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anti-cancer treatments
Block 3 - Dr. Williams
74
Pharmacology
Professional
11/07/2011

Additional Pharmacology Flashcards

 


 

Cards

Term
types of treatment and some applications
Definition

1) surgery - prevention; diagnosis; cure; palliation

 

2) radiation - cure; palliation

 

3) chemotherapy - cure; palliation; adjuvant; neoadjuvant

 

4) biologic therapy - ex: immunotherapy

Term
adjuvant
Definition
ex: treatment first with surgery and then treat with chemotherapy to get the rest of the tumor cells
Term
neoadjuvant
Definition
ex: chemotherapy is first treatment, used to shrink a large tumor; then take it out with surgery
Term
log kill hypothesis
Definition

represents tumors in a rodent model; not solid tumors

 

cytotoxic drugs with first order kinetics

 

dose kills a constant proportion of cell population and not a constant number

 

inverse relationship between tumor cell number and curability

Term
Gompertzian kinetics
Definition

solid tumors - as they get bigger, growth factor decreases - outgrows blood supply

 

each dose may not kill a certain %

Term
Cell cycle specific (CCS) drugs
Definition

an anticancer agent that acts selectively on tumor stem cells when they are traversing the cell cycle and not when they are in the G0 phase

 

ex: vinca alkaloids (M phase specific)

ex 2: Cytarabine (S phase specific)

 

most effective against tumors that are rapidly dividing

Term
Cell cycle-nonspecific (CCNS) drug
Definition

an anticancer agent that acts on tumor stem cells when they are traversing the cell cycle and when they are in resting phase

 

ex: alkylating agents - agents against DNA

Term
alkylating agents
Definition

includes: bis(chloroethyl)amines, nitrosoureas, alkyl sulfonate, ethyleneimine

 

similarities:

1) bis(choloroethyl)amines - form a cyclic ion that reacts with tissue NUCLEOPHILES = = alkylation tissue molecules (Does this on DNA = very important antitumor effect)

 

2) one possible mechanism of resistance involves a) DNA repair; b) decreased tumor uptake; c) increased incativation

 

3) toxicities: myelosuppression, GI, reproductive; carcinogenesis possible

Term
mechlorethamine
Definition

alkylating agent

 

strong vesicant = don't give orally because it will cause blisters on skin = IV use

 

Hodgkin's disease (MOPP)

Term
cyclophosphamide
Definition

alkylating agent

 

prodrug that is converted in liver by P-450

 

effective immunosuppressant

 

toxicities: hemorrhagic cystitis - excretion of active metabolites - risk is reduced with HYDRATION

 

used in hematologic and solid tumors

Term
ifosfamide
Definition

alkylating agent

 

analog of cyclophosphamide

 

hemorrhagic cystitis

 

use mensa (sodium 2-mercaptoethane sulfonate)

 

CNS toxicity

 

use in testicular cancer

Term
chlorambucil
Definition

alkylating agent

 

use in chronic lymphocytic leukemia

Term
melphalan
Definition

alkylating agent

 

use in multiple myeloma

Term
carmustine and lomustine
Definition

nitrosoureas

 

high lipid solubility; crossed BBB well


delayed myelosuppression (4-6 weeks delay)


use: brain tumors

Term
streptozocin
Definition

nitrosourea

 

toxicities: myelosuppression in 20%; renal damage

 

use: pancreatic islet cell carcinoma

Term
busulfan
Definition

alkyl sulfonate

 

use: chronic myelogenous leukemia

Term
temozolomide
Definition

alkylation of DNA

 

use in brain cancer

Term
thiotepa
Definition
ethyleneimine (aziridine)
Term
dacarbazine
Definition

nonclassical alkylating agent

 

(DTIC)

 

triazene

 

use in malignant melanoma; Hodgkin's dz

Term
altretamine
Definition

(hexamethylmelamine)

