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Flashcards in Antineoplastics Deck (114)
1

Mechlorethamine: (explain/give the following) a. Class b. Mechanism c. Pharmacokinetics d. Therapeutic use e. adverse effects

a. Alkylating agent (nitrogen mustard) b. Type I. Bifunctional alkylating agent: produces cross-links in DNA. c. IV. No CNS penetration. Highly reactive. Disappears from blood in seconds to minutes d. Hodgkin's and non-hodgkin's lymphoma e. nausea/vomiting, myelosuppression, mild alopecia

2

Name three alkylating agent antineoplastic drugs

1. mechlorethamine (nitrogen mustard) 2. cyclophosphamide (nitrogen mustard) 3. carmustine (BCNU) (nitrosourea)

3

Name two vinca alkaloid antineoplastic drugs

1. Vinblastine 2. Vincristine

4

Name five antimetabolite antineoplastic drugs

1. methotrexate (MTX) 2. 5-fluorouracil (5-FU) 3. cytarabine (Ara-C) 4. mercaptopurine (MCP) 5. hydroxyurea

5

Name one taxane antineoplastic drug

1. Paclitaxel

6

Name four antiestrogenic antineoplastic drugs and the sub-class of each

1. temoxifen (TAM) - nonsteroidal antiestrogen 2. letrozole - aromatase (CYP19) inhibitor 3. leuprolide - GnRH analog 4. flutamide - nonsteroidal antiandrogen

7

Name one corticosteroid antineoplastic drug

1. prednisone

8

Name one atypical alkylating agent antineoplastic drug

1. procarbazine

9

Name one metal complex used as an antineoplastic drug

1. cisplatin (platinum coordination complex)

10

Name one monoclonal antibody used as an antineoplastic drug

1. trastuzumab (Herceptin)

11

Name two antibiotic agents used as antineoplastic drugs

1. doxorubicin 2. bleomycin (BLM)

12

Name one epipodphyllotoxin used as an antineoplastic drug

1. etoposide (VP16)

13

Name one BRM used as an antineoplastic drug

1. filgrastim

14

15

Mechlorethamine: mechanism of action





Type I (nitrogen mustard). Bifunctional alkylating agent: produces cross-links.

 

16

Cyclophosphamide: mechanism of action





Type III (nitrogen mustard). Prodrug activated in liver by CYP450 → active compound phosphoramide mustard acts as akylating agent. Acrolein (byproduct) causes bladder toxicity

 

17

Mechanism of action: carmustine (BCNU)

alkylating agent. produces cross-links in DNA

18

Mechanism of action: Methotrexate

antimetabolite:





Binds to DHFR → blocks formation to FH4 → blocks purine and pyrimidine synthesis

 

19

Mechanism of action: 5-fluorouracil (5-FU)

antimetabolite





Pyrimidine analog → activated to FUTP → inhibits RNA synthesis
Pyrimidine analog → activated to FdUMP → interferes with thymidylate synthase → inhibit DNA synthesis

 

20

Mechanism of action: cytarabine (Ara-C)

antimetabolite





Pyrimidine (cytadine) analog → competes for phosphorylation of cytidine → also competes with cytidine for incorporation into DNA → causes chain termination

 

21

Mechanism of action: mercaptopurine

antimetabolite
Purine analog → converted in cells (by HGPRT) to ribonucleotide that inhibits purine synthesis. Further converted and misincorporated into DNA and RNA







 

22

Mechanism of action: hydroxyurea

antimetabolite





Substituted urea → inhibits ribonucleotide reductase → blocks conversion to dNTPs → prevents DNA synthesis → arrests cell at G1-S interface

 

23

Mechanism of action: vinblastine

vinca alkaloid

Binds tubulin → prevents formation of microtubules and mitotic spindle

24

Mechanism of action: vincristine

vinca alkaloid

Binds tubulin → prevents formation of microtubules and mitotic spindle

25

Mechanism of action: paclitaxel

taxane

Binds tubulin beta-subunity → enhances assembly and stability of microtubules → arrests cells in late G2 phase (G2/M interface)

Can also interfere with DNA repair – intensifying effect of cisplatin or cyclophosphamide

26

Mechanism of action: doxorubicin

Antibiotic

Antitumor antibiotic (similar to tetracyclines) →  intercalates in DNA (distorts helix). Also causes lipid peroxidation and ROS generation. Also binds DNA topoisomerase II → prevents resealing of DNA strand breaks

27

Mechanism of action: bleomycin (BLM)

Antibiotic

Iron-containing glycopeptide that binds to DNA → causes oxidative-like damage to DNA → DNA strand breaks (single and double)

