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MEDSCI302 > 33 Drug Resistance > Flashcards

33 Drug Resistance Flashcards

1
Q

2 classes of resistance

DEFINE both

A

Intrinsic - present BEFORE the Tx

Acquired - develops DURING the Tx

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2
Q

3 reasons why ACQUIRED resistance occurs?

A
  1. Subpopulations survive and REGEN the tumor
  2. New mutations arising during Tx
  3. ADAPTIVE response to compensate
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3
Q

2 major FACTORS affecting resistance

DEFINE these

A

Pharmacokinetics - what BODY does to the drug

Pharmacodynamics - what CELL does to the drug

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4
Q

Explain pharmacokinetics

A

What the BODY does to the drug

= LIMITS amount of drug reaching the tumor

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5
Q

List some ASPECTS of pharmacokinetics

A

Metabolism
Absorption
Distribution
Degradation

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6
Q

List some ASPECTS of pharmacodynamics

A

What CELLS do to drugs

  • Influx
  • Cellular - activation, target, response
  • Efflux
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7
Q

What are some issues that can arise during DELIVERY

A

COMPLEX tissues must be crossed - stromal, BVs
Pharmacological SANCTUARY due to chaotic BVs
HYPOXIC areas - affects action of some drugs

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8
Q

Name the 5 CLASSES of how resistance arises

A

DAILO

  1. Inadequate IC concentrations
  2. Loss of TARGET protein
  3. ⬆️DNA repair
  4. ⬇️Apoptosis
  5. Other
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9
Q

Name 4 steps at which IC drug conc can be decreased

A
  1. Influx
  2. Efflux
  3. Enzymatic activation
  4. Enzymatic degradation
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10
Q

Why do many tumors OVERexp some inward transporters?

A

To SCAVENGE nutrients

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11
Q

How does resistance arise at influx step?

A

Transporters may be ABSENT or INACTIVE

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12
Q

Give examples of drugs that need specific INWARD transporters?

A

Ara-C (Nucleotide transporter)
Cisplatin (Cu transporter)
Nitrogen mustard (Choline transporter)

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13
Q

How do some cells develop ONE-STEP resistance to drugs with widely VARIABLE structures

A

P-glycoprotein transporter (ABC family)

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14
Q

What is the NATURAL function of P-glycoprotein transporters

A

ATP-dependent removal of TOXINS (esp. intestinal epi cells)

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15
Q

How do tumor cells use P-glycoprotein to create resistance?

A

UP-regulated into tumor cells to remove DRUGS

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16
Q

Examples of drugs pumped out by P-glycoprotein transporters?

A

Paclitaxel
Etopisides
Doxorubicin

17
Q

How does degradation of drugs cause resistance?

Give examples

A

Up-regulation of endogenous degradation enzymes

DPD for 5-FU
Cytidine deaminase for Ara-C

18
Q

Name drugs that need enzymatic ACTIVATION?

How can this lead to resistance

A

Ara-C needs cytidine KINASE

Resistance = ABSENT activating enzyme

19
Q

3 Tx-approaches to overcome IC drug conc resistance mechanisms

A

EEE
Engage - combo of pump-inhibitors AND drug
Evade - use drugs that BYPASS EFFLUX
Exploid - search for COLLATERAL sensitivity (alternative targets)

20
Q

Example of LOSS of TARGET protein causing resistance
What DRUGS does this affect the function of?
What is a Tx-approach to overcome this?

A

TopoII deficiency
Prevents activity of doxorubicin, daunorubicin, etopisides

Tx = use ALTERNATIVE drug

21
Q

Explain why ⬆️DNA repair causes resistance

A

Drugs that cause DNA dmg = activate S-phase checkpoint = APOP

⬆️DNA repair = resistance

22
Q

How to overcome resistance from ⬆️DNA repair

A

INHIBIT DNA repair

23
Q

How does ⬇️Apoptosis ARISE

A

Loss of Bak/Bax

Increase Bcl-2/Bcl-XL

24
Q

Tx-approaches to resistance from ⬇️apoptosis

A

∆BALANCE of apoptotic proteins to FAVOR apoptosis

siRNA/small molecules to bind and INHIBIT Bcl-2

25
Q

Name 5 “other” resistance mechanisms

