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2 Pharm Unit > 17 and 18 Antineoplastics > Flashcards

17 and 18 Antineoplastics Flashcards

1
Q

Cancer causes over how many deaths annually in the USA?

A

500,000 second only to heart disease

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2
Q

What is the % of diagnosed patients cured?
What percentage cured by chemotherapy?
What % cured by local measures?

A
  • 50%
  • 17%
  • 33%
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3
Q

What are the 5 shortcomings mentioned of chemotherapies?

A
  1. cancer is a group of diseases
  2. cancers result from genetic alterations
  3. No foreign organism to target
  4. Harm to normal host
  5. low therapeutic indices
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4
Q

T-F—chemotherapeutic agents have high therapeutic indices?

A

False–a low index means its more toxic at lower doses

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5
Q

What 3 ways do conventional chemotherapeutic agents act?

A

inhibit metabolism (RNA synthesis)
Damage DNA
Interfere with mitotic machinery

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6
Q

T-F–chemotherapeutics do not attack the host cell?

A

False–they do

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7
Q

Does activation or inactivation of oncogenes overrides G_ arrest?

A

Activation, G1 arrest

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8
Q

Inactivation of tumor suppressor genes overrides what cell cycle arrest?

A

G2

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9
Q

When is the DNA replication checkpoint?

A

End of G2 phase

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10
Q

When is the restriction point checkpoint?

A

End of G1

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11
Q

What does S phase stand for?

A

synthetic phase, DNA replication

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12
Q

What is the order of the cell cycle starting from G0?

A

G1–>S—>G2—>M

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13
Q

What is the tumor cell growth fraction?

A

Fraction of cells not in G0

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14
Q

Are differentiated tumor cells responsive to chemotherapy?

A

not responsive they are in G0

[cycling cells are sensitive to cytotoxic drugs attacking cell cycle]

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15
Q

Which tumor cells are are responsive to conventional chemotherapy?

A

non G0

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16
Q

What is micro metastases derived from what does it lead to?

A

presumably derived from tumor stem cells, generally the ultimate cause of lethality

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17
Q

Is micrometastases susceptible to chemotherapeutic agents?

A

yes

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18
Q

Toxic side effects are most pronounced on what types of cells?

A

Noncancerous proliferating cells

  • bone marrow
  • intestinal epithelial cells
  • oral mucosa
  • gonadal cells
  • hair follicles
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19
Q

according to the log kill hypothesis how many cells does each intervention kill?

A

eradicates the same percentage of tumor cells (you have to stop to take breaks to relieve the adverse effects in which the cancer cells grow again)

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20
Q

What are the 4 primary applications for chemotherapy?

A

1- metastatic/hematopoietic cancer
2- surgical adjuvant
3- lymphomas, leukemias
4- palliative/prolong life

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21
Q

What are the 3 major alkylating agents/classes of alkylating agents?

A

bischloroethyl amines, nitrosoureas, procarbazine

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22
Q

What drug was the nitrogen mustard that was used in mustard gas World War 1?

A

mechlorethamine

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23
Q

What less highly reactive derivative has been developed to replace mechlorethamine? What does it require?

A

cyclophophamide

-activation in liver or tumor tissues

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24
Q

Dechlorination of the bischloroethyl amines leaves what energy state?

A

+ state- electrophile

[this is what attacks neutrophils nitrogen in DNA bases]

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25
Q

T-F–cross linked guanine residues leads to less DNA damage?

A

False- more significant DNA damage

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26
Q

T-F–nitrosoureas have strong cross-resistance with other alkylating agents?

A

false-little, and this is why you can use multiple alkylating agents in multi drug treatment.

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27
Q

What alkylating agents cross-brain barrier, useful against brain tumors?

A

Nitrosoureas

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28
Q

What alkylating agents are effective against Hodgkin’s disease?

A

procarbazine

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29
Q

does Procarbazine have little or a lot of cross-resistance with other antineoplastic agents?

A

little cross-resistance

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30
Q

What alkylating agent might cause leukemia? what risk?

A

procarbazine, 5-10%

[it’s because alkylating agents are mutagenic so increase risk of another cancer]

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31
Q

What is the major anti-tumor antimetabolites?

A

Methotrexate

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32
Q

What metabolic substrate is methotrexate an analog of?

A

folic acid

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33
Q

What does methotrexate inhibit?

A
  • dihydrofolate reductase

- blocks synthesis of DNA, RNA, and protein precursors

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34
Q

What does methotrexate accumulate as?

