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4q Pharm Test2 > Antineoplastics > Flashcards

Antineoplastics Flashcards

1
Q

Resistance to antineoplastic drugs may occur b/c of:

A
  • changes in level/affinity of target enzymes
  • decreased drug activation
  • increased DNA repair
  • increased salvage pathways for purines & pyrimidines
  • decreased drug uptake
  • increased drug efflux
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2
Q

How do alkylating agents work? (4)

A
  • alkylate DNA
  • cause miscoding, breaking, crosslinking
  • not cell-cycle phase specific
  • most effect on rapidly proliferating cells (tumor cells, BUT: GI, hair, bone marrow too)
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3
Q

Alkylating agent toxicity

A

-vesicant: tissue damage at injection site
-rapidly proliferating cells: bone marrow, GI, sperm, hair
-Nausea/vomiting: CTZ & local
bone marrow depression
-immunosuppression
-teratogenesis, reproduction

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4
Q

Mechlorethamine (Mustargen):
CLASS
TOXICITIES

A

alkylating agent
phase nonspecific but M & G1 most sensitive
Toxicity: vesicant, hematologic, hyperuricemia, renal damage, nausea/vomiting, sterility, teratogenesis

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5
Q

Cyclophosphamide (Cytoxan): class, characteristics, use, SEs

A

Class: alkylating agent
NOT a vesicant
activated by cytochrome P-450
BROAD SPECTRUM OF USES

SEs: immunosuppressive, alopecia, hematologic toxicity, hemorrhagic cystitis (tx: MESNA), inappropriate ADH secresion

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6
Q

Major therapeutic approaches to cancer tx (3)

A
  1. surgery
  2. radiation
  3. chemotherapy
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7
Q

Goal of cancer chmotherapy

A

achieve SELECTIVE TOXICITY against malignant tumor cells & spare normal host cells

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8
Q

In general, antineoplastic agents do what?

A

suppress rapidly proliferating cells

so routine SE of CA chemo: toxicity to actively dividing normal cells (bone marrow, GI & germinal epithelia, hair follicles, lymphoid organs

SUCCESSFUL TX DEPENDS ON KILLING MALIGNANCY CELLS WITH DOSES THAT ALLOW RECOVERY OF NORMAL CELLS

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9
Q

When are cells most vulnerable to chemotherapy?

A

when in the actively dividing state

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10
Q

2 major classes of antineoplastic agents:
administered when?
effective in what?

A
  1. CELL CYCLE-SPECIFIC AGENTS: given continuously to hit cells as they go through dif. stages.
    - effective in HEMATOLOGIC MALIGNANCIES & other tumors w/large proportion of cells proliferating or in growth fraction
  2. CELL CYCLE-NONSPECIFIC AGENTS: affect cells regardless of where they are in the cell cycle, so long as they are proliferating
    - often administered in ONE LARGE DOSE
    - effective in low-growth solid tumors (e.g. ALKYLATING AGENTS, ANTIBIOTICS, CISPLATIN, NITROSOUREAS)
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11
Q

Susceptibility to chemotherapy:
rapidly growing tumors (4)
slower growing cancers (3)

A

RAPIDLY GROWING TUMORS (leukemias, lymphomas, choriocarcinoma, testicular CA)MORE SUSCEPTIBLE THAN
SLOWER GROWING TUMORS (non-small cell lung, colon, breast)

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12
Q

Growth fraction

A

percentage of viable cells actively dividing & potentially susceptible to chemotherapy

tumors with high growth fractions are easier to treat

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13
Q

Tumor size & response to chemo

A

small tumors have more cells in growth phase & are more sensitive to chemo

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14
Q

4 chemo difficulties a large tumor imposes

A
  1. PENETRATION: therapeutic concentrations of drug may not penetrate large tumors
  2. METASTASES: more likely to have occurred
  3. RESISTNANCE: increase potential for drug resistance
  4. MORE TUMOR CELLS to be killed
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15
Q

mechanisms of drug-resistance in chemotherapy

A
  1. decreased cellular uptake or enhanced efflux from cells (many drugs)
  2. increased or decreased levels of target enzyme (e.g. methotrexate)
  3. altered affinity for target enzyme (methotrexate)
  4. decreased activation/increased inactivation of the drug (6-mercaptupurine)
  5. increased DNA repair (alkylating agents)
  6. increased utilization of salvage pathways for purine & pyrimidine biosynthesis (antimetabolites)
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16
Q

P-glycoprotein

A

high molecular weight glycoprotein

  • present in elevated levels in the plasma membrane of resistant cells
  • functions as a drug efflux pump; can cause resistance to multiple drugs
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17
Q

How is drug resistance minimized in CA chemotherapy?

