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86 Cards in this Set

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strategies for designing anti-neoplastic regimens
start when tumor is small
use the maximum tolerated dose
administer drug as frequently as possible
repeat treatments in multiple cycles
use combination therapy:
drugs with different mechanisms and toxicities
drugs susceptible to different mechanisms of resistance
log-kill hypothesis
cytotoxic drugs act by first-order kinetics killing a constant proportion of a cell population
cell cycle
G1: synthesis of DNA precursors
S: DNA replication (synthesis)
G2: synthesis of mitotic components
M: mitosis
G0: resting phase
alkylating agents
form strong electrophile intermediates that covalently alkylate nucleophilic groups
What does alkylation of DNA and proteins do?
causes cell cycle arrest (non-specific phase), apoptosis
What are the toxicities of Alkylating agents
bone marrow, GI mucosa, CNS

myelosuprression
nucleophile
forms a chemical bond with an electrophile by donating both electrons
nitrogen mustards: drug class and names
alkylating agents

mechlorethamine
cyclophosphamide
nitrogen mustards mechanism and drug names
mechlorethamine
cyclophosphamide

bifunctional alkylating agents
-cross-link DNA strands
-cross-link DNA and protein
-more cytotoxic than monofunctional agents

non-specific cell cycle target
mechlorethamine: drug class and use
alkylating agent
nitrogen mustard

Hodgkin's disease
most reactive agent, generally replaced with more stable agents
cyclophosphamide
alkylating agent
nitrogen mustard

most widely used alkylating agent
selective for malignant tissues: normal tissue is protected by capacity to enzymatically degrade activated intermediates

give with 2-mercaptoethanesulfonate (mesna/MESNEX)

SE: metabolizes to acrolein (nephrotoxic, make sure adequate fluid intake), immunosuprresion, alopecia
nitrosoureas drugs:
carmustine (BCNU)
streptozocin (streptozotocin)
Carmustine
nitrosurea alkylating agent

highly lipophilic

tx: malignant gliomas
Hodgkins, non-hodgkins lymphoma, multiple myeloma

SE: myelosuppression
streptozocin
nitrosurea alkylating agent

targets pancreatic islet cell

SE:
hypoglycemia- insulin shock
renal and hepatic toxicity
triazenes
dacarbazine

methylating agent
methylhydrazines: drug
procarbazine
procarbazine: mechanism
methylhydrazine

uses cytochrome P450
methylates DNA: inhibits DNA, RNA, protein synthesis

monofunctional: produces chromosomal damage
platinum complexes
cis-platinum (cisplatin)
carboplatin
oxaliplatin
cisplatin/cis-platinum

carboplatin

mechanism and use
mechanism: reacts with nucleophilic sites on DNA (esp. N7 of guanine) and proteins

use: CMV

carboplatin: much less toxic, major SE is myelosuppression
oxaliplatin
alkylating platinum complex

MOST WIDELY USED FIRST LINE TREATMENT FOR ADVANCED COLORECTAL CANCER- COMBINED WITH 5FU AND LEUCOVORIN (FOLFOX)

SE: peripheral neuropathy: dose limiting, reversible

does not exhibit cross resistance with other platinum agents (cisplatin, carboplatin)
antimetabolites
folic acid analogs
folate antagonist rescue agent
pyrimidine analog
purine analogs and related inhibitors
purine analogs and related inhibitors
6 thiopurines
6 mercaptopurine
6 thioguanine
fludarabine-5-phosphate
purine analogs and related inhibitors drug names and mechanism
6-thioguanine (purine antagonist)
6-mercaptopurine (purine antagonist)
fludarabine-5-phosphate (adenosine analog, inhibit DNA and RNA synthesis-> apoptosis)

mechanism of mercaptopurine, thioguanine:
inhibit purine synthesis
1 in 300 have a mutation that blocks the metabolism of 6MP, drug accumulates and can become fatal
folic acid analog drug name
methotrexate
methotrexate:
class
mechanism
use:
SE
folic acid analog
mechanism: inhibits dihydrofolate reductase, deplete tetrahydrofolate cofactors required for synthesis of purines, thymidylate

use: curative for osteogenic sarcomas, choriocarcinomas (placental epithelium), breast cancer in post menopausal women with no tumor estrogen receptor expression

SE:
renal damage- hydrate
toxicity prevented or reversed with leucovorin
folate antagonist rescue agent
leucovorin
pyrimidine analogs
5- fluorouracil 5-FU
cytarabine (AraC)
gemcitabine
5-fluorouracil
drug class
mechanism
treat
pyrimidine analog

mechanism: uracil analog, decreases DNA synthesis

most commonly used for COLORECTAL cancer
cytoarabine:
drug class
mechanism
drug class: pyrimidine analog

mechanism: cytosine deoxyriboside analog
gemcitabine

drug class

mechanism
pyrimidine analog

cytosine deoxyriboside analog
plant alkaloids
vinca alkaloids
epipodophyllotoxins
camptothecins
taxanes
Vinca alkaloids
plant alkaloids:

vinblastine
vincristine
epipodophyllotoxins
plant alkaloids

etoposide
teniposide
camptothecins
plant alkaloid

topotecan
taxanes
plant alkaloid

paclitaxel
vincristine
vinblastine

mechanism
plant alkaloids
vinca alkaloids
anti-mitotic drugs, M phase specific
bind tubulin
vincristine: main treatment for

side effect
childhood acute lymphoblastic leukemia

peripheral neuropathy
vinblastine main treatment for

SE
curative therapy of metastatic testicular tumors in combination with bleomycin (antitumor antibiotics) and cisplatin (platinum complexes)