A

polyglutamate derivative

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35
Q

T-F methotrexate is G1 phase-specific?

A

False- s phase

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36
Q

What nucleic acid base does methotrexate impair?

A

thymidine

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37
Q

What are the mechanisms of resistance for methotrexate? 4

A
  1. amplification of DHFR gene
  2. DHFR gene mutation
  3. decreased uptake
  4. increased drug efflux
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38
Q

How do you rescue methotrexate? drug?

A

folinic acid—leucovorin

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39
Q

What are the 2 major purine antagonists? What phase are they specific to?

A

6-mercapto-purine
6-thioguanine
-S phase specific because block purine synthesis

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40
Q

What is a common mechanism of resistance for purine antagonists?

A

down regulation of HGPRT

[hypoxanthine-guanine phophoribosyl transferase-activates the antagonists]

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41
Q

T-F–6-thioguanine is metabolically inactivated by xanthine oxidase?

A

False__6-mercaptopurine

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42
Q

When does 6-mercaptopurine have low bioavailability?

A

administered with cow’s milk

43
Q

What is administered to inhibit xanthine oxidase and therefore reduce uric acid accumulation? [gout]

A

allopurinol

44
Q

What are the 2 pyrimidine antagonists?

A

5-FU[fluorouracil]

cytosine arabinoside [cytarabine]

45
Q

What phase is fluorouracil specific to?

A

S phase

46
Q

What is the oral prodrug of fluorouracil?

A

capecitabine

47
Q

Review of the capecitabine metabolism–compound—>enzyme—> compound

A

capecitabine–>carboxylesterase—>5’-DFCR—>cytidine deaminase—> 5’DFUR—> thymidine phosphorylase—>5-FU—>dihydropyrimidine dehydrogenase—> alpha-fluoro-beta-alanine

48
Q

Metabolic activation of cytarabine requires what? what is the significance of this enzyme?

A

deoxycytidine kinase—mutational loss of this is important mechanism of tumor cell resistance

49
Q

What anti-tumor class and subclass does daunorubicin and doxorubicin fall under?

A

anti-tumor antibiotics–anthracyclines

50
Q

How does anthracyclines work?

A

DNA intercalation, DNA topoisomerase II binding, DNA scission

51
Q

What is the major side effect of anthracyclines?

A

irreversible cardiac toxicity at high doses

52
Q

What is the main cytotoxic action of bleomycin? side effect?

A

DNA strand scission–side effect pulmonary fibrosis

53
Q

does bleomycin have much myelosuppression?

A

No

54
Q

Bleomycin is a natural product, what is the significance of that?

A

anaphylactic reactions—administer small test doses

55
Q

What cell cycle is vinblastine specific to? how does it work?

A

M-phase–inhibitor of microtubule polymerization

56
Q

What are the side effects of vinblastine?

A

acute nausea, vomiting, dose limiting bone marrow depression

57
Q

how is resistance conferred to vinblastine?

A

tubulin gene mutations

58
Q

What is the non-dose limiting bone marrow depression alternative to vinblastine?

A

vincristine [major use in childhood leukemia]

59
Q

What is the mitotic spindle poison? how does it work?

A

paclitaxel-enhance tubulin polymerization which blocks microtubule disassembly

60
Q

What is paclitaxel used for?

A

ovarian and advanced breast cancers

61
Q

What are the 2 camptothecin topoisomerase inhibitors?

A

topotecan and irinotecan

62
Q

Topoisomerase II creates how many breaks?

A

double-strand—which occurs in DNA replication therefore is Sphase -specific

63
Q

Topoisomerase inhibitors block what when bound to topoisomerase I and DNA?

A

block relegation of single-strand break

64
Q

What drug is a platinum coordination complex?

A

Cisplatin–similar to alkylating agent interacts with Ns in guanine

65
Q

Is cisplatin cell cycle specific?

A

No

66
Q

When is cisplatin often used?

A

ovarian and testicular cancer

67
Q

What toxicity side-effects does cisplatin have?

A

nephrotoxicity, acoustic nerve dysfunction

68
Q

What are the two main hormone-dependent cancers?

A

prostate and breast—[cause second most cancer deaths in each sex behind lung cancer]

69
Q

Estrogen promotes development and proliferation of estrogen responsive tissues and which tumors?

A

estrogen responsive tumors are breast and uterine

70
Q

What is the competitive inhibitor of estrogen binding to estrogen receptor? is it a selective estrogen response modulator?