A

combinations of drugs w/different mechanosms of action against the specific tumor are employed and therapy is initiated when tumor burden is small

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18
Q

most drugs used in chemotherapy:
therapeutic index?
selective toxicity?

A

LOW THERAPEUTIC INDEX

LACK SELECTIVE TOXICITY

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19
Q

Chemotherapy toxicity is common in which 5 areas? what is the result of each?

A

BONE MARROW: decreases platelet & WBC count->HEMORRHAGE &/OR INFECTIONS

GI TRACT: stomatitis, dysphagia, diarrhea due to direct toxic effect on cells. N/V may result from stimulation of the chemoreceptor trigger zone, tx w/anti-emetics

HAIR FOLLICLES: alopecia

RENAL: destruction of tumor cells increases nucleic acids, increasing lvl of uric acid->precipitate in renal tubules->nephrotoxicity

REPRODUCTION & TERATOGENESIS: fetal abnormalities, impaired fertility, spermatogenesis & menstrual cycle

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20
Q

Alkylating agents: basics of how they work

A

-not cell-cycle specific

form highly reactive intermediate compounds, which covalently attach an alkyl group to DNA

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21
Q

Alkylation can result in (3)

A
  1. miscoding of DNA strands, leading to DNA strand breakage
  2. incomplete repair of alkylated segment leading to strand breaks
  3. excessive crosslinking of DNA & loss of strand separation at mitosis
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22
Q

Alkylation toxicity

A 
VESICANT
RAPIDLY DIVIDING CELLS
N/V
BONE MARROW DEPRESSION
REPRODUCTIVE SYSTEMS
TERATOGENESIS
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23
Q

resistance to alkylating agents occurs b/c

A
  • increased ability to REPAIR DNA
  • DECREASED PERMEABILITY to drug
  • increase in GLUTATHIONE
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24
Q

name the 2 Nitrogen Mustards

A

Mechlorethamine (Mustargen)

Cyclophosphamide (Cytoxan)

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25
Q

Mechlorethamine (Mustargen): phases, indication

A

phase nonspecific but M and G1 most sensitive

WIDELY USED IN TREATMENT FOR HODGKIN’S DISEASE

26
Q

Mechlorethamine (Mustargen): toxicity (8)

A
  • strong VESICANT
  • HEMATOLOGIC toxicity
  • HYPERURICEMIA
  • acute RENAL failure
  • alkalinization of the urine & use of allopurinol can prevent nephropathy
  • nausea/vomiting
  • gonadal suppression
  • teratogenic
27
Q

Cyclophosphamide (Cytoxan): describe, routes of admin, spectrum

A

nitrogen mustard

prodrug, MUST BE ACTIVATED by CYP450

***NOT A VESICANT

IV (not a vesicant), ORAL

BROAD SPECTRUM, widely used: breast, lung, ovarian, endometrial & cervical carcinoma, immunosuppression

28
Q

Cyclophosphamide (Cytoxan) toxicity (4)

A

HEMATOLOGIC TOXICITY: less severe than other alkylating agents
marked ALOPECIA

HEMORRHAGIC CYSTITIS (5-10% of pts): build up of acrolein in bladder (prevent w/hydration, frequent voids, admin MESNA [provides syfahydryl groups to hind acrolein & red renal toxicity])

SIADH: pos. water intoxication

anorexia & N/V

29
Q

Cisplatin (Platinol)

A

alkylating agent, cell cycle nonspecific (but esp. S)

TOXICITY:
ACOUSTIC NERVE DAMAGE
renal dysfunction
electrolyte disturbances 2* to renal dysfunction

30
Q

Hemorrhagic cystitis a/w which cancer med?
how many pts get this?
what causes it?
how is it prevented?

