anti-cancer Flashcards
primary chemotherapy
primary tx in pt with adv CA without alternative tx possible
neoadjuvant chemo
given before sx. goal is to dec size of primary tumor so surgical resection can be made easier
adjuvant chemo
after local tx modalities (surgery) has been perforemd.
destroyed microscopic cells that may be present after local tx modalities.
dec incidence of both local and systemic recurrence and improve overall survival of pt
site directed chemo
direct instillation - into sanctuary sites
regional perfusion - of tumor
log kill hypothesis
action of cytotoxic drugs follows FIRST ORDER KINETICS
given dose kills a constant fraction of tumor cell population (rather than constant number)
repeat doses are required to eradicate
common AE
nausea/vomiting
stomatitis
alopecia
myelosupression (tx with filgrastim)
drugs with STRONG myelosuppression
cytarabine alkylating agents doxorubicin danunorubicin vinblastine
drugs with MODERATE myelosuppression
carboplatin
MTX
5-FU
drugs with MILD myelosuppression
bleomycin
vincristine
asparaginase
which drug causes cardiotoxicity
doxorubicin
which drug(s) causes hemorrhagic cystitis
cyclophosphamide
ifosphamide
which drug causes pulmonary fibrosis
bleomycin
which drug is most likely cause cause tx-induced neoplasms
aklylating agents
which drug rescues BM from MTX
leucovorin
which drug reduces hemorrhagic cystitis caused by cyclophosmaide and ifosfamide
mesna
which drug reduces anthracycline-induced cardiotoxicity
dexrazoxane
which drug reverses neutropenia caused by many anti-CA agents
filgrastim
which drugs is a cytoprotective agent that reduces renal toxicity cauesd by cisplatin
amifostine
primary resistance
no response to drug on first exposure
acquired resistance - single drug resistance
due to inc expression of 1 or more genes
acquired resistance - MDR
emerges to several drugs after exposure to a single agent
cell cycle specific vs cell cycle nonspecific drugs
specific: exert action only on cells traversing cell cycle
nonspecific: exert action whether they are cycling or resting in G0
what is more effective in hematological malignancies: cell cycle specific or nonspecific
cell cycle specific - assoc with high growth fraction
what is more useful in solid tumors with low growth fraction: cell cycle specific or nonspecific
nonspecific
cell cycle specific drugs
antimetabolites microtubule inhibitors epipodophyllotoxins camptothecins bleomycin
cell cycle nonspecific drugs
alkylating agents
platinum coordination complexes
antitumor abx
anti-metabolites drugs
active against S phase of cell cycle - mainly affect DNA synthesis
folate analogs
purine analogs
pyrimidine analogs
folate analog
MTX
MTX
inhibits DHFR enzyme
- inhibits purine nucleotides and deoxythymidylate nucleotide synthesis
DNA and RNA synthesis inhibited
leucovorin
activated folate - bypasses action of MTX - “provides normal tissues with reduced folate”
cells are immune to toxic effects of MTX with leucovorin. “antidote to drugs that decrease levels of folic acid to rescue BM”
if excessive amts are given, can enter tumor cells and counteract actions of MTX
MTX AE
stomatitis mucositis myelosuppression alopecia n/v
Renal damage - uncommon (complic of high dose MTX)
hepatic fibrosis and cirrhosis
pneumonitis
neurologic toxicities
Purine analogs
6-mercaptopurine
6-thioguanine
6-mercaptopurine
pro-drug
hypoxanthine analog
converted to thio-IMP via salvage pathway with HGPRT
thio-IMP inhibits first step of de novo purine synthesis (amidotransferase) - and formation of AMP and GMP (from IMP)
thio-IMP –> TGTP (can incorp self into RNA) and TdGTP (can incorporate self into DNA) = terminate synthesis
6-mercaptopurine use
ALL (childhood)
6-mercaptopurine AE
n/v/d
hepatotoxicity
BM suppresion
6-mercaptopurine metabolism
Xanthine oxidase (check if taking allopurinol)
Thiopurine methyltransferase (check for genetic deficiency)
if either are inhibited, must dec 6-MP dose to prevent AE with accumulation of drug
pt on MTX, now reports gouty like arthritis, what drug should be avoided?