28

Mechanism of action: etoposide (VP16)

Epipodphyllotoxin

Irreversible stabilizes DNA-topoisomerase II complexes → results in dsDNA breaks that cannot be repeaired → arrests cell in late G2 phase (G2/M interface)

29

Mechanism of action: fligrastim (G-CSF)

BLM

Granulocyte colony stimulating factor → promotes neutrophil progenitors → expands absolute population of neutrophils → counteracts the effects of chemotherapy-induced neutropenia

30

Mechanism of action: trastuzumab (Herceptin)

Monoclonal antibody

Monoclonal antibody → binds HER2 receptor (human epidermal growth factor receptor 2) → blocks proliferation of cells (25-30% of metastatic breast cancers express HER2R

31

32

Mechanism of action: cisplatin

Metal complex

Platinum coordination complex → hydrolysis yields activated species which cross-links DNA → inhibits transcription, repair, protein recognition → produces apoptosis

Also covalently binds thioredoxin reductase (TrxR – overexpressed by many cancers) → directly promotes apoptosis

33

Mechanism of action: procarbazine

atypical alkylating agent

activated in vivo by liver to methylating agent → chromosomal damage

34

Mechanism of action: prednisone

Corticosteroid

Bind steroid receptors → modulate cell growth, including: arrest cells at G1, depress growth gene expression, induce nucleases (promote cell lysis)

35

Mechanism of action: tamoxifen (TAM)

Antiestrogenic - non-steroidal

Nonsteroidal antiestrogen → competitively blocks estrogen receptors in breast tissue. → cells halt at G0/G1 interface. Also elevates sex hormone-binding globulin → decreases free estradiol levels

Off-label use: estrogen agonist in bone tissue → may prevent post-menopausal osteoporosis

36

Mechanism of action: letrozole

Antiestrogenic

Aromatase (CYP19) inhibitor → binds heme domain → blocks conversion of androgens to estrogens → prevents stimulation of ER+ cells

37

Mechanism of action: leuprolide

Antiandrogenic

GnRH analog → initially stimulates LH and FSH → testosterone surge (and disease flare) → LH/FSH burnout after 2-4 wks → decrease testosterone to castration levels

38

Mechanism of action: flutamide

Antiandrogenic

Nonsteroidal antiandrogen → blocks androgen receptors

39

Therapeutic use: mechlorethamine

Hodgkin's and non-Hodgkin's lymphoma

40

Therapeutic use: cyclophosphamide

Broad spectrum anti-cancer (most widely used alkylating agent)

41

Therapeutic use: carmustine (BCNU)

Brain tumors

multiple myeloma

melanoma

42

Therapeutic use: methotrexate

Acute lymphblastic leukemia (ALL)
Choriocarcinoma

43

Therapeutic use: 5-fluorouracil (5-FU)

Broad spectrum: stomach, colon, pancreas, overy, head, neck, breast, bladder. Basal cell carcinoma.
**GI and breast are most common applications**

44

Therapeutic use: cytarabine (Ara-C)

Acute leukemias
Acute myelocytic leukemia (AML)

Lymphomas
Head and neck cancer

45

Therapeutic use: mercaptopurine

Acute leukemias

Chronic granulocytic anemia

46

Therapeutic use: hydroxyurea

Granulocytic leukemia

47

Therapeutic use: vinblastine

Lymphomas
Breast cancer

Testicular cancer
Bladder cancer

48

Therapeutic use: vincristine

Acute lymphocytic leukemia
Lymphomas
Wilm's tumor
Neuroblastoma

49

Therapeutic use: paclitaxel

Ovarian cancer (with cisplatin) → high TGF-beta tumors

50

Therapeutic use: doxorubicin

Wide spectrum (most prescribed in its class)
Lymphomas, breast, ovary, small cell lung

51

Therapeutic use: bleomycin

Germ cell tumors of testes and ovaries
Head, neck, lung, lymphomas

Skin, esophagus, genitourinary

52

Therapeutic use: etoposide (VP16)

Lymphomas, acute leukemia, small cell lung, testis, Kaposi's sarcoma

53

Therapeutic use: filgrastim (G-CSF)

Lessens risk of infection and restores neutrophil count enough for patients to resume therapies that otherwise suppress bone marrow

54

Therapeutic use: trastuzumab (Herceptin)

Metastatic breast cancer (1st line with paclitaxel)
Other HER2-positive cancers

55

Therapeutic use: cisplatin

Wide anti-tumor spectrum
Testicular cancer (with etoposide and belomycin)
Ovarian cancer (cisplatin + paclitaxel)
Head, neck, bladder, small cell lung, colon, esophagus

