Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Chemotherapy intercalation > Lecture 15 Chemotherapy targeting DNA, replication, transcription and cell division > Flashcards

Lecture 15 Chemotherapy targeting DNA, replication, transcription and cell division Flashcards

1
Q

Explain how curative chemotherapy is used for solid tumours

A

Tumour is initially reduced via surgery/radiation

Then chemotherapy is used after the clinical signs are gone in order to reduce chances of relapse

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Explain how curative chemotherapy is used for disseminated cancers e.g. leukemia

A

chemo is 1st line therapy

combination therapy used to reduce the chance of drug resistance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Explain how palliative chemotherapy is used

A

used to extend survival and reduce symptoms but patient will eventually die

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

what is meant by the phrase ‘cell cycle specific drugs’?

A 
effective for high growth fraction malignancies i.e. rapidly cycling 
examples:
antimetabolites 
bleomycin peptide antibiotics
vinca alkaloids
etoposide
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

what is meant by the phrase ‘non cell cycle specific drugs’?

A 
effective for low growth fraction malignancies such as solid tumours as well as high growth malignancies
Examples:
alkylating agents
antibiotics
cisplatin
nitrosoureas
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

generally how do anti-metabolites work?

A

inhibit/interfere with DNA/RNA synthesis

specifically S phase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Name examples of anti-metabolites

A 
Methotrexate
6-mercaptopurine
5-flurouracil
Gemcitbine
Cytarabine
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Explain how methotrexate works

A

targets cells in S phase
structurally related to folic acid
competitively inhibits dihydrofolate reductase (DHFR)
retained in cell as MTX-polyglutamate compounds
therefore inhibits production of precursor for amino acids/DNA nucleotides = no DNA
[see slide for pathway inhibited]

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is methotrexate used for?

A

used against acute lymphoblastic leukaemia (ALL), breast cancer, head and neck cancer
low doses used to treat rheumatoid arthritis/psoriasis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

In what form is methotrexate given?

A

High doses given intramuscularly (IM), intravenously (IV), intrathecally (into the brain and CNS as poor CNS penetration)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is the importance of hydration with methotrexate?

A

Adequate hydration must be sustained at high doses to avoid renal toxicity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Explain how 6-mercaptopurine works

A

Purine analogue
Drug phosphorylated by the enzyme Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) to produce thio-IMP
this inhibits purine biosynthesis =
incorporated into DNA and RNA leading to non-functional molecules
Thio-IMP also inhibits the production of AMP/XMP which are precursor molecules for nucleic acid biosynthesis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is 6-mercaptopurine used for?

A

used in maintenance of remission in Acute Lymphoblastic leukaemia (ALL)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Explain how resistance to 6-mercaptopurine can occur

A

resistance due to lack of Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
or increased drug metabolism in individual

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Explain how 5-flurouracil works

A

Modified pyrimidine Drug is phosphorylated and competes with dUMP for thymidylate synthetase = inhibits production of dTMP (needed for DNA synthesis and cell growth)
Depletes intracellular nucleotide pools

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Explain why 5-flurouracil and methotrexate are given together

A

The enzyme thymidylate synthetase also requires tetrahydrofolate therefore giving methotrexate will inhibit the ligand and reduce the function of the enzyme to produce nucleotides
synergistic effect

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

In what form is 5-flurouracil given?

A

IV

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

How does gemcitabine work?

A

analogue of deoxycytidine

incorporates into DNA and stops DNA synthesis via acting like a stop codon due to its structure

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What can gemcitabine be used to treat?

A

used in treatment of advanced metastatic pancreatic cancer as a way to prolong the lifespan of the patient but not cure

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

In what form is gemcitabine given?

A

IV

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

How is gemcitabine excreated?

A

deaminated to non-toxic product (difluorodeoxyuridine)

excreted in urine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What is the main side effect of gemcitabine?

A

myelosuppression is a major side-effect

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

How does cytarabine work?

A

chain terminator of DNA synthesis by incorporating itself into DNA and stopping translation
AraCTP also inhibits DNA polymerases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

In what form is cytarabine given?

A

IV

Intrathecal due to poor CNS penetration

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What is the main side effect of cytarabine

A

myelosuppression

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Generally how does antibiotic chemotherapy work?

A

bind to DNA, disrupt function of DNA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Name examples of antibiotic chemotherapy

A 
Dactinomycin
Anthracyclines
Alkylating agents
Platinum coortination complexes
Topoisomerase inhibitors
Telomerase inhibitors
Vinca alkaloids
Taxanes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

How does dactinomycin/actinomycin D work?

A

Binds to DNA (minor groove)and interferes with transcription and DNA replication
may also cause DNA strand breaks

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

Resistance to dactinomycin is caused by what?

A

P-glycoprotein

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

In what form is dactinomycin given?

A

IV

Though poor penetration into CNS

31
Q

How is dactinomycin excreted?

A

bile

urine

32
Q

Name examples of anthracyclines

A

Doxorubicin Daunorubicin

33
Q

How do anthracyclines work?

A

intercalate into DNA
generate free radicals that break DNA strands - interacts with O2 which produces superoxide ions and hydrogen peroxide = single strand breaks in DNA
can also interfere with DNA breakage repair system
target cells in S and G2 phases

34
Q

What conditions are treated with anthracyclines?

A

Used in combination , for breast, lung, leukaemia

35
Q

What is the name of the drug that is not an anthracycline but acts via a similar mechanism

A

Bleomycin

36
Q

What form is anthracycline given as?