 

alkylating agent

 

use: ovarian cancer

Term
procarbazine
Definition

nonclassical alkylating agent - methylhdrazine derivative

 

multiple effects: inhibition of DNA, RNA, and protein synthesis

 

toxicities: 1) myelosuppression

2) CNS depression

3) disulfiram-like effect after alcohol

4) some monoamine ozidase inhibition - potential interactions

5) carcinogenic

 

Use: Hodgkin's dz (MOPP)

Term
bendamustine
Definition

nonclassical alkylating agents

 

use: chronic lymphocytic leukemia

Term
cisplatin
Definition

platinum compounds

 

binds to DNA and inhibits DNA synthesis/function (mechanism similar to alkylating agents); also binds to proteins

 

tox.: 1) nephrotoxicity (diminished by HYDRATION and DIURESIS) - use mannitol

2) myelosuppression, highly emetogenic, ototoxicity, peripheral neuropathy, electrolyte disturbances, anaphylactic-like rxns

 

use: testicular carcinoma, ovarian, bladder, lung, head, and neck cancers

Term
carboplatin
Definition

platinum compound

 

analog with less renal and GI toxicity

 

dose-limiting myelosuppression

 

multiple uses: ovarian carcinoma

Term
oxaliplatin
Definition

platinum compound

 

dose-limiting peripheral neuropathy

 

use: colorectal cancer

Term
antimetabolities class
Definition

separated into folic acid analogs and purine & pyrimidine analogs

 

folic acid analogs include: methotrexate and premetrexed

 

purine analogs: 6-mercaptopurine and 6-thioguanine

 

pyramidine analogs: 5-fluorouracil, cytarabine, gemcitabine

Term
methotrexate (pathway?)
Definition
[image]
Term
methotrexate - mechanism of action
Definition

treansported into target cell; inhibits dihydrofolate reductase; therefore, tetrahydrofolate formation is inhibited - this is involved in synthesis of thymidylate, purine nucleotides, and some amino acids - -> therefore you have decreased DNA, RNA, and protein synthesis

 

also converted in cells to polyglutamates (contributes to its activity)

Term
methotrexate - toxicities and mechanisms of resistance
Definition

Resistance: decrease cellular uptake

increase efflux

increase synthesis DHFR, altered DHFR

decrease formation of polyglutamates

 

administration via several routes (oral, IV, and intrathecal)

 

eliminated mainly by renal excretion

 

tox.: myelosuppression, GI, hepatic (with long-term Rx)

 

use: choriocarcinoma, breast, osteosarcoma

other uses: RA, psoriasis

Term
leucovorin
Definition

folic acid analog (folinic acid, 5-formlytetrahydrofolate, Citrovorum factor)

 

antidote for OD of MTX

 

also used as part of high-dose MTX regimens (leucovorin rescue)

Term
Pemetrexed
Definition

transported into cell and converted to polyglutamates


inhibits thymidylate synthase


also targets DHFR and enzymes involved in de novo purine nucleotide biosynthesis


*** folic acid and vitamin B12 supplementation "appear to reduce toxicity associated with pemetrexed while not interfering with clinical efficacy"


adverse effects: myelosuppression, GI, rash


use: mesothelioma, non-small cell lung cancer

Term
purine and pyrimidine analogs
Definition

similarities:

1) most are prodrugs - must be converted to nucleotides (base + sugar + phosphate)

2) most are also converted to inactive products

3) interferes with many biochemical Rx's (cytotoxicity), but interferes with DNA synthesis/function = important

4) MYELOSUPPRESSION

Term
6-mercaptopurine (6-MP)
Definition

purine analog (-SH group instead of -OH)

 

active nucleotides interfere with multiple reactions in purine synthesis; also incorporated into DNA and RNA

 

other metabolic pathways include oxidation to 6-thiouric acid, catalyzed by xanthine oxidase

 

S-methylation, catalyzed by thiopurine-S-methyltransferase (TPMT)

 

TPMT activity varies in different patients due to genetic polymorphism = increased risk of toxicity in patients with low enzyme activity

 

important drug interaction with allopurinol which inhibits xanthine oxidase; reduce dose of 6-MP if taking allopurinol for gout

