:
has 100% bioavailabilty
TMZ
DTIC or TMZ:
is poorly absorbed
DTIC
what is the other name for DTIC
Dacarbazine
T or F:
Platinum drugs are monoalkyating drugs`
false as hell
they do cross linking (covalently!)
but they are not alkylating groups because they do not have alkyl groups…
Cisplatin:
has a planar complex with leaving groups of _____ and has ___ geometry
Chloride groups
cis geometry
Cisplatin:
undergoes _______ in aqueous solution
reversible hydrolysis
Cisplatin:
Equilibrium favors _____ in plasma (because of _____)
Equilibrium favors _____ inside the cell (because of _____)
which one rapidly reacts with other nucleophiles (especially thiols)
plasma: Cisplatin because high Cl- concentration
inside cell: aquo form: b/c low Cl- concentration
aquo form reacts fast
Platinum crosslink geometry:
aquo form reacts primarily with _______ and ____ in DNA
guanine N-7
Adenine N-7
Platinum crosslink geometry:
cross links are mainly _____strand
this leads to severe geometrical constraints on DNA and makes a _____ int he cross link strand
intrA
sharp bend
what are the platinum drugs
cisplatin
Carboplatin
oxaliplatin
Cisplatin has dose limiting _____
but minimal ______
nephrotoxicity
bone marrow toxicity
can cisplatin used be at any time in the cell cycle?
yes!!
best in G1 phase over S phase though
Pro of Carboplatin and Oxaliplatin compared to cisplatin
minimal nephrotxicity
Carboplatin and Oxaliplatin
are they converted to aquo form slower or faster than cisplatin
slower
Carboplatin or Oxaliplatin
has dose limiting toxicity of acute sensory nephropathy
oxaliplatin
Carboplatin or Oxaliplatin
has significant bone marrow toxicity
carboplatin
Drug resistance to alkylating agents can happen via what 3 main events
increased expression of DNA repair enzymes
increased intracellular concentration of non protein thiols (like glutathione)
increased expression of GST (glutahtione s transferase)
Drug resistance to alkylating agents:increase expression of DNA repair enzymes:
2 main options of repiar?
excision repair (cut out the alkylated bases and replae)
or alkyl group is removed by guanine o-alkyl transferase
Other DNA damaging agents from alkylating lecture:
Radium 223 dichloride gets absorbed selectively into \_\_\_\_\_ and is used to treat \_\_\_\_\_\_ metastases and Procarbazine biggest pro is that \_\_\_\_\_\_
radium: bone; bone
pro: it is not cross resistant w/ other alkylating agents
Difference b.w nucleobase, nucleoside, and nucleotide
base: just the base
side: has the sugar
tide: sugar and phosphate
Most antimetabolites are enzyme inhibitors and work as
_______ mimics
_______ mimics
substrate
cofactor
which nucleobases are the double ringed ones?
A & G (purines)
Uridine analogs
primarily inhibit ______ synthesis
thymidine
Antimetabolite Lecture:
Folate typically acts a _____ donor
methyl
Antimetabolite Lecture:
what drugs are uridine analogs?
5-FU (5-fluorouracil)
FUdR (fluorodeoxyuridine)
Capecitabine
Antimetabolite Lecture:
5-FU gets translated to _____ by a 2 step transformation
FdUMP
Antimetabolite Lecture:
what enzymes and steps are used in the 5-FU transformation
1st step: thymidine phosphorylase (adding a sugar)
2nd step: thymidine kinase (adding a phosphate)
Antimetabolite Lecture:
Uracil or thymidine has a methyl group?
thymidine!!
folate is needed to make thymidine — folate will donate the methyl group
for uridine analogs:
______ replacement can be given to treat toxicities
thymidine