A

IV

Poor penetration into CNS

37
Q

How are anthracyclines excreted

A

bile

urine

38
Q

Name examples of alkylating agents

A

Mechlorethamine, cyclophosphamide, ifosphamide, carmustine, dacarbazine, temezolomide

39
Q

How do the alkylating agents work?

A

transfer alkyl groups to DNA
Interfears with the link between G-G
are mutagens (possible problem as could cause new mutations)
target rapidly dividing cells to inhibit DNA replication

40
Q

Which enzyme is involved in the activation of alkylating agents?

A

cytochrome P450

41
Q

What conditions are treated with alkylating agents?

A

used in combination to treat solid and lymphatic tumours

42
Q

In what form is alkylating agents given?

A

IV

Oral - drug crosses the BBB

43
Q

How are alkylating agents excreted?

A

urine

44
Q

What are examples of platinum coordination complexes?

A

Cisplatin, carboplatin, oxaliplatin

45
Q

How does platinum coordination complexes work?

A

Mechanism of action similar to alkylating agents
Binds to double stranded DNA and forms intra- and inter-strand crosslinks
Interferes with DNA replication and transcription
Act in G1 and S phases

46
Q

What conditions are treated with platinum coordination complexes?

A

Cisplatin used in solid tumours e.g.testicular cancer (with VBL and bleomycin) and single agent in bladder cancer
Oxaliplatin used in advanced colorectal cancer

47
Q

In what form is platinum coordination complexes given?

A

IV

Poor penetrance into CNS

48
Q

How are platinum coordination complexes excreted?

A

urine

49
Q

Name examples of topoisomerase I inhibitors

A

Topotecan

irinotecan

50
Q

How do topoisomerase I inhibitors work?

A

S phase specific
Topo I makes reversible single-stranded breaks (knicks) in the DNA duplex to allow it to unwind
Topotecan and irinotecan bind to enzyme-DNA intermediate, preventing re-ligation/reformation of DNA strand

51
Q

In what form are topoisomerase I inhibitors given?

A

IV

52
Q

What conditions are treated with topoisomerase I inhibitors?

A

Topotecan used against metastatic ovarian cancer and lung cancer
Irinotecan used against colon and rectal cancer along with 5-FU and leucovorin

53
Q

How is topoisomerase I inhibitors excreted?

A

urine

54
Q

What is a side effect of topoisomerase I inhibitors?

A

Myelosupression - specifically topotecan

55
Q

Name examples of topoisomerase II inhibitors

A

Daunorubicin
Doxorubicin
Etoposide
teniposide

56
Q

How do topisomerase II inhibitors work?

A

S phase specific

Daunorubicin and Doxorubicin intercalate into DNA, preventing topo II – catalysed breakage/reunion of DNA strands therefore breaks not repaired
Etoposide, teniposide bind to transient cleavable form of enzyme-DNA complex leading to double-strand breaks in DNA.

57
Q

What conditions are treated with topoisomerase II inhibitors?

A

Etoposide used in combination with bleomycin and cisplatin for testicular cancer

Teniposide used for ALL, gliomas and neuroblastomas

58
Q

In what form are topoisomerase II inhibitors given?

A

IV (both teniposide and etopside) or oral (etoposide)

59
Q

How are topoisomerase II inhibitors excreted?

A

urine

60
Q

What is the function of telomerase inhibitors?

A

replicate the end of chromosomes in order to keep the DNA functional
Binds to RNA in stem cells/cancer cells and works via reverse transcription

61
Q

How do telomerase inhibitors work?

A

Direct enzyme inhibitors e.g. Imetelstat (Geron; Phase I trial)
Modified oligonucleotides – compete for binding with telomerase RNA

62
Q

Name examples of vinca alkaloids

A

Vincristine (VX)

vinblastine (VBL)

63
Q

How do vinca alkaloids work?

A

block mitosis in metaphase
Bind to tubulin and inhibit its polymerisation into microtubules
Induce spindle dysfunction
Chromosome segregation therefore blocked

64
Q

What are side effects/problems associated with vinca alkaloids?

A

Drug resistance a problem
VX is neurotoxic inducing peripheral neuropathy
VBL is myelosuppressant

65
Q

What types of tumours are vinca alkaloids used for?

A

Used against rapidly dividing tumours, in combination with other anticancer drugs

66
Q

Name examples of taxanes

A

Paclitaxel

Docetaxel

67
Q

How do taxanes work?

A

Active in the G2/M phase of the cell cycle
Taxanes bind to tubulin and promote polymerization but stabilise (“freeze”) the microtubules preventing chromosome segregation - spindles are not formed

68
Q

What conditions are treated with taxanes?

A

advanced ovarian and breast cancers and non-small cell lung cancer

69
Q

What are the side effects/problems associated with taxanes?

A

Dose-limiting toxicity is neutropenia

Drug resistance is a problem

70
Q

What can be used to reverse the side effect of neutropenia?

A

Granulocyte colony –Stimulating Factor (Filgrastim)

71
Q

What is drug resistance in chemotherapy drugs mediated by

A

mediated by P-glycoprotein
ATP-dependent membrane transport protein (ABC transporter family)
present on most cells but gene amplification can take place in cancer cells

72
Q

What drug can be used to inhibit P-glycoprotein?

A

Verapamil - closes the channel so that the drug cannot leave the cell

73
Q

How can the problem of myelosupression from chemotherapy be treated?

A

can remove patient’s bone marrow, treat then re-implant - must keep the patient in sterile conditions
can mitigate toxicity in certain cases e.g. leucovorin given with methotrexate

Chemotherapy intercalation (14 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions