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PMC II (2021) > Anticancer Drugs Exam 1 > Flashcards

Anticancer Drugs Exam 1 Flashcards

1
Q

what is a cytotoxic drug?

A

a drug that kills cancer cells (but also kills human cells) that is widely used in treating cancer

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2
Q

what are the categories of cytotoxic drugs?

A
  • cell cycle specific (CCS)

- cell cycle nonspecific (CCNS)

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3
Q

what does a cell cycle specific drug kill?

A

only kills cells that are cyclin though phases of cell cycle (not resting cells/cells in G0)

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4
Q

what does a cell cycle nonspecific drug kill?

A

kills cells that are cycling though phases and cells in the resting phase (G0)

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5
Q

which cells are more sensitive to being killed by cell cycle nonspecific drugs?

A

cycling cells

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6
Q

is a cell cycle specific (CCS) or cell cycle nonspecific (CCNS) drug more effective at killing?

A

cell cycle nonspecific (CCNS)

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7
Q

major classes of CCS agents

A
  • antimetabolites
  • bleomycin
  • epipodophyllotoxins
  • taxanes
  • epothilones
  • vinca alkaloids
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8
Q

major classes of CCNS agents

A
  • alkylating agents
  • anthracyclines
  • dactinomycin
  • mitomycin
  • camptothecins
  • platinum analogs
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9
Q

types of resistance to anticancer drugs

A
  • primary resistance

- acquired resistance

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10
Q

what causes primary resistance?

A

genomic instability

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11
Q

what is primary resistance?

A

use anticancer drug for the first time and it does not work

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12
Q

what is acquired resistance?

A

use anticancer drug and it works and after a while it stops working

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13
Q

what is multidrug resistance?

A

resists two or more drug classes

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14
Q

what is single drug resistance?

A

resists 1 drug class

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15
Q

which drug resistance (multidrug or single) is harder to treat?

A

multidrug

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16
Q

what causes multidrug resistance?

A

upregulation of active efflux pumps.

  • increased expression of MDR1 gene - results in more p-glycoproteins involved in efflux
  • MRP1 (multidrug resistance protein 1) increases resistance to natural product cancer drugs (vinca alkaloids, taxanes, anthracyclines) and acts as a drug export pump
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17
Q

what is the best way to treat MDR?

A

administer anticaner drug in combo with drug that inhibits active efflux pumps (ex. verapamil)

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18
Q

polyfunctional alkylating agents (CCS or CCNS)

A

CCNS

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19
Q

polyfunctional alkylating agents toxicity

A
  • nausea, vomiting, diarrhea
  • alopecia
  • bone marrow suppression (myelosuppression)
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20
Q

polyfunctional alkylating agents moa

A

form covalent bonds with macromolecules in DNA molecule to cause DNA damage

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21
Q

polyfunctional alkylating agents are highly _ and form bonds with nucleophiles in DNA

A

electrophilic

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22
Q

what are the ways polyfunctional alkylating agents form bonds with DNA?

A
  • Bifunctional Alkylating Drug (Crosslinker): the drug can form 2 covalent bonds (one bond with each strand of the DNA)
  • Monofunctional Alkylating Drug: the drug can form a single covalent bond with a single strand
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23
Q

mechanisms of acquired resistance to the alkylating agents

A
  • increase ability to repair DNA
  • decreased permeability of the drug
  • increased production of glutathione (inactivates alkylating agent via conjugation)
  • increased glutathione s-transferase activity (enzyme that catalyzes the glutathione conjugation reaction)
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24
Q

Cyclophosphamide

A

polyfunctional alkylating agents

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25
Q

What is the most widely used polyfunctional alkylating agents?

A

Cyclophosphamide

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26
Q

how is Cyclophosphamide administered?

A

orally

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27
Q

is Cyclophosphamide a prodrug?

A

yes, it requires activation by cyt P450 enzymes in the liver

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28
Q

what tissues does Cyclophosphamide effect?

A

everything except the liver because it is able to protect itself

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29
Q

what are the forms of Cyclophosphamide?

A

4-hydroxycyclophosphamide and aldophosphamide

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30
Q

what is the active form of Cyclophosphamide?

A

4-hydroxycyclophosphamide

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31
Q

what does aldophosphamide have that 4-hydroxycyclophosphamide not have?

A

aldehyde group (electrophilic)

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32
Q

what metabolites are aldophosphamide converted into?

A

phosphoramide mustard and acrolein

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33
Q

what metabolites are 4-hydroxycyclophosphamide converted into?

A

4-ketocyclo-phophamide and carboxy-phosphamide

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34
Q

which form of Cyclophosphamide produces active metabolites?

A

aldophosphamide

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35
Q

Antimetabolites (CCS or CCNS)

A

CCS

36
Q

Antimetabolites MOA

A

inhibit DNA and/or RNA synthesis by either binding tot he catalytic site of the enzyme or binding to an allosteric regulatory site

37
Q

Methotrexate

A

Antimetabolite

38
Q

Methotrexate MOA

A

inhibit purine synthesis and THF (in normal and cancer cells) by binding to dihydrofolate reductase

39
Q

Methotrexate forms _ after a glutamine residue is added.

A

methotrexate polyglutamate

40
Q

What is the function of methotrexate polyglutamate?

A
  • inhibit enzymes responsible for the formation of DNA and purines
  • act as intracellular storage form of methotrexate
41
Q

Methotrexate is a derivative of _

A

folic acid

42
Q

what does methotrexate inhibit?

A

dihydrofolate reductase

43
Q

what does methotrexate polyglutamate inhibit?

A
  • dihydrofolate reductase
  • thymidylate synthase
  • GAR transformylase
  • AICAR transformylase
44
Q

Methotrexate resistance

A
  • decreased drug transport into cell
  • decreased ability to synthesize methotrexate polyglutamates
  • synthesis of increased levels of intracellular DHFR
  • altered DHFR with reduced affinity for methotrexate
  • active effluxx though activation of MDRP170 glycoprotein transporter
45
Q

Methotrexate toxicities (regular dose)

A
  • bone marrow depression,
  • leucopenia
  • thrombocytopenia
46
Q

Methotrexate toxicities (high dose)

A
  • bone marrow depression

- nephrotoxicity (unable to excrete methotrexate due to nephrotoxicity)

47
Q

how to decrease toxicity to healthy cells? (regular dose)

A

Decrease intracellular concentration of methotrexate in normal cells by using leucovorin

48
Q

Leucovorin MOA

A

establish high concentration in normal cells

  • decrease influx of methotrexate
  • increase efflux of methotrexate
  • restore DNA and purine synthesis by being concerted into N5, N10-Methylenetetrahydrofolate
49
Q

how to decrease toxicity to healthy cells? (high dose)

A
  • use leucovorin

- use glucarpidase

50
Q

Glucarpidase MOA

A
  • decrease plasma levels by converting Methotrexate to inactive metabolites
51
Q

Where does Leucovorin affect levels of methotrexate?

A

intracellularly

52
Q

Where does Glucarpidase affect levels of methotrexae?

A

in plasma

53
Q

Why can you not give Leucovorin and Glucarpidase at the same time?

A

Glucarpidase is a substrate for Leucovorin. Glucarpidase should be given first, then Leucovorin 4-6 hours later

54
Q

Mercaptopurine (6-MP)

A

Antimetabolite

55
Q

Is Mercaptopurine a prodrug?

A

yes, the active form is 6-thioinosinic acid activated by HGPRT

56
Q

Mercaptopurine MOA

A

Compete with Inosinate (IMP) to inhibit the conversion of AMP and GMP (without, the cell cannot make DNA)

57
Q

Mercaptopurine MOR

A
  • downregulation of HGPRT

- upregulation of alkaline phosphatase (destroy drug)

58
Q

Mercaptopurine Toxicity

A
  • myelosuppression

- hepatotoxicity

59
Q

Mercaptopurine is an analog of _

A

inosine

60
Q 
What class of drugs can inactivate the active form of mercaptopurine? Give an example. 
What happens if you use these drugs together?
A

Xanthine Oxidase Inhibitors. Allopurinol.

Xanthine oxidase inhibitors (allopurinol) will enhance the activity of mercaptopurine

61
Q

If a xanthine oxidase inhibitor is used with mercaptopurine, what must be done?

A

the dose of mercaptopurine must be decreased

62
Q

Fluorouracil (5-FU)

A

Antimetabolite

63
Q

Fluorouracil (5-FU) is an analog of _

A

uracil

64
Q

Is fluorouracil (5-FU) a prodrug?

A

yes, it has 2 active forms 5-FdUMP and 5-FUTP

65
Q

What is fluorouracil used in combination with?

A

Levoleucovorin (S-enantiomer of Leucovorin)

66
Q

Fluorouracil MOA

A
  • 5-FUTP = inhibit RNA synthesis

- 5-FdUMP = inhibit DNA synthesis by inhibiting thymidylate synthase

67
Q

Fluorouracil Toxicity

A
  • myelosuppression

- neurotoxicity

68
Q

Fluorouracil Antidote for Overdose

A

Uridine Triacetate

69
Q

What is the active form of Uridine Triacetate?

A

Uridine Triphosphate

70
Q

Uridine Triacetate (Triphosphate) MOA

A
  • compete with 5-FUTP and win against UTP to restore RNA synthesis
71
Q

Will administering Uridine Triacetate fully eliminate toxicity from overdosing on 5-FU?

A

No, DNA toxicity will still occur.

72
Q

How early must Uridine Triacetate be given to someone who overdosed on 5-FU?

A

96 hours

73
Q

Vinca Alkaloids (Vinblastine, Vincristine, Vinorelbine)

A

Natural Products

74
Q

Vinca Alkaloids MOA

A

bind to tubules, causing depolymerization of microtubules, resulting in mitotic arrest in M phase

75
Q

Vinca Alkaloids (Vinblastine) Toxicity

A
  • myelosuppression
76
Q

Vinca Alkaloids (Vincristine) Toxicity

A
  • acute myelosuppression

- neurotoxicity

77
Q

Vinca Alkaloids (Vinorelbine)

A
  • myelosuppression
78
Q

Epipodophyllotoxins (Etoposide & Teniposide)

A

Natural Product

79
Q

Epipodophyllotoxins MOA

A

inhibit topoisomerase II and cause DNA damage (strand breakage) to arrest the cell in S-G2 phase which inhibits mitosis

80
Q

Epipodophyllotoxins Toxicity

A
  • myelosuppression
81
Q

Camptothecins (Topotecan & Irinotecan)

A

Natural Products

82
Q

Camptothecins MOA

A
  • inhibit topoisomerase I, resulting in DNA damage
83
Q

Camptothecins Toxicity

A
  • myelosuppression
84
Q

Taxanes (Paclitaxel, Docetaxel, Cabazitaxel)

A

CCS

85
Q

Taxanes MOA

A
  • bind to microtubule and cause polymerization of microtubles and leads to cell arrest in G2-M phase.
86
Q

Taxanes Toxicity

A
  • Arrhythmias
  • Myelosuppression
  • Peripheral sensory neuropathy

PMC II (2021) (4 decks)

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