 

tox : myelosuppression, hepatotoxicity, immunosuppression

 

use: certain patients with leukemia

 

 

Term
6-thioguanine (6-TG)
Definition

converted to active nucleotide(s)

 

1) also undergoes S-methylation by TPMT

2) deaminated to 6-thioxanthine (do not have to lower dose when using allopurinol)

 

use: certain patients with leukemia

Term
Fludarabine phosphate
Definition

nucleotide - dephosphorylated extracellularly; in cell = converted to active nucleotide

 

MECHANISM: inhibition of DNA synthesis/repair; inhibition of ribonucleotide reductase; incorporation into DNA; induction of apoptosis

 

tox. : myelosuppression, immunosuppression

 

use: chronic lymphocytic leukemia

Term
cladribine (2-chlorodeoxyadenosine)
Definition

incorp. into DNA; also decreases DNA synthesis/repair

 

some toxicities - myelosuppression, immunosuppresion

 

use: hairy cell leukemia

Term
5-fluorouracil (5-FU)
Definition

FdUMP (a deoxyribonucleotide) inhibitor of thymidylate synthase -> decrease thymidylate and DNA synthesis

 

5-FU incorp. into DNA and RNA

 

tox.: myelosuppression, GI, neurotoxicity

 

use: colorectal, breast

 

capecitabine converted into 5-FU

Term
capecitabine
Definition

converted into 5-FU

 

tox.: myelosuppression, GI, hand-foot syndrome, (neurotoxicity)

 

use: breast cancer

Term
cytarabine
Definition

cytosine (arabinoside; Ara-C)

 

inhibition of DNA synthesis/repair; incorp. into DNA; inhibition of DNA chain elongation

 

Tox: myelosuppression, GI, neurotoxicity

 

use: acute myelogenous leukemia

Term
Gemcitabine
Definition

inhibition of ribonucleotide reductase, incorp. into DNA, inhibition of DNA syntehsis/repair

 

Tox. : myelosuppression, GI

 

use: pancreatic carcinoma, non-small cell lung cancer

Term
dactinomycin
Definition

ANTIBIOTIC

(actinomycin D)

 

binds to DNA = decrease RNA synthesis

 

given IV

 

Tox.: myelosuppression, GI, alopecia, tissue damage if extravasated

 

Use: Wilms' tumor

Term
doxorubicin and danurubicin
Definition

antibiotics

 

mech.: 1) inhibition of topoisomerase II

2) intercalation into DNA

3) free radical formation = cardiotox :(

4) binding to membranes

 

iv and hepatic metabolism (lower dose if there is hepatic dysfunction)

Term
doxorubicin (toxicities)
Definition

meylosuppression, nausea, stomatitis, alopecia, tissue damage if extravasated (necrosis), cardiotoxicity


Cardiotoxicity -  thought to be related to free radical damage - heart failure related to cumulative dose !! (pg 332)


acute form of toxicity = ECG abnormalities (arrhythmias); pericarditis-myocarditis possible


if you have to continue this drug, give dexrazoxane (an iron chelator) to decrease the toxicity (after cumulative dose of 300 mg/m2)

Term
daunorubicin (toxicities)
Definition
myelosuppression and cardiac toxicity (risk related to cumulative dose), nausea, tissue damage if extravasated, alopecia
Term
bleomycin
Definition

antibiotic


mixture of glycopeptides; binds to DNA and causes strand breaks (formation of iron complex and generation of free radicals)


eliminated mainly in urine


tox.: ***1)PULMONARY : cough and dyspnea --> pulm. infiltrate --> pulmonary fibrosis (increased risk with old age and increasing cumulative dose)

2) skin rxns: tenderness, erythema

3) allergic reactions (anaphylaxis)

4) relatively bone marrow sparing


use: testicular carcinoma, lymphomas

Term
mitomycin (mitomycin C)
Definition

antibiotic

 

reduced to an alkylating agent

 

tox.: nausea, myelosuppression, hemolytic uremic syndrome, pulmonary toxicity


use: squamous cell cancer of anus (adenocarcinoma of stomach/pancreas?)