allopurinol
hyperuricemia is common in anti-CA tx because of buildup of purine/pyrimidine building blocks
6-thioguanine
guanine analog
converted to TGMP by HGPRT
TGMP is able to:
- inhibit purine synthesis (PRPP amidotransferase inhibited)
- inhibits phosphorylation of GMP –> GDP (guanylate kinase enzyme inhibited)
- can convert to TGTP and dTGTP = both incorporate into RNA and DNA respectively
6-thioguanine use
nonlymphocytic leukemias
compare to 6-MP
6-thioguanine AE
n/v/d
hepatotoxicity
BM suppression
6-thioguanine metabolism
1) thiopurine methyltransferase: check for genetic deficiency
2) deamination
NO allopurinol interaction - no need to reduce 6-TG dose
DO need to reduce 6-TG dose if genetic deficiency is present
pyrimidine analogs
5-FU
capecitabine
deoxycytidine analogs: cytarabine, gemcitabine
5-fluorouracil MOA
converted to deoxyribonucleotide 5-FdUMP
5-FdUMP inhibits thymidylate synthase = DNA synthesis is inhibited
“thymineless death”
5-FU also is converted to 5’FUTP - incorporated into RNA = interfere with RNA fxn
what enzyme metabolizes 5-FU
dihydropyrimidine dehydrogenase
deficiency can result in severe toxicity = myelosuppression, neurotoxicity, life threatening diarrhea
5’fluorouracil administrated with what
leucovorin
colorectal CA tx
5-FU + leucovorin
also for solid tumors
topical for keratoses and superficial basal cell CA
5-FU AE
n/v alopecia, BM depression
“HAND FOOT SYNDROME” - erythematous desquamation of palms and soles
[eccrine sweat glands excrete 5-FU. highest concentration of eccrine sweat glands are in palms and soles - lots of 5-FU excreted here]
capecitabine
ORAL prodrug of 5-FU
activated by 3 step enzymatic conversion to 5-FU (1st two steps in liver, then in tumor cells with thymidine phosphorylase)
expression of enzyme is higher in tumor cells than normal cells
first line tx for metastatic colorectal cancer
capecitabine
also used for metastatic breast cancer
(b/c of specific activation in cancer cells)
capecitabine AE
diarrhea
hand food syndrome
myelosuppresion, n/v = incidence is a lot less than IV 5-FU
cytarabine
deoxycytidine analog
gemcitabine
deoxycytidine analog
cytarabine MOA
converted to cytarabine triphosphosphate
- competitively inhibits DNA Pol-alpha (blocks DNA synthesis)
- competively inhibtis DNA Pol-beta (blocks DNA repair)
- incorporated into DNA, RNA = interference with chain elongation and ligation of fragments
cytarabine use
hematological malignancies
NOT solid tumors
cytarabine AE
myelosuppression
mucositis
n/v
neurotoxicity
Gemcitabine
prodrug - phosphorylated to nucleoside di and tri phosphate = inhibits DNA synthesis (ribonucleotide reductase)
incorporation of gemcitabine triphosph into DNA = chain termination
Gemcitabine use
solid tumors
hematological malignancies
gemcitabine AE
flu like
n/v
myelosuppresion
renal microangiopathy syndromes
vinca alkaloids
(microtubule inhibitors)
vinblastine
vincristine
metabolized by liver P450
dose modific required in liver dysfunction
MOA: binds b-tubulin = disrupts assembly
- mitotic arrest in metaphase
AE - neurotoxicity, may disrupt functions that require microtubules
taxanes
(microtubule inhibitors)
paclitaxel
docetaxel
vinblastine use
hodgkins
nonhodgkins
breast CA
germ cell CA
vinblastine AE
BM suppression*****
alopecia
peripheral neuropathy
n/v
potent vesicant (causes nearby tissue damage)
vincristine
hematological tumors
pediatric tumors
vincristine AE
neurotoxicity - peripheral neuropathy** worry about this
SIADH
**mild myelosuppression
taxanes
paclitaxel
docetaxel
PK: liver metabolism, dose reduction in liver dysf pt
taxanes MOA
bind beta tubulin at dif site than vinca binding side
PROMOTE microtubule polymerization, inhibits epolym and promotes microtubule polymerization
paclitaxel use
solid tumors
paclitaxel AE
HS, myelosuppression, peripheral neuroatphy
Abraxane can act as albumin form= no HS,no premedication, less incidence of myelosuppresion
Docetaxel
2nd line for adv breast CA and NSLC
Docetaxel AE
myelosuppresion
fluid retention - t with dexamethasone
- neurotoxicity
- dec chance to cause nephrotoxicity as paclitaxel does
epipodophyllotoxins
etoposide