56

Therapeutic use: procarbazine

Hodgkin's lymphoma

57

Therapeutic use: prednisone

Lymphoma, lymphocytic leukemia
Breast cancer

Palliative effects: anti-emetic, stimulates appetite, anti-inflammatory

58

Therapeutic use: tamoxifen (TAM)

Advanced post-menopausal breast cancer (adjuvant, in combo with surg/rad/chemo)
Pre-menopausal metastatic breast cancer
Breast cancer prophylaxis for high-risk populations

59

Therapeutic use: letrozole

Post-menopausal locally-advanced or metastatic breast cancer (1st line treatment)

60

Therapeutic use: leuprolide

Prostate cancer (advanced, hormonally-responsive – 1st line)

61

Therapeutic use: flutamide

Metastatic prostate cancer (used in combination with GnRH agonist or a 2nd line therapy)

62

Which of the alkylating agents has the greatest CNS penetration?

carmustine (BCNU)

63

Adverse effects: alkylating agents

  1. Nausea/vomiting
  2. myelosuppression
  3. alopecia

mechlorethamine: 1, 2, mild 3

cyclophosphamide: 1, limited 2, 3. Also bladder toxicity

carmustine: 1, delayed 2

64

Which of the alkylating agents has bladder toxicity as a major adverse effect? What is used to counter it?

Cyclophosphamide

counteract with: mesna

65

What is leucovorin?

Example of rescue

leucovorin = folinic acid, does not require DHFR

Used following high-dose methotrexate therapy

Normal cells have greater capacity to take up leucovorin than tumor cells

66

Side effects: methotrexate

Intestinal epithelial damage (diarrhea, bleeding), bone marrow supporession, renal tubular necrosis (counter: alkalinize urine), displacement of other drugs

67

All antimetabolites are specific for what phase of the cell cycle?

S phase

68

Adverse effects: 5-fluorouracil

(usually delayed): Nausea, anorexia, diarrhea, myelosuppression

69

Adverse effects: cytarabine (Ara-C)

myelosuppression (dose-limiting)
Neurotoxicity

70

Adverse effects: mercaptopurine

Bone marrow suppression, vomiting, nausea, anorexia, jaundice

TPMT polymorphism related toxicity

71

Adverse effects: hydroxyurea

Hematopoietic depression, GI disturbances

72

Adverse effects: vinblastine

Strong myelosuppression
Epithelial ulcerations

73

Adverse effects: vincristine

Less myelosuppression than vinblastine
Alopecia
Neuromuscular abnormalities and peripheral neuropathy
Bronchospasm, cramps, nausea/vomiting/diarrhea

74

Adverse effects: paclitaxel

Leukopenia (dose-limiting)
Peripheral neuropathy
Myalgia, arthralgia

Hypersensitivity, alopecia, nausea/vomiting, mild cardiotoxicity

75

Adverse effects: doxorubicin

Dilated cardiomyopathy (cumulative) → due to ROS and low GSH peroxidase in heart tissue → reduce effect with detrazoxane (Fe chelating agent)
Bone marrow depression
Alopecia
GI problems

76

Adverse effects: bleomycin (BLM)

Minimal myelosuppression
***Pulmonary toxicity (cumulative, fatal) → due to low levels of bleomycin hydrolase
Skin vesiculation, hyperpigmentation
Fever, alopecia

77

Which antineoplastic has the unique adverse effect of pulmonary toxicity

bleomycin (BLM)

78

Adverse effects: etoposide (VP16)

leukopenia (dose-limiting), nausea/vomiting/diarrhea, alopecia

79

Adverse effects: filgrastim (G-CSF)

Bone pain (33%)
Hyperuricemia, leukocytosis

80

Adverse effects: trastuzumab (Herceptin)

Cardiomyopathy (reversible)
Hypersensitivity (severe)
Infusion reactions (fever, chills)

81

Adverse effects: cisplatin

**Nephrotoxicity (dose-related, lethal)
Ototoxicity (tinnitus, HF loss)
Peripheral neuropathy
Electrolyte disturbances
Nause/vomiting (100%)
Myelosuppression (mild/moderate)

82

Which antineoplastic drug has the dose-related nephrotoxicity as a major adverse effect?

cisplatin

83


Adverse effects: procarbazine

Myelosuppression, nausea/vomiting
Secondary malignancies (prolonged use)
Central & peripheral neurotoxicity

84

Adverse effects: prednisone

Immunosuppression
Myelosuppression (limited)
Weight gain, fluid retention, psychological effects