Term
vincristine
Definition

plant derived drug: vinca alkaloid

 

mitotic inhibitor: binds to tubulin and inhibits polymerization to microtubules -->mitotic arrest

 

tox.: 1) mild BM suppression

2) neurotoxicity = peripheral neuropathy, consitipation

3)irritation with extravasation

4) alopecia

Term
vinblastine
Definition

plant derivative: vinca alkaloid

 

binds to tubulin and inhibits formation of mitotic spindle

 

tox.: 1) severe myelosuppression ("vinblastine blasts bone marrow")

2) nausea; vomitting

3) alopecia

Term
vincristine and vinblastine toxicities (comparison)
Definition
[image]
Term
paclitaxel
Definition

plant derivative: taxane

 

binds microtubules and promotes polymeration --> inhibition of mitosis (remember to contrast with vinca alkaloids)

 

tox. : 1) hypersensitivity reaction, myelosuppression, peripheral neuropathy, arrhythmias

 

use: ovarian and breast cancer

 

(new form of the drug for breast cancer tx = bound to albumin and it has decreased toxiticy

Term
docetaxel
Definition

plant derivative: taxane

 

binds microtubules and promotes polymeration --> inhibition of mitosis (remember to contrast with vinca alkaloids)

 

tox. : hypersensitivity reaction, myelosuppression, peripheral neuropathy, arrhythmias

 

use: breast cancer

Term
etoposide
Definition

plant derivative: podophyllotoxin - - epipodophyllotoxin

 

inhibits topoisomerase II - -> DNA strand breaks

 

tox. : myelosuppression, alopecia, N&V, allergic reactions; leukemias have been reported

 

use: testicular carcinoma; small cell lung cancer

Term
teniposide
Definition

Used only outside the US, but now there are package inserts for it (so now used in US)

 

plant derivative: podophyllotoxin - - epipodophyllotoxin

 

inhibits topoisomerase II - -> DNA strand breaks

 

tox. : myelosuppression, alopecia, N&V, allergic reactions; leukemias have been reported

Term
topotecan
Definition

plant derivative: camptothecins

 

inhibits topoisomerase I causing DNA damage

 

tox: myelosuppression (neutropenia), GI

 

use: ovarian carcinoma, small cell lung cancer

Term
irinotecan
Definition

plant derivative: camptothecins

 

inhibits topoisomerase I causing DNA damage

 

rxn involving glucuronyl transferase, but enzyme often has polymorphisims, requiring one to reduce doses of this drug and do genetic testing before administration

 

tox: myelosuppression, diarrhea, N&V

 

use: colorectal cancer

Term
asparaginase
Definition

bacterial enzyme (use E Coli)


catalyzes hydrolysis of circulating L-asparagine to aspartic acid and NH3 --> depletes asparagine in certain leukemic cells --> decrease protein synthesis


tox. allergic reactions, hepatotoxicity, clotting factor changes --> bleeding or clotting, pancreatitis, hyperglycemia


use: acute lymphocytic leukemia

Term
Bcr-Abl tyrosine kinase
Definition

this is a fusion protein; part of signaling pathway that leads to cell proliferation

 

unlike other receptors, does NOT need ligand to stimulate it; consitutively active in CML cells

Term
imatinib
Definition

(Gleevec) - inhibits Bcr-Abl tyrosine kinase --> inhibits proliferation and induction of apoptosis

 

also inhibits some other receptor tyrosine kinases

 

hepatic CYP metabolism

 

tox.: N&V; diarrhea; fluid retention/edema; muscle cramps; anemia; neutropenia; thrombocytopenia; hepatotoxicity; drug interactions

 

use: chronic myeloid leukemia; gastrointestinal stromal tumor

Term
dasaitinib
Definition

inhibit Bcr-Abl and some other kinases

 

may be used if become resistant to imatinib

 

use: CML

Term
nilotinib
Definition

inhibit Bcr-Abl and some other kinases

 

may be used if become resistant to imatinib

 

use: CML

Term
cetuximab
Definition

growth factor receptor inhibitors

 

monoclonal antibody that binds to extracellular domain of epidermal growth factor receptor (EGFR) --> inhibit downstream receptor signaling (preventing cell proliferation and angiogenesis)