teniposide
MOA: inhibits topoisomeriase II - DNA damage. blocks cells in late S-G2 phase
etoposide indication
testicular CA
SCLC
teniposide indication
refractory ALL
camptothecin
topotecan
irinotecan
inhibits topoisomerase I = DNA damage
topotecan
2nd line for advanced ovarian CA following inital tx with platinum based chemo
2nd line for SCLC
topotecan PK
renal excretion
adjust with pt with renal impairment
irinotecan PK
prodrug converted in liver to active metabolite
eliminated in bile and feces
dose reduction in liver dysfunction
irinotecan application
metastatic colorectal CA + 5-FU + leucovorin
antitumor Abx
bleomycin
anthracyclines
bleomycin MOA
G2 phase specific! 1 binding site for DNA, another for iron
binds DNA = single and double strand breaks
once iron reduces - Fe3+ = forms free radicals
bleomycin PK
excretion is renal excretion
dose reduction in renal failure pt
bleomycin application
hodgkin/non hodgkins
germ cell tumor, head, neck, squamous skin, cervix and vulva
bleomycin AE
dose limiting = acute pulm toxicity: pneumonitis, fibrosis
***skin hyperpigmentation
**minimal BM suppression (toxic to lung and skin)
[bleomycin hydrolase is found everywhere besides lung and skin]
anthracyclines MOA
binds cellular membranes to alter fluidity and ions transport
inhibits topo II
binding to DNA through intercalation - blockade of DNA/RNA synthesis = DNA breakage
free radicals form via iron dependent enzyme
anthracycline AE
mainly myelosuppression
**cardiotoxicity
dose dependent cardiomyopathy
d/t free radicals
dexrazoxane can reduce cardiotoxicity = iron chelating agent
erythema and desquamation of skin at sites of prior radiation
what drug can reduce cardiotoxicity of anthracyclines
dexrazoxane
anthracyclines
doxorubicin
daunorubicin
doxorubicin
childhood CA, hematological malignancies, solid cancers
daunorubicin
AML
limited use against solid tumors
akylating agents
@N7 position of guanine within DNA
lead to cell death
can occur on a single strand or both strands of DNA through cross linking/”intrastrand linking”
alkylating agents (5)
nitrogen mustards nitrosoureas alkyl sulfonates methylhydrazines triazines
alkylating agents AE
carcinogenic in nature - inc risk of AML
nitrogen mustards
cyclophosphamide
ifosfamide
mechlorethamine
melphalan
cyclophoshpamide AE
***hemorrhagic cystitis - prevent with adequate hydration and admin of mesna
aldophsophamide - excreted as acrolein = causing hemorrhagic cystitis
mesna binds acrolein
sterility
cyclophosphamide use
solid ca and hemotlogical cancers
ifosfamide
prodrug
IV
activated in liver with 3A4
more toxic than cyclophosphamide - b/c can be metabolized to lots metabolites including CHLOROACETALDEHYDE = nephro and neurotoxicity
ifosfamide AE
hemorrhagic cystitis (prevented with mesna) same reasons
platelet suppression
neurotoxicity
urinary tract toxicity
mechlorethamine
powerful vesicant
replaced by cyclophasmide and other alkylating agnets
severe n/v
melphalan
useful for **multiple myeloma
breast CA
ovarian CA
melphalan AE
oral ulceration
hepatotoxicity
pulmonary fibrosis
nitrosoureas
carmustine IV
lomustine oral
lipid soluble - cross BBB - tx brain tumors and lymphomas
nitrosoureas AE
pulmonary fibrosis
myelosuppression
renal failure
alkyl sulfonate
busulfan
busulfan use
CML
busulfan AE
pulmonary fibrosis
methylhydrazines
procarbazine
procarbazine use
hodgkin/non hodgkins lymphoma
brain tumors
procarbazine AE
CNS depression
leukopenia – potent immunosuppressive
*disulfiram like rxn
one metabolite = weak MAOI - AE when given with other MAOI and tyramine containing foods –> HTN CRISIS
high carcinogenic potential is higher
which drug has a metabolite that is a weak MAOI
procarbazine
triazines
dacarbazine
dicarbazine use
malignant melanoma
hodgkins
soft tissue sarcoma
neuroblastoma
dacarbazine AE
potent vesicant - avoid extravasation
n/v
platinum coordination complexes
PK: kidney excretion (requires dose modification)
MOA: formation of intrastrand and interstrand cross links = inhibition of DNA synthesis and function
N7 position of guanine
platinum analogs
cisplatin
carboplatin
cisplatin use
testicular tumor**
