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Intro to path > 082914 antineoplastics part two > Flashcards

082914 antineoplastics part two Flashcards

1
Q

alkylating agents mechanism

A

introduce alkyl groups into DNA, RNA, proteins (DNA is likely the most important target)

causes DNA crosslinks, strand breaks, misreading of code

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2
Q

cell cycle specificity of alkylating agents

A

can be:

cell cycle non specific (also affect G0 cells)–ex are mechlorethamine, carmustine

cell cycle specific phase nonspecific-ex are cyclophosphamide

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3
Q

what is unique of the alkylating agents?

A

least selective of the antineoplastics (tend to kill tumor and normal cells equally)

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4
Q

toxicities of alkylating agents

A

mechlorethamine-nausea and vomiting, myelosuppresion

carmustine-nausea and vomiting, delayed myelosuppression

cyclophosphamide-nausea and vomiting, limited myelosuppression, alopecia

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5
Q

what are the typical side effects of alkylating agents in general? (not for specific drugs)

A

hematopoeisis suppression (often used as indicator of therapeutic effectiveness and normal cell recovery)

GI effects (damage to intestinal mucosa…nausea and vomiting

alopecia

affect RAPIDLY DIVIDING tissues most

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6
Q

what two drugs are examples of nitrogen mustards in alkylating agents?

A

mechlorethamine

cyclophosphamide

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7
Q

what drug is an ex of nitrosoureas in alkylating agents?

A

carmustine

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8
Q

mechlorethamine cell cycle specificity

A

cell cycle nonspecific

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9
Q

what is mechlorethamine used for

A

in combo therapy for Hodgkin’s and non-Hodgkin’s LYMPHOMA

breast, lung, ovarian cancer

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10
Q

MOA of mechlorethamine

A 
bifunctional alkylating agent:
produces DNA cross links
highly reactive (disappears from blood in seconds to minutes)
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11
Q

what is the cell cycle specificity of cyclophosphamide

A

cycle specific phase nonspecific

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12
Q

what is unique about cyclophosphamide?

A

PRODRUG activated by liver cytochrome P450s

actual alkylating agent is phosphoramide mustard

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13
Q

toxicity of cyclophosphamide

A

bladder toxicity-sterile hemorrhagic cystitis (can be partially prevented with mesna)

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14
Q

what is good about cyclophosphamide?

A

very broad spectrum of activity, so used against wide variety of cancers

BREAST CANCER

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15
Q

cell cycle specificity of carmustine

A

cycle nonspecific

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16
Q

what is unique about carmustine?

A

crosses BBB very well

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17
Q

uses of carmustine

A

brain tumors, multiple myeloma, melanoma

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18
Q

when are antimetabolites most effective?

A

against tumors where cell proliferation is rapid

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19
Q

cell cycle specificity of antimetabolites

A

S phase specific

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20
Q

what are antimetabolites?

A

structural analogs of precursors of nucleic acid synthesis or other related pathways

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21
Q

MOA of methotrexate and what type of drug is it?

A

type: antimetabolite

MOA: binds to dihydrofolate reductase and prevents formation of tetrahydrofolate, which is needed for synthesis of dTMP

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22
Q

leucovorin rescue

A

high doeses of methotrexate are necessary to bind all dihydrofolate reductase

rescue host cells with leucovorin–leucovorin is folinic acid, which is a fully reduced folate that does not require to be reduced by DHFR (normal cells have increased ability to bring in leucovorin relative to tumor cells)

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23
Q

side effects of methotrexate

A

intestinal epithelium damage
bone marrow suppression
renal tubular necrosis
displaces other drugs from serum albumin

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24
Q

uses of methotrexate

A

acute lymphocytic leukemia
choriocarcinoma (methotrexate is #1 drug for this)
head neck breast lung
osteosarcoma

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25
Q

fluorouracil: type of drug and MOA

A

antimetabolite

pyrimidine analog that is activated in cells to FUTP which inhibits RNA synthesis. also activated to FdUMP which interferes with thymidylate synthase and ultimately DNA synthesis

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26
Q

side effects of fluorouracil

A

nausea, anorexia, diarrhea

myelosuppression

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27
Q

uses of fluorouracil

A

BROAD spectrum:
COLON, BREAST, stomach, pancreas, ovary, head, neck, bladder (mostly GI)

basal cell carcinoma

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28
Q

cytarabine: type of drug and MOA

A

antimetabolite

pyrimidine (cytidine) analog that competes for phosphoyrlation of cytidine; competes for incorrporation into DNA and causes chain termination

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29
Q

side effects of cytarabine

A 
marked myelosuppresion (limits dose)
neurotoxic
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30
Q

uses of cytarabine

A

acute leukemias (acute myelocytic leukemia for ex)

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31
Q

mercaptopurine: type of drug and MOA

A

antimetabolite

purine analog-converted in cells to ribonucleotide that inhibits RNA and DNA synthesis

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32
Q

sides effects of mercaptopurine

A

bone marrow depression
vomiting, nausea, anorexia
jaundice

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33
Q

uses of mercaptopurine

A

acute leukemias

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34
Q

TPMT is important for mercaptopurine b/c?

