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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
What is the most widely used polyfunctional alkylating agents?
Cyclophosphamide
26
how is Cyclophosphamide administered?
orally
27
is Cyclophosphamide a prodrug?
yes, it requires activation by cyt P450 enzymes in the liver
28
what tissues does Cyclophosphamide effect?
everything except the liver because it is able to protect itself
29
what are the forms of Cyclophosphamide?
4-hydroxycyclophosphamide and aldophosphamide
30
what is the active form of Cyclophosphamide?
4-hydroxycyclophosphamide
31
what does aldophosphamide have that 4-hydroxycyclophosphamide not have?
aldehyde group (electrophilic)
32
what metabolites are aldophosphamide converted into?
phosphoramide mustard and acrolein
33
what metabolites are 4-hydroxycyclophosphamide converted into?
4-ketocyclo-phophamide and carboxy-phosphamide
34
which form of Cyclophosphamide produces active metabolites?
aldophosphamide
35
Antimetabolites (CCS or CCNS)
CCS
36
Antimetabolites MOA
inhibit DNA and/or RNA synthesis by either binding tot he catalytic site of the enzyme or binding to an allosteric regulatory site
37
Methotrexate
Antimetabolite
38
Methotrexate MOA
inhibit purine synthesis and THF (in normal and cancer cells) by binding to dihydrofolate reductase
39
Methotrexate forms _ after a glutamine residue is added.
methotrexate polyglutamate
40
What is the function of methotrexate polyglutamate?
- inhibit enzymes responsible for the formation of DNA and purines - act as intracellular storage form of methotrexate
41
Methotrexate is a derivative of _
folic acid
42
what does methotrexate inhibit?
dihydrofolate reductase
43
what does methotrexate polyglutamate inhibit?
- dihydrofolate reductase - thymidylate synthase - GAR transformylase - AICAR transformylase
44
Methotrexate resistance
- 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
Methotrexate toxicities (regular dose)
- bone marrow depression, - leucopenia - thrombocytopenia
46
Methotrexate toxicities (high dose)
- bone marrow depression | - nephrotoxicity (unable to excrete methotrexate due to nephrotoxicity)
47
how to decrease toxicity to healthy cells? (regular dose)
Decrease intracellular concentration of methotrexate in normal cells by using leucovorin
48
Leucovorin MOA
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
how to decrease toxicity to healthy cells? (high dose)
- use leucovorin | - use glucarpidase
50
Glucarpidase MOA
- decrease plasma levels by converting Methotrexate to inactive metabolites
51
Where does Leucovorin affect levels of methotrexate?
intracellularly
52
Where does Glucarpidase affect levels of methotrexae?
in plasma
53
Why can you not give Leucovorin and Glucarpidase at the same time?
Glucarpidase is a substrate for Leucovorin. Glucarpidase should be given first, then Leucovorin 4-6 hours later
54
Mercaptopurine (6-MP)
Antimetabolite
55
Is Mercaptopurine a prodrug?
yes, the active form is 6-thioinosinic acid activated by HGPRT
56
Mercaptopurine MOA
Compete with Inosinate (IMP) to inhibit the conversion of AMP and GMP (without, the cell cannot make DNA)
57
Mercaptopurine MOR
- downregulation of HGPRT | - upregulation of alkaline phosphatase (destroy drug)
58
Mercaptopurine Toxicity
- myelosuppression | - hepatotoxicity
59
Mercaptopurine is an analog of _
inosine
60
``` What class of drugs can inactivate the active form of mercaptopurine? Give an example. What happens if you use these drugs together? ```
Xanthine Oxidase Inhibitors. Allopurinol. Xanthine oxidase inhibitors (allopurinol) will enhance the activity of mercaptopurine
61
If a xanthine oxidase inhibitor is used with mercaptopurine, what must be done?
the dose of mercaptopurine must be decreased
62
Fluorouracil (5-FU)
Antimetabolite
63
Fluorouracil (5-FU) is an analog of _
uracil
64
Is fluorouracil (5-FU) a prodrug?
yes, it has 2 active forms 5-FdUMP and 5-FUTP
65
What is fluorouracil used in combination with?
Levoleucovorin (S-enantiomer of Leucovorin)
66
Fluorouracil MOA
- 5-FUTP = inhibit RNA synthesis | - 5-FdUMP = inhibit DNA synthesis by inhibiting thymidylate synthase
67
Fluorouracil Toxicity
- myelosuppression | - neurotoxicity
68
Fluorouracil Antidote for Overdose
Uridine Triacetate
69
What is the active form of Uridine Triacetate?
Uridine Triphosphate
70
Uridine Triacetate (Triphosphate) MOA
- compete with 5-FUTP and win against UTP to restore RNA synthesis
71
Will administering Uridine Triacetate fully eliminate toxicity from overdosing on 5-FU?
No, DNA toxicity will still occur.
72
How early must Uridine Triacetate be given to someone who overdosed on 5-FU?
96 hours
73
Vinca Alkaloids (Vinblastine, Vincristine, Vinorelbine)
Natural Products
74
Vinca Alkaloids MOA
bind to tubules, causing depolymerization of microtubules, resulting in mitotic arrest in M phase
75
Vinca Alkaloids (Vinblastine) Toxicity
- myelosuppression
76
Vinca Alkaloids (Vincristine) Toxicity
- acute myelosuppression | - neurotoxicity
77
Vinca Alkaloids (Vinorelbine)
- myelosuppression
78
Epipodophyllotoxins (Etoposide & Teniposide)
Natural Product
79
Epipodophyllotoxins MOA
inhibit topoisomerase II and cause DNA damage (strand breakage) to arrest the cell in S-G2 phase which inhibits mitosis
80
Epipodophyllotoxins Toxicity
- myelosuppression
81
Camptothecins (Topotecan & Irinotecan)
Natural Products
82
Camptothecins MOA
- inhibit topoisomerase I, resulting in DNA damage
83
Camptothecins Toxicity
- myelosuppression
84
Taxanes (Paclitaxel, Docetaxel, Cabazitaxel)
CCS
85
Taxanes MOA
- bind to microtubule and cause polymerization of microtubles and leads to cell arrest in G2-M phase.
86
Taxanes Toxicity
- Arrhythmias - Myelosuppression - Peripheral sensory neuropathy

PMC II (2021) (4 decks)

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