ovarian and bladder cancer
cisplastin + vinblastine + bleomycin = advancement of testicular cancers***
what triple combo therapy is used with testicular cancer**
vinblastine + bleomycin + cisplastin
cisplastin AE
peripheral sensory neuropathy (via apoptosis of DRG)
ototoxicity
nephrotoxicity
electrolyte disturbances: low Mg, Ca, K, and PO4
anaphylactic rxns
cisplastin nephrotoxicity prevention
prevented by hydration and diuresis (loops)
OR
amifostine: thiophosphate cytoprotective agent - reduce renal toxicity
carboplatin
ovarian
nonsmall cell
SCLC
breast, head/neck/bladder CA
carboplatin
less AE than cisplastin
dose limiting toxicity is myelosuppression
hormonal agents
glucocorticoids
estrogen inhibitors
androgen inhibitors
prednisone
induces lymphocyte apoptosis
lymphocyte derived neoplasms: lymphomas, leukemias, multiple myeloma
AND autoimmune hemolytic anemia, thrombocytopenia assoc with CLL
estrogen inhibitors
selective estrogen receptor modulators
selective estrogen receptor downregulators
aromatase inhibitors
SERMs
tamoxifen
raloxifene
tamoxifen
SERM
ANTAGONIST @ breast CA
AGONST @ nonbreast tissue
used for receptor + breast CA
***risk of endometrial hyperplasia
raloxifene
antiestrogen in uterus and breast
promotes estrogenic effects in bone to inhibit resporption
Tx and prevention of post menopausal osteoporosis
prophylaxis against breast CA in high risk post menop women
NO RISK OF ENDOMETRIAL HYPERPLASIA
NOT USED IN BREAST CA TX
which drug can cause endometrial hyperplasia: raloxifene or tamoxifen
tamoxifen
SERD
fulvestrant
fulvestrant
pure estrogen antagonist - NO AGONIST ACTIVITY
inc ER degradation
useful in tamoxifen resistant breast CA
aromatase inhibitors
anastrozole
letrozol
exemstane
used in ER + breast CA (adjuvant)
anastrozole and letrozole: NOT steroid and is a competitive inhibitor
androgren inhibitors
androgen receptor blockers: flutamide
gonadotropin releasing hormone analgos: goserelin, leuprolide
flutamide
nonsteroid
competitive antagonist
tx: prostatic CA
causes gynecomastia
reversible hepatic toxicity
GNRH analogs
pulsatile administration stimulates FSH and LH from AP – stimulating gonadal hormone release
prostate CA
biphasic response:
initial - inc LH, FSH, testosterone; counteract with flutamide
delayed - downregulation of GnRH receptors: dec LH, FSH, testosterone
signal transduction inhibitors
EGFR and HER2/neu inhibitors (ErbB1 and ErbB2)
BCR-ABL & C-KIT inhibitors
RAS/MAP Kinase inhibitors
Proteasome inhibitors
angiogenesis inhibitors
EGFR inhibitors
tyrosine kinase
gefitinib
erlotinib
cetuximab
gefitinib
NSCLC
erlotinib
NSCLC
pancreatic CA
cetuximab
colorectal CA - restricted to KRAS expressing
head/neck CA
lapatinib
EGFR and ErbB2 inibitor
Tx: NSCLC, pancreatic CA
trastuzumab
humanized monoclonal ab against ErbB2 (HER2)
tx: breast ca with inc HER2
cardiotoxic**
imatinib
Bcr-ABL inhibitor = CML tx
inhibits C-kit = tx GIST
tx idiopathic hypereosinophilic syndrome
sorafenib
inhibits RAF serine/threonine kinase
inhibits VEGF-R2, VEGF-R3, PDGFR-beta = stopping angiogenesis - stopping blood supply to tumor
RCC
bortezomib
proteasome inhibitor = induce growth inhibition and apoptosis of tumor cells
use: multiple myeloma, mantle cell lymphoma
sunitinib
inhibits angiogenesis
inhibits VEGFR-1, VEGFR-2, PDGFR
Use: RCC, GIST
asparaginase
breaks down asparagine –> aspartate + NH3
No asparagine synthase in tumor cells - therefore tumor cells deprived of asparagine = apoptose and die
SPECIFIC FOR ALL
inhibition of protein synthesis
normal cells have asparagine synthase - minimum toxicity
asparaginase AE
HS
dec in clotting factors
liver abnl
pancreatitis
seizures, coma
hydroxyurea MOA
kills cells in S phase
inhibits ribonucleotide reductase = depletion of deoxyribonucleoside triphosphate pool = DNA synthesis is inhibited
hydroxyurea use
malignant melanoma
CML
ovarian CA
primary squamous CA of head/neck (not including lip)
adult sickle cel ldisease
hydroxyurea AE
**macrocytosis = inc MCV
rash, hyperpigmentation
IFN-alpha MOA
stimulatse NK to kil ltransformed cells
inc expression of HLA on tumor cells
IFN-alpha use
kaposi sarcoma
hairy cell
RCC
HPV, HBV, HCV