 

EGFR is over expressed in some tumors


some genetic consideration: K-RAS --> mutation renders this drug ineffective

 

tox: infusion reactions, rash (acne type), hypomagnesemia, interstitial lung disease

 

use: head and neck cancer, colorectal cancer

Term
panitumumab
Definition

growth factor receptor inhibitors

 

monoclonal antibody that binds to extracellular domain of epidermal growth factor receptor (EGFR) --> inhibit downstream receptor signaling (preventing cell proliferation and angiogenesis)

 

EGFR is over expressed in some tumors


some genetic consideration: K-RAS --> mutation renders this drug ineffective

 

tox: infusion reactions, rash (acne type), hypomagnesemia, interstitial lung disease

 

use: colorectal cancer

Term
gefitinib
Definition

(enters cytoplasm) inhibits the tyrosine kinase domain of EGFR --> inhibits receptor signaling

 

oral; hepatic metabolism

 

tox: diarrhea, rash, interstitial lung dz; potential drug interactions

 

use: non-small cell lung cancer

Term
erlotinib
Definition

(enters cytoplasm) inhibits the tyrosine kinase domain of EGFR --> inhibits receptor signaling

 

oral; hepatic metabolism

 

tox: diarrhea, rash, interstitial lung dz; potential drug interactions

 

use: non-small cell lung cancer; pancreatic cancer

Term
bevicizumab
Definition

monoclonal antibody binds VEGF --> prevents VEGF action on its receptors

 

tox: hypertension, infusion reaction, GI perforation, wound healing complications, bleeding, arterial thromboembolic events, proteinuria

 

use: colorectal cancer, non-small cell lung cancer

Term
sorafenib
Definition

inhibit multiple tyrosine kinases, including some VEGF receptors, some PDGF, and others

 

oral, metabolized by CYP

 

adverse: hypertension, fatigue, bleeding, hand-foot syndrome (unique to this drug)

 

use: renal cell cancer, hepatocellular cancer

Term
sunitinib
Definition

inhibit multiple tyrosine kinases, including some VEGF receptors, some PDGF, and others

 

oral, metabolized by CYP

 

adverse: hypertension, fatigue, bleeding;  cardiac dysfunction, possibly with heart failure (decrease ejection fraction) (unique to this drug)

 

use: renal cell cancer, gastrointestinal stromal tumor

Term
tretinoin
Definition

differentiating agent: retinoic acid derivative:

all trans-retinoic acid


induction of differentiation to cells that cannot proliferate


tox: vitamin A toxicity, retinoic acid syndrome (fever, increase white count, weight gain, pulmonary problems)


use: acute promyelocytic leukemia

Term
arsenic trioxide
Definition

differentiating agent

 

induction of differentiation

 

tox: QT prolongation, arrhythmias, syndrome similar to retinoic acid syndrome

 

use: actue promyelocytic leukemia

Term
bortezomib
Definition

proteasome inhibitor: ubiquinated proteins enter proteasome and get broken down - so this drug saves some important proteins (but we don't really know which ones)

 

tox: peripheral neuropathy, GI, hypotension, thrombocytopenia, neutropenia

 

use: multiple myeloma

Term
hydroxyurea
Definition

substitued urea

 

inhibits ribonucleotide reductase (which takes ribonucleotides to deoxy ribonucleotides = DNA synthesis) --> decreased DNA synthesis

 

tox: myelosuppression, GI, dermatologic reactions (Rash, ulcerations)

 

use: chronic myelogenous leukemia

Term
rituximab
Definition

CD 20 antigen

 

use: B cell non-Hodgkin's lymphoma

Term
transtuzumab
Definition

HER-2/ neu

 

BREAST CANCER

Term
resistance involving p-glycoprotein
Definition

tumor cells increase p-glycoprotein

 

= increased efflux of drug from tumor cells

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