Brainscape's Knowledge GenomeTM

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


See full index

Drug Treatment of Disease > Cancer (2) Anticancer Agents 1 > Flashcards

Cancer (2) Anticancer Agents 1 Flashcards

1
Q

Main approaches to cancer treatment

A

Surgery
Irradiation
Chemotherapy

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

Cancer cells characterised by

A

Invasiveness
>loss of recognition of normal restraints
>expression of matrix-degrading enzymes

Ability to metastasise
>secondary tumours distant from primary
>often through lymphatics

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

Tumour suppressor genes

A

Act as sentinels to detect DNA damage
E.g. p53
>gene most commonly mutated in human cancer (>50% cancers)
>if DNA damaged, p53 arrests replication

DNA damage > loss of p53 deactivation > cell cycle arrest > dna repair or irreversible dna damage >apoptosis

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

If p53 altered through mutation (loss of function)

A

DNA damage goes unchecked
>no repair
>loss of apoptotic removal of cells whose DNA is irreparably damaged

> Other mutations in cells will accumulate
cancer

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

Protooncogenes

A

Normally responsible for cell growth and differentiation

Mutation leads to abnormal growth

Exmaples
>growth factors,
>growth factor receptors
>Members of growth factor signalling pathways
>cell cycle transducers
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

E.g. Ras gene

A

Codes for Ras, a guanine nucleotide binding protein (GTPase)

  • Ras-GTP = “on”
  • Ras-GDP = “off”

Common component of many cell signalling pathways leading to proliferation

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

Mutations in Ras

A

Found in 20-30% human tumours

Reduced inactivation of Ras
>reduced intrinsic GTPase ability
>reduced susceptibility to GTPase activating proteins

Ras-GTP becomes predominant form
>constitutively activated

Cell divides in absence of growth factor binding

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Principles of cancer chemotherapy

A

Exploit a difference between normal and tumour cells
>rate of growth (traditional)
>some other aspect of biology (contemporary)

Tumour growth may be exponential
>need near total removal of tumour cells for effective treatment

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

Log cell kill model

A

Cell destruction is first order i.e. constant fraction of cells killed
E.g. 10^12 cells in tumour, kill 99.99%
>10^8 cells after 1 cycle of treatment
>10^4 cells after 2 cycles

Side effects requires intermittent dosing

Intermittent dosing allows for
>tumour regrowth
>development of resistant cells

Resistant cells grow exponentially regardless of treatment

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

Principles of cancer chemotherapy

Therapeutic window

A

In practice, growth limited by blood supply to tumour
>angiogenesis
>current new target in therapy

“Resting” cells may be resistant to treatment
>tumour stem cells

Therapeutic window often non-existent
>dose for treatment is same or greater than dose giving side effects

> > Limits dose and duration of therapy

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

Principles of cancer chemotherapy

Selective toxicity

A

If selective toxicity is via rapid cell division

Toxicity will result from effects on other fast-dividing cells
>bone marrow suppression
>impaired wound healing
>hair loss
>gut epithelium damage
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Classes of anticancer drugs

A 
Cytotoxic drugs
>alkylating agents
>antimetabolites
>anthracyclines
>microtubule inhibitors

Drugs that exploit other aspects of tumour biology
>Hormones and related agents
>antiangiogenesis agents
>kinase inhibitors

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

Cytotoxic anticancer drugs

A

Kill cells
>damage DNA
>interfere with DNA synthesis
>mitosis

Cells that are traversing cell cycle more frequently
>i.e. rapidly dividing cells will be most affected

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

Alkylating agents

A

Bind covalently with nucleophilic cell components
>N7 and O6 of guanine

Many are bifunctional
>cross linking of DNA (intrastrand)

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

Cisplatin (alkylating agent)

A

Discovered by chance while examining effects of electric currents on bacteria
>bacteria at platinum electrode had reduced DNA synthesis

Used for testicular and ovarian cancer
>revolutionised treatment of testicular cancer in 1970s

Causes intrastrand cross linking
>denaturation of DNA

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

Cisplatin (MOA)

A

Two leaving groups (Cl)

Bis-alkylation causes intrastrand crosslinks between adjacent guanine residues
>denaturation of DNA

Trans-isomer inactive (although can still bind to DNA, cannot form crosslinks)

17
Q

Cisplatin side effects

A

Nephrotoxic, neurotoxic
>causes dose-limiting sensory neuropathy (numbness)

Severe nausea and vomiting
>enhances nephrotoxicity
>can be controlled with ondansetron
(serotonin receptor 5HT3 antagonist)

18
Q

Antimetabolites

A

Inhibit DNA synthesis pathways
>methotrexate
>5-flutouracil

19
Q

Synthesis of thymidylate

A

Folate > dihydrofolate > tetrahydrofolate

Tetrahydrofolate + 2-deoxy uridylate (dUMP) = 2-deoxy thymidylate (dTMP)
- enzyme is thymidylate synthetase
= required for new DNA synthesis

20
Q

Methotrexate

A

Inhibits enzyme dihydrofolate reductase
(converts folate into dihydrofolate into tertahydrofolate - same enzyme)

Cells > “thymineless” death

21
Q

Methotrexate MOA

A

Inhibts dihydrofolate reductase (DHFR)

Has higher affinity for DHFR than natural substrate (folate)
>prevents generation of tetrahydrofolate (FH4)
(FH4 is a cofactor in thymidylate production)

> Blocks thymidylate production
disrupts DNA synthesis

22
Q

Methotrexate administration

A

Low lipid solubility, therefore does not cross BBB

Get bone marrow depression, gut epithelium damage

Resistance common (with all cytotoxic drugs)
>use high dose + folate
>why give folate?
>>in many tumour types, differences in mechanisms uptake of folate into cell
23
Q

5-Fluorouracil

A

Converted to false nucleotide
>5-fluorodeoxyuridine monophosphate (FdUMP)

FdUMP directly inhibits thymidylate synthetase
>inhibition of DNA synthesis

Administered with folate
>increases toxicity, as inhibited enzyme is a complex with FdUMP and cofactor derived from folate (make sure cell has enough folate to carry out this pathway to get cell cytotoxicity with the false FdUMP nucleotide)

Side effects:
>Gut damage and bone marrow toxicity

24
Q

Anthracyclines

A

E.g. doxorubicin

Binds to DNA by interaclation
>sliding between base pairs

Affects the enzyme topoisomerase II
>required for DNA unwinding and rewinding to relieve supercoiling
>nicks and rejoins DNA

25
Q

Doxorubicin

A

Stabilises DNA/topoisomerase II complex
>DNA remains nicked

Cardiotoxic
>generates free radicals which damage cardiac tissue

Can be reduced by co-administration of dexrazoxane
>Fe chelator
>reduced Fe2+ mediated free radical production

26
Q

Microtubule inhibitors

A

Microtubules
>hollow cylindrical fibres of alpha and beta tubulin
>involved in separation of diploid pairs of chromosomes

Exhibit dynamic instability
>length dependent on relative rates of polymerisation versus depolymerisation (GTP-to-GDP dependent)

27
Q

Paclitaxel

A

Paclitaxel (microtubule inhibitor)

Derived from yew tree bark

Promotes polymerisation and inhibits depolymerisation
>stabilise microtubules in polymerised state
>prevents spindle formation

Bone marrow suppression and neurotoxicity
>microtubules required for axonal transport

Drug Treatment of Disease (14 decks)

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