A

cyclophosphamide (Cytoxan)

5-10% of pts get this
build up of acrolein in the bladder

preventative measures: hydration, frequent voiding, MESNA: provides sulfahydryl groups to bind acrolein & reduce renal toxicity

31
Q

3 antimetabolites

A

Methotrexate (folic acid analogue)
Mercaptopurine(purine/pyramidine analogue)
5-Flurouracil (purine/pyramidine analogue)

32
Q

Methotrexate (Folex):basic activity

A

FOLIC ACID ANALOGUE antimetabolite

inhibits DIHYDROFOLATE REDUCTASE, blocks conversion of folic acid to tetrahydrofolate (FH4)

resistance develops through decreased uptake by tumor cell & INCREASED CONCENTRATION OF TARGET ENZYME

33
Q

Leucovorin (folinic acid) does what?

A
  1. bypasses metabolic block by methotrexate
    “leucovorin rescue” REDUCES TOXICITY of methotrexate
  2. INCREASES response to 5-FU by providing folate
34
Q

Methotrexate uses (the bolded ones) 3

A

leukemia
choriocarcinoma
immunosuppression: RA psoriasis

35
Q

Methotrexate toxicity (bold ones)

A

HYDRATION is imp (methotrexate will precipitate in renal tubules)
HEPATOTOXICITY
PULMONARY INFILTRATES

36
Q

Purine and pyramidine analoges do what?

A

interfere w/DNA & RNA

by substituting themselves for nat purines & pyramidines, stopping synthesis

37
Q

6-Mercaptupurine (Purinethol): metabolism, interactions, use

A
  • inhibits purine nucleotide synthesis & metabolism
  • must be converted by HGPRT to nucleotide, resistance develops through decreased HGPRT

metabolized by XANTHINE OXIDASE to 6-thiouric acid

breakdown blocked by ALLOPURINOL; REDUCED DOSE if allopurinol is used

used for: LEUKEMIA, IMMUNSUPRESSANT

38
Q

6 mercaptopurine toxicity

A

gradual BONE MARROW DEPRESSION

CHOLESTATIC JAUNDICE

HYPERURICEMIA MAY REQUIRE USE OF ALLOPURINOL (note metabolic interaction above)

39
Q

5 Fluorouracil (5-FU, Adrucil): structure, mechanism

A

pyramidine analogue

binds to THYMIDYLATE SYNTHASE & locks it in inhibited state (form of thymidylate is RATE-LIMITING STEP in DNA synth

CELL CYCLE SPECIFIC-selectively toxic to cells in G1 & S phases

LEUCOVORIN (folinic acid INCREASES responses to 5-FU)

40
Q

5-FU uses

A

TOPICAL CREAM for premalignant keratosis of skin & BCCs

combined w/LEUCOVORIN for COLORECTAL CA

41
Q

5-FU toxicity

A

oral & GI ULCERATION
BONE MARROW DEPRESSION
anorexia & nausea, stomatitis & diarrhea

42
Q 
Doxorubicin hydrochloride (Adrianmycin): 
what is it
what does it do
use is limited by what
when is max effort
resistance is due to what
A

antibiotic that messes with DNA, inhibits RNA & DNA polymerases

generates free radicals-exacerbated by IRON

use limited by CARDIOTOXICITY

max effort during S phase

resistant due to diminished drug uptake by tumor cells or P GLYCOPROTEIN pumping drug out

43
Q

Doxyrubicin hydrochloride toxicity

A

N/V/GI

CARDIOMYOPATHY: may be acute & not very serious, or may develop into CHF unresponsive to digitalis, with mortality >50%, likelihood is decreased by giving IRON CHELATORS

arrhythmias, bone-marrow depression, alopecia

44
Q

Bleomycin sulfate (Blenoxane)

A

antibiotic

  • group of GLYCOPROTEINS
  • causes chain-breaks & FRAGMENTATION of DNA
  • CELL CYCLE SPECIFIC: most toxic in late G2 & early M phase
45
Q

Bleomycin sulfate: uses

A

advanced TESTICULAR CANCER (abt. 75% remission rt when given w/vinblastine & cisplatin)

OVARIAN CANCER

[SCC & lymphomas,not bolded]