bone marrow suppression
etoposide
teniposide

drug class

mechanism
plant alkaloid: epipodophyllotoxins

mechanism: inhibits topoisomerase 2: block DNA replication
topotecan

mechanism
plant alkaloid
camptothecin

bind to and inhibit activity of topoisomerase 1: single strand breaks

bronzing of skin
paclitaxel
plant alkaloid

Taxane

mechanism: promotes microtubule polymerization and stabilization
antimitotic- M phase specific

metastatic ovarian and breast cancer
Anti tumor antibiotics
actinomycin D
anthracyclines
adriamycin (doxorubicin)
bleomycin
mitomycin
Antitumor antibiotics
-mycin
actinomycin D
anthracyclines
Adriamycin (doxorubicin)
bleomycin
mitomycin
Actinomycin D (dactinomycin)
antitumor antibiotic

binds DNA by intercalating between GC base pairs and blocks RNA synthesis and ultimately DNA synthesis

one of the most potent antitumor agents known

curative in wilm's kidney tumor and rhabdomyoasarcoma
adriamycin (doxorubicin)
intercalate with DNA and binds to the backbone of DNA

blocks synthesis of DNA and RNA

cardiotoxicity
bleomycin
G2 phase specific: cells accumulate in G2

Binds DNA
generates free radicals
produces strand breaks
inhibits ATP dependent DNA ligase, preventing DNA repair
mitomycin
anti-tumor ABX

cross-links DNA, inhibits DNA synthesis

used only if alternative are not effective
adrenocorticosteroids
prednisone

hormonal agent
long acting gonadotrophin releasing hormone agonist
leuprolide acetate
progestin
medroxyprogesterone
anti-estrogen
fulvestrant
selective estrogen receptor modulator
tamoxifen

raloxifene
aromatase inhibitor
exemestane

anastrozole
anti-androgens
flutamide
classes of hormonal agents
adrenocorticosteroids
long-acting gonadotropin releasing hormone agonists
estrogens
progestins
anti-estrogens
anti-androgens
selective estrogen receptor modulators
aromatase inhbitors
prednisone
adrenocorticosteroid

metabolized to prednisolone which binds to glucocorticoid receptor

regulates the transcription of specific proteins involved in metabolism and inflammatory response

SE: cushing syndrome, immunosuppression
leuprolide acetate
long acting GnRH agonist

prolonged exposure to long acting agonists downregulates GnRH receptor number-> suppresses gonadotropin release

MOST COMMON TX FOR METASTATIC GONADAL STEROID-DEPENDANT PROSTATE CANCER
Fulvestrant
anti-estrogen

high affinity estrogen receptor antagonist

TX: hormone responsive metastatic breast cancer in post-menopausal women
Flutamide
anti-androgen

androgen receptor antagonist- prostate cancer
Tamoxifen
selective estrogen receptor modulator: acts as an estrogen receptor agonist in some tissues and an ER antagonist in other tissues

anti-estrogen on breast
estrogen on endometrium-> increased risk of cancer
raloxifene
second generation selective estrogen receptor modulator

acts anti-estrogen on breast

postmenopausal osteoporosis prevention
reduction of risk of breast cancer in high risk post-menopausal women
neutral effect on endometrium
exemestane
anastrozole
aromatase inhibitors

inhibit estrogen synthesis
enzymes
L-asparaginase
substituted ureas
hydroxyurea
differentiating agents
tretinoin
protein tyrosine kinase inhibitors
imatinib mesylate
gefitinib
proteasome inhbitors
bortezomib
monoclonal antibodies
trastuzamab
rituximab
cetuximab
bevacizumab
biological response modifiers
interferon-alfa
interleukin 2
granulocyte colony stimulating factor
granulocyte/macrophage colony stimulating factor
L-asparaginase
enzyme
catalyzed the hydrolysis of circulating asparagine

Tx: acute lymphocytic leukemia

SE: hypersensitivity
inhibition of protein synthesis
hydroxyurea
substituted urea

inhibits ribonucleotide reductase-> decreased deoxynucleoside

decreases DNA synthesis

S phase specific

high oral bioavailability
tretinoin (all-trans retinoid acid)
regulates the transcription of genes that have retinoic acid inhibitors
induced differentiation- cells do not proliferate

TX: acute promyelocytic leukemia

SE: retionic acid syndrome, vit. A toxicity
imatinib mesylate
protein tyrosine kinase inhibitor

remission in patients with chronic myelogenous leukemia
gefitinib
inhibits EGFR tyrosine kinase, blocks signal transduction pathways required for cell proliferation and survival
bortezomib
proteosome inhibitor

reversible inhibitor of the 26S proteasome-> silences NK-kB (transcription factor that promotes cell survival)
trastuzumab
monoclonal antibody

use in metastatic breast cancers where the HER2/neu gene is amplified

Blocks HER2/neu gene is amplifeid
rituximab
monoclonal antibody
cetuximab
monoclonal antibody
bevacizumab
monoclonal antibody
interferon alfa
immunomodulatory
anti-proliferative
antiviral activity
interleukin-2
induces a T-Cell response that is cytolytic for tumor cells
granulocyte colony stimulating factor
stimulate neutrophils
granulocyte/macrophage colony-stimulating factor
increases production of neutrophils and monocytes and stimulates migration and phagocytic and cytotoxic activities
target synthesis phase of cell cycle
epipodhyllotoxins (inhibit Topo2)
antimetabolites: folic acid analogs/folate antag. rescue agent/pyrimidine analogs
purine analogs/related inhibitors (purine)
targets G2 phase
bleomycin

epipodophyllotoxins
targets mitotic phase
vinca alkaloids

taxol