17 and 18 Antineoplastics Flashcards Preview

2 Pharm Unit > 17 and 18 Antineoplastics > Flashcards

Flashcards in 17 and 18 Antineoplastics Deck (103):
1

Cancer causes over how many deaths annually in the USA?

500,000 second only to heart disease

2

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

-50%
-17%
-33%

3

What are the 5 shortcomings mentioned of chemotherapies?

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

4

T-F---chemotherapeutic agents have high therapeutic indices?

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

5

What 3 ways do conventional chemotherapeutic agents act?

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

6

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

False--they do

7

Does activation or inactivation of oncogenes overrides G_ arrest?

Activation, G1 arrest

8

Inactivation of tumor suppressor genes overrides what cell cycle arrest?

G2

9

When is the DNA replication checkpoint?

End of G2 phase

10

When is the restriction point checkpoint?

End of G1

11

What does S phase stand for?

synthetic phase, DNA replication

12

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

G1-->S--->G2--->M

13

What is the tumor cell growth fraction?

Fraction of cells not in G0

14

Are differentiated tumor cells responsive to chemotherapy?

not responsive they are in G0
[cycling cells are sensitive to cytotoxic drugs attacking cell cycle]

15

Which tumor cells are are responsive to conventional chemotherapy?

non G0

16

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

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

17

Is micrometastases susceptible to chemotherapeutic agents?

yes

18

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

Noncancerous proliferating cells
- bone marrow
-intestinal epithelial cells
-oral mucosa
-gonadal cells
-hair follicles

19

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

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)

20

What are the 4 primary applications for chemotherapy?

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

21

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

bischloroethyl amines, nitrosoureas, procarbazine

22

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

mechlorethamine

23

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

cyclophophamide
-activation in liver or tumor tissues

24

Dechlorination of the bischloroethyl amines leaves what energy state?

+ state- electrophile
[this is what attacks neutrophils nitrogen in DNA bases]

25

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

False- more significant DNA damage

26

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

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

27

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

Nitrosoureas

28

What alkylating agents are effective against Hodgkin's disease?

procarbazine

29

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

little cross-resistance

30

What alkylating agent might cause leukemia? what risk?

procarbazine, 5-10%
[it's because alkylating agents are mutagenic so increase risk of another cancer]

31

What is the major anti-tumor antimetabolites?

Methotrexate

32

What metabolic substrate is methotrexate an analog of?

folic acid

33

What does methotrexate inhibit?

-dihydrofolate reductase
-blocks synthesis of DNA, RNA, and protein precursors

34

What does methotrexate accumulate as?

polyglutamate derivative

35

T-F methotrexate is G1 phase-specific?

False- s phase

36

What nucleic acid base does methotrexate impair?

thymidine

37

What are the mechanisms of resistance for methotrexate? 4

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

38

How do you rescue methotrexate? drug?

folinic acid---leucovorin

39

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

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

40

What is a common mechanism of resistance for purine antagonists?

down regulation of HGPRT
[hypoxanthine-guanine phophoribosyl transferase-activates the antagonists]

41

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

False__6-mercaptopurine

42

When does 6-mercaptopurine have low bioavailability?

administered with cow's milk

43

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

allopurinol

44

What are the 2 pyrimidine antagonists?

5-FU[fluorouracil]
cytosine arabinoside [cytarabine]

45

What phase is fluorouracil specific to?

S phase

46

What is the oral prodrug of fluorouracil?

capecitabine

47

Review of the capecitabine metabolism--compound--->enzyme---> compound

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

48

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

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

49

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

anti-tumor antibiotics--anthracyclines

50

How does anthracyclines work?

DNA intercalation, DNA topoisomerase II binding, DNA scission

51

What is the major side effect of anthracyclines?

irreversible cardiac toxicity at high doses

52

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

DNA strand scission--side effect pulmonary fibrosis

53

does bleomycin have much myelosuppression?

No

54

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

anaphylactic reactions---administer small test doses

55

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

M-phase--inhibitor of microtubule polymerization

56

What are the side effects of vinblastine?

acute nausea, vomiting, dose limiting bone marrow depression

57

how is resistance conferred to vinblastine?

tubulin gene mutations

58

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

vincristine [major use in childhood leukemia]

59

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

paclitaxel-enhance tubulin polymerization which blocks microtubule disassembly

60

What is paclitaxel used for?

ovarian and advanced breast cancers

61

What are the 2 camptothecin topoisomerase inhibitors?

topotecan and irinotecan

62

Topoisomerase II creates how many breaks?

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

63

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

block relegation of single-strand break

64

What drug is a platinum coordination complex?

Cisplatin--similar to alkylating agent interacts with Ns in guanine

65

Is cisplatin cell cycle specific?

No

66

When is cisplatin often used?

ovarian and testicular cancer

67

What toxicity side-effects does cisplatin have?

nephrotoxicity, acoustic nerve dysfunction

68

What are the two main hormone-dependent cancers?

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

69

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

estrogen responsive tumors are breast and uterine

70

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

tamoxifen--yes

71

Is tamoxifen an antagonist?

no-partial agonist
[efficacy differs in different tissues]

72

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?

false---high risk women only
True

73

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

True

74

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

False---tamoxifen increased both

75

What is another selective estrogen response modulator?

raloxifene

76

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

aromatase inhibitors
[inhibits conversion of androgen to estrogen]

77

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

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

78

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

aromatase inhibitors

79

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

75%

80

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

False and False

81

Aromatase inhibitors may cause what problems?

joint pain, loss of bone density

82

What are the 2 anti-androgen drugs?

flutamide and leuprolide

83

Leuprolide is a synthetic peptide of what?

gonadotropin releasing hormone

84

Pulsatile delivery of leuprolide causes?

elevations of androgens in men and estrogens in women

85

Continuous, high dose delivery of leuprolid causes?

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

86

T-f---flutamide is an endrogen receptor agonist?

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

Why is flutamide alone ineffective against prostate cancer?

due to rapid androgen receptor mutations

88

Prednisone induces apoptosis in what cells?

leukemia

89

Does prednisone cure leukemia?

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

90

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

palliative agent to reduce inflammation and nausea

91

What is oncogene addiction?

Tumor cell proliferation/survival apparently becomes dependent upon activated oncogenes

92

Targeted agents inhibit what?

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

93

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

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

94

What are the two EGF receptor protein tyrosine kinase?

erlotinib and cetuximab

95

What are the 2 HER2 protein kinase target drugs?

lapatinib and trastuzumab

96

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

Iapatinib

97

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

trastuzumab

98

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

True

99

What does brentuzimab vedotin do?

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

100

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

resistance to the agents.

101

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

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

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

nonspecific drug efflux pumps

103

What are the 3 rules of multi drug regimens?

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