46
Q

Bleomycin sulfate: toxicity

A

very LITTLE myelosupression

PULMONARY FIBROSIS-may be fatal, occurs in 7-10%

sxs sim to ANAPHYLAXIS, w/fever, hypotension, cardioresp. collpse

47
Q

Vinblastine sulfate & Vincristine sulfate: class mechanism

A

plant alkaloids

bind to TUBULIN, disrupts mitotic spindle apparatus

CELL CYCLE SPECIFIC FOR M phase

resistance due to increased levels of P-glycoprotein

doesn’t get into brain

metabolized by liver, adjust dose in hepatic or biliary dz

48
Q

Vicristine: use & toxicity

A

Wide use:
Hodgkins-MOPP regimen
LEUKEMIA IN KIDS (w/corticosteroids
NONHODKINS LYMPHOMA

toxicity:
NEUROTOXICITY (limiting factor in use), PERIPHERAL NEUROPATHY
constipation (use laxatives), alopecia, little myelosuprresion

49
Q

Vinblastine: use & toxicity

A

TESTICULAR CA (combo w/bleomycin & cisplastin)

less neurotoxicity than vincristine
BONE MARROW DEPRESSION (limiting factor in use)

50
Q

Paclitaxel (Taxol): mechanism, metabolized by, activity, toxicity

A

binds to TUBULIN & MICROTUBULIN-ARRESTS MITOSIS

disrupts AXONAL TRANSPORT in nerve fibers

resistence dvlps due to INCREASED TRANSPORT out of cells-P glycoprotein

metabolized by liver

one of MOST ACTIVE of all anticancer drugs, but quite TOXIC

51
Q

Paclitaxel (Taxol) uses & toxicity

A

BREAST & OVARY CA

myelosuppression (greatest effect on neutrophils)

peripheral neuropathy

myalgias

severe hypersensitivity rxns

52
Q

Imatinib (Gleevac): mechanism/type or drug, use, administration, metabolized by, what is used if pt is intolerant/resistant

A

inhibits Bcr-Abl tyrosine kinase, which underlies CML

use: chronic myelogenouse leukemia

can be given orally, metabolized by CYP3A4, drug interactions possible

dasatanib & nilotibib are tyrosine kinase inhibitors used in pts who are intolerant or resistant to imatinib

53
Q 
Cetuximab (Erbitux): 
how does it work?
how is it administered?
for what?
SEs?
A

binds to epidermal growth factor (EGFR), blocking signals for growth & survival
-may have some direct toxicity against tumor cells

IV for head/neck CA & EGFR positive colon CA

SEs: rash, itching, HA,D, poss/ anphylactoid rxns (esp. Southern US)

54
Q

Erlotinib (Tarceva):
how does it work?
what does it tx?

A

inhibits HER1/EGFR tyrosine kinase

  • 2nd line tx for non-small cell lung ca
  • w/gemcitabine for pancreatic CA
55
Q

Bevacizumab (Avastatin): does what?

SEs

A

inhibits vascular endothelial growth factors->decrease antiogenesis & slow tumor growth

rare SE: vessel injury & bleeding
surgery should be delayed in pts on this drug due to excess bleeding & impaired would heeling

incr. risk of thromboembolism

(C) SEs include HTN & proteinuria

56
Q

Prednisone (Deltasone)

A

suppresses mitosis in lymphocytes

used for managment of LEUKEMIA & LYMPHOMA in adults & for acute leukemia in kids

57
Q

Dexamethasone use

A

to reduce radiation-treatment induced CNS edema

58
Q

Prednisone (Deltasone) Dexamethasone (Decadron) toxicity (4)

A
  • iatrogenic Cushing’s syndrome
  • osteoporosis, infections
  • psych disturbances
  • HTN, edema
59
Q

Tamoxifen: type of drug, use, toxicity

A

estrogen antagonist in the breast

PREVENTION of breast CA in women w/previous hx

hot flashes, nausea, uterine hyperplasia/CA

60
Q

Trastuzumab (Herceptin)

A

antibody against HER2 protein, only used in pts w/ HER2 overexpression

used for metastatic breast CA

CARDIOMYOPATHY is most serious SE

61
Q

Flutamide (Eulexin)
Bicalutamide (Casodez)
Nilutamide (Nilandron)

what do they do?
what are the used for?

A

block ANDROGEN RECEPTORS of androgen-sensitive tissues or tumors

used for METASTATIC PROSTATE CARCINOMA

4q Pharm Test2 (7 decks)

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