85

Adverse effects: tamoxifen (TAM)

nausea/vomiting, menopause-like symptoms (hot flashes), fatigue, bone/musculoskeletal pain
May increase risk of uterine/endometrial cancer (prolonged use → increases cell growth in these tissues)

86

Adverse effects: letrozole

Hot flashes
Nausea
Fatigue
Bone/musculoskeletal pain
Decreased bone mineral density

87

Adverse effects: leuprolide

Disease flare (1st 1-2 wks)
Hot flashes
Impotence

88

Adverse effects: flutamide

Gynecomastia, impotence
Diarrhea
Hepatotoxicity (rare)

89

What is the active form of tamoxifen (TAM)?

endoxifen, converted from tamoxifen by CYP2D6

2D6 ultrafast metabolizers experience greater adverse effects

90

Which antineoplastic drugs destabilize microtubles?

Vinca alkaloids:

vinblastine

vincristine

91

Which antineoplastic drugs stabilize microtubules?

Taxanes:

paclitaxel

locks cells in the G2/M interface -> may have some use as a radiosensitizer since cells may be more vulnerable to radiation therapy here

92

Which anti-neoplastic drug has anti-angiogenic properties?

doxorubicin

93

Which drug has major dilated cardiomyopathy as a side effect and state the reason for this specific side effect

Doxorubicin - generates H2O2, which is normally quenched by glutathione peroxidase. Cardiac muscle expresses little of this enzyme and is therefore especially vulnerable.

dexrazoxane can be used to lessen cardiomyopathy (chelates Fe -> preventing free radical damage)

94

Which antineoplast requires chelated Fe?

Bleomycin (BLM)

95

What is a BRM?

Biological response modifier - naturally occurring proteins or therapeutic molecules designed to mimic or impact natural proteins

example: filgrastim (G-CSF)

96

Which enzyme is responsible for the conversion of androgens to estrogens?

aromatase (CYP19)

97

Multi-drug resistance (MDR) to antineoplastic drugs is accomplished primarily by what mechanism? For which classes of drugs is this a prominent problem?

ATP-dependent drug efflux pumps

example: p-glycoprotein

Especially prominent for: vinca alkaloids, antibiotics, etoposide, taxanes

98

What is sequential blockade?

Simultaneous action of two inhibitors acting on different steps of a linear metabolic pathway

examples: hydroxyurea + cytarabine

methotrexate + 5-FU

99

What is concurrent inhibition?

Inhibitors block two separate pathways that lead to the same end product

examples: none

100

What is complementary inhibition?

One drug affects the function of an end-product, and the other drug affects the synthesis of that end product

example: cytarabine + doxorubicin

cytarabine inhibits DNA synthesis, doxorubicin cause DNA damage

101

What is rescue?

Counteract a major toxicity or particular effect on normal cells so that dose or length of treatment may be increased (or continue)

examples: methotrexate + leucovorin

bone marrow transplant

102

What is synchronization?

Synchronize cells so that most are in the same phase. Then use a drug specific to that phase to kill as many tumor cells as possible.

example: low-dose 5-FU to block in S-phase, followed by high-dose cytarabine to kill cells in S-phase

103

What is recruitment?

Mobilize slowly-proliferating or G0 cells back into the cell cycle so that they are more vulnerable to therapy

example: cycle-nonspecific (alkylating agent), following by cycle-specific drug

104

Which antineoplastic drugs are known to have a high risk of secondary malignancy in humans (3)

mechlorethamine

carmustine

etoposide

105

Killing of tumors follows what order of kinetics?

First-order kinetics

(constant dose of drug kills a constant fraction of tumor cells)

106

Define Class I antineoplastic drug

Cell cycle-nonspecific

107

Define Class II antineoplastic drug

Cell cycle-specific, phase-specific

108

Define class III antineoplastic drug

Cycle-specific, phase-nonspecific

109

Which Class II drugs act in:

  1. G1 phase
  2. S phase
  3. G2 phase
  4. M phase

  1. prednisone
  2. cytarabine, fluorouracil, methotrexate, mercaptopurine, hydroxyurea
  3. bleomycin, etoposide, paclitaxel
  4. vinblastine, vincristine

110

Class II drugs are usually administered how often?

Continuous infusion or frequent small dose

111

Class III drugs are usually administered how often?

single large dose - to take advantage of their sparing effect of normal cells that may be in G0 during treatment

112

113

Define IC90

The dose of an antineoplastic drug that results in 90% reduction in a cell population (1 log kill)

114

2-log kill results in the death of what percentage of a cell population?

99%