A

TPMT degrades mercaptopurine (6MP) to inactive form of 6 methyl MP. If person has non functional allele for it, has increased risk of serious bone marrow toxicity with normal dose

if pt has two copies of nonfunctional TPMT, then can’t tolerate the 6MP

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35
Q

hydroxyurea: type of drug and MOA

A

antimetabolite

inhibits ribonucleotide reductase (blocks conversion of ribonucleotides to dNTPs, preventing DNA synthesis

arrests cells then at G1-S point

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36
Q

major uses of hydroxyurea

A

granulocytic leukemia

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37
Q

side effects of hydroxyurea

A

hematopoietic depression

GI disturbances

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38
Q

examples of the vinca alkaloids, and what class of drug are the vinca alkaloids?

A

vincristine, vinblastine

class: natural products

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39
Q

MOA of vinca alkaloids

A

binds to tubulin, inhibiting proper formation of microtubules and mitotic spindle

arrests cells in metaphase

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40
Q

how are vincristine and vinblastine similar or different?

A

similar in that structurally related

different in their toxicities and their antitumor spectrum

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41
Q

side effects of vinblastine

A

strongly myelosuppressive

epithelial ulcerations

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42
Q

side effects of vincristine

A

significantly less bone marrow toxic. than vinblastine

alopecia, neuromuscular abnormalities (peripheral neuropathy)

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43
Q

uses of vinblastine

A

lymphomas, breast cancer

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44
Q

uses of vincristine

A

acute lymphocytic leukemia
lymphomas
Wilm’s tumor
neuroblastoma

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45
Q 
MOA of taxanes
and what class are taxanes under?
A

class: natural products

MOA: enhances assembly and stability of microtubules by binding to beta subunit of tubulin, blocks late in G2 phase (this phase is more sensitive to radiation so paclitaxel may be used as a radiosensitizer)

46
Q

paclitaxel is an example of what type of drug? what class?

A

taxane, natural products

47
Q

uses of paclitaxel

A

refractory ovarian cancer

breast cancer

48
Q

sides effects of paclitaxel

A

dose limiting leukopenia
peripheral neuropathy
myalgia, arthralgia

49
Q

doxorubicin: drug type/class?

A

antitumor antibiotic, natural products

50
Q

cell cycle specificity of doxorubicin

A

cycle specific phase non specific

51
Q

uses of doxorubicin

A

wide spectrum of activity
lymphomas, breast, ovary
most widely prescribed agent in its class

52
Q

MOA of doxorubicin

A

intercalates in DNA, distorting the DNA helix
binds to DNA and topoisomerase II
causes lipid peroxidation and free radical generation

53
Q

which drug has as a side effect CARDIOMYOPATHY?

A

doxorubicin

54
Q

side effects of doxorubicin

A

cardiomyopathy
bone marrow depression
alopecia
GI problems

55
Q

bleomycin: class of drug

A

natural products

56
Q

MOA of bleomycin

A

mix of IRON-containing glycoypeptides that bind to DNA

causes oxidative-like damage to DNA which lead to DNA strand breaks

57
Q

cell phase specificity of bleomycin

A

phase specific for G2

58
Q

uses of bleomycin

A

germ cell tumors of testes and ovaries

head, neck, lung, lymphomas

59
Q

side effects of bleomycin

A

minimal myelosuppression
PULMONARY TOXICITY
skin vesiculation, hyperpigmentation

*lung and skin have lowest levels of bleomycin hydrolase for inactivating the drug

60
Q

etoposide: class of drug

A

natural compounds

61
Q

MOA of etoposide

A

irreversibly stabilizes DNA-topoisomerase II complexes (causing dsDNA breaks that can’t be repaired)

62
Q

cell cycle specificity of etoposide

A

late G2 phase

63
Q

uses of etoposide

A

lymphomas, acute leukemia, small cell lung, testis

64
Q

side effects of etoposide

A 
leukopenia
nausea
vomiting
diarrhea
alopecia
65
Q

biological response modifiers

A

naturally occurring proteins designed to mimic natural proteins

limitation is that response can be variable,;serious side effects have happened

66
Q

filgrastim

A

goal is to limit chemo-induced neutropenia

promotes progenitors of neutrophils

67
Q

side effect of filgrastim

A

bone pain

68
Q

trastuzumab drug type and class

A

monoclonal antibodies, natural compounds

69
Q

MOA of trastuzumab

A

humanized monoclonal antibody that binds to HER2 (human epidermal growth factor) receptor to block proliferation of cells; may illicit immune response against HER2+ cells

70
Q

uses of trastuzumab

A

breast cancers that overexpress HER2, so is a target therapy

71
Q

side effects of trastuzumab

A

cardiomyopathy-often reversible
hypersensitivity
infusion rxns-fever, chills

72
Q

cisplatin: class of drug?

A

miscellaneous agents

73
Q

MOA of cisplatin

A

platinum coordination complex-hydrolysis yields activated species which causes DNA crosslinks

74
Q

cell cycle specificity of cisplatin

A

cycle specific phase non specific

75
Q

uses of cisplatin

A

wide spectrum

testicular cancer
ovarian cancer

76
Q

side effects of cisplatin

A 
NEPHROTOXICITY
ototoxicity
peripheral neuropathy
electroylyte distrubances
nausea, vomiting
mylosuppression
77
Q

MOA of procarbazine

A

activated in vivo to a methylating agent which causes chromosomal damage

an atypical alkylating agent

78
Q

uses of procarbazine

A

Hodgkin’s lymphoma

79
Q

side effects of procarbazine

A

myelosuppression, nausea, vomiting

80
Q

uses of hormone and hormone antagonist therapies against cancer

A

good for tumors that are steroid hormone dependent

81
Q

possible strategies for hormone therapy against cancer

A

opposite steroidal compounds (estrogens for prostate cancer, etc)

anti-hormonal compounds

82
Q

benefits of hormonal therapy against cancer

A

responses to it can be dramatic and prolonged

and has other beneficial side effects (not just for tumor)-ex is progestins as an appetite stimulant for cancer pts

83
Q

prednisone MOA

A

binds to steroid receptors which act to modulate several aspects of cell growth (may arrest cells at G1; depress expression of many growth-related genes, induce nucleases which may modulate cell lysis)

84
Q

what forms of antiestrogenic therapies are used to treat cancer?

A

estrogen receptor antagonists (tamoxifen, raloxifene)

aromatase inhibitors (letrozole)

85
Q

advantages of nonsteroidal aromatase inhibitors

A

oral, rapid onset
estrogen below detectable levels
no androgenic side effects

86
Q

tamoxifen MOA

A

antiestrogen that compoetitively blocks estrogen receptors in breast tissue (estrogen agonist bone tissue)

87
Q

cell cycle specificity of tamoxifen

A

cytostatic

tumor regrows when tamoxifen is removed

88
Q

uses of tamoxifen

A

advanced post menopausal breast cancer

premenopausal metastatic breast cancer

breast cancer prophylaxis

89
Q

what is tamoxifen activated by?

A

CYP2D6

90
Q

side effects of tamoxifen and letrozole

A

nausea
menopause like symptoms
fatigue
bone and other musculoskeletal pain

91
Q

MOA of letrozole

A

blocks conversion of androgens to estrogens by inhibiting aromatase

92
Q

uses of letrozole

A

1st line treatment of post menopausal locally advanced or metastatic breast cancer

93
Q

what are some antiandrogenic approaches to prostate cancer?

A 
GnRH analogs (leuprolide)
non-steroidal androgen receptor blockers (flutamide)
94
Q

leuprolide MOA

A

analog of GnRH (initially stimulates LH and FSH release causing testosterone surge, but after 2-4 weeks, it desensitizes GnRH signaling, decreasing LH/FSH and decreasing testosterone

95
Q

uses of leprolide

A

advance hormonally response prostate cancer

96
Q

side effects of leprolide

A

hot flashes

impotence

97
Q

flutamide MOA

A

nonsteroidal antiandrogen that blocks androgen receptor

98
Q

uses of flutamide

A

treatment of metastatic prostate cancer

99
Q

side effects of flutamide

A

gynecomastia
diarrhea
hepatotoxicity

100
Q

cell cycle specificies of all the antineoplastics

A

see part one lecture with three slides

101
Q

major cause of chemotherapeutic failure

A

selection and overgrowth within tumor-resistance

102
Q

what is a key strategy in overcoming resistance from tumor cells with chemotherapy?

A

combination therapy

103
Q

how does multi-drug resistance occur?

A

mediated by ATP-dependent drug efflux pumps

104
Q

principles of combination chemotherapy

A

different cell cycle specificites (to hit both those in and out of cell cycle)

active as single agents

non-overlapping toxicities

different MOA

105
Q

sequential blockade

A

simultaneous action of two inhibitors acting on different steps of linear metabolic pathway

106
Q

concurrent inhibition

A

inhibitors block two sepearte pathways that lead to same end product

107
Q

complementary inhibition

A

one drug affects fxn of an end product and the other drug affects the synthesis of that end product

ex: cytarabine and doxorubicin

108
Q

rescue

A

rescue the pt’s normal cells from the cancer treatment

examples:
leucovorin (folinic acid) to rescue cells after high dose methotrexate

autologous bone marrow or stem cel transplant

109
Q

synchronization

A

synchronize cells so they are in one phase and then use drug specific for that phase

ex: low doses of fluorouracil to block in S phase, then high dose of cytarabine to kill in S phase

110
Q

recruitment

A

mobilize slowly proliferatin or non proliferating cells to more rapid proliferation-bring cells out of G0 and back into cell cycle and then hit them with cycle specific drugs

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