A

tamoxifen–yes

71
Q

Is tamoxifen an antagonist?

A

no-partial agonist

[efficacy differs in different tissues]

72
Q

T-F–prophylactic tamoxifen treatment has been suggested as an effective means of breast cancer prevention in all women? T-F—it does not significantly increases life span?

A

false—high risk women only

True

73
Q

T-F—tamoxifen therapy in postmenopausal women has been shown to reduce risks of bone fractures?

A

True

74
Q

T-F—There is an increased risk of thrombosis/embolism but decreased risk of endometrial cancer with tamoxifen?

A

False—tamoxifen increased both

75
Q

What is another selective estrogen response modulator?

A

raloxifene

76
Q

What drug class does letrozole, anastrozole, and exemestane fall into?

A

aromatase inhibitors

[inhibits conversion of androgen to estrogen]

77
Q

T_F—aromatase inhibitors effectively block estrogen production in in premenopausal women? Why?

A

False–postmenopause use…pre menopause women have compensatory gonadotropin and ovarian estrogen production

78
Q

What drug class is more effective than tamoxifen for ER+ breast cancers or useful in tamoxifen-resistant tumors in postmenopausal women?

A

aromatase inhibitors

79
Q

Exemestane greatly reduces risk of breast cancer in what % of high risk postmenopausal women?

A

75%

80
Q

T-F—aromatase inhibitors enhance thrombosis? enhance uterine cancer?

A

False and False

81
Q

Aromatase inhibitors may cause what problems?

A

joint pain, loss of bone density

82
Q

What are the 2 anti-androgen drugs?

A

flutamide and leuprolide

83
Q

Leuprolide is a synthetic peptide of what?

A

gonadotropin releasing hormone

84
Q

Pulsatile delivery of leuprolide causes?

A

elevations of androgens in men and estrogens in women

85
Q

Continuous, high dose delivery of leuprolid causes?

A

greatly lowers androgen levels in men and estrogen levels in women.

86
Q

T-f—flutamide is an endrogen receptor agonist?

A

False-antagonist
[used with leuprolide to block effects of the initial pulse of androgen levels and flare of prostate cancer at start of therapy]

87
Q

Why is flutamide alone ineffective against prostate cancer?

A

due to rapid androgen receptor mutations

88
Q

Prednisone induces apoptosis in what cells?

A

leukemia

89
Q

Does prednisone cure leukemia?

A

No [but useful for inducing remission in acute lymphoblastic or undifferentiated leukemia in children]

90
Q

In cancers other than leukemia, what is prednisone used for?

A

palliative agent to reduce inflammation and nausea

91
Q

What is oncogene addiction?

A

Tumor cell proliferation/survival apparently becomes dependent upon activated oncogenes

92
Q

Targeted agents inhibit what?

A

function of activated oncogenes or proteins necessary for tumor cell proliferation and tumor angiogenesis

93
Q

T-F—targeted agents are humanized chimeric antibodies? What does humanized mean?

A

True

- antigen recognition elements Fab of a mouse antibody and structural portions Fc of a human antibody

94
Q

What are the two EGF receptor protein tyrosine kinase?

A

erlotinib and cetuximab

95
Q

What are the 2 HER2 protein kinase target drugs?

A

lapatinib and trastuzumab

96
Q

Which HER2 protein tyrosine kinase is the small molecule EGFR and HER2 kinase inhibitor in breast cancer?

A

Iapatinib

97
Q

What HER2 antibody is humanized and used in breast cancer a lot?

A

trastuzumab

98
Q

T-F–imatinib just got approved for chronic myelogenous leukemia?

A

True

99
Q

What does brentuzimab vedotin do?

A

CD30 surface antigen–chimeric IgG conjugated to highly toxic mitotic spindle poison

100
Q

Tumor cells surviving an initial chemotherapeutic intervention freq. show what?

A

resistance to the agents.

101
Q

What are the 5 specific mechanisms of resistance? [review]

A
  1. drug uptake
  2. increased concentration of target enzyme
  3. decreased rate of metabolic drug activation
  4. increased rate of drug metabolism
  5. Increased rate of drug efflux.
102
Q

Resistance to a variety of natural product anticancer drugs can result from the elaboration of ____???

A

nonspecific drug efflux pumps

103
Q

What are the 3 rules of multi drug regimens?

A
  1. employ drugs not showing cross-resistance
  2. minimize side effects
  3. maximize anti-tumor effects [use each drug at highest possible

2 Pharm Unit (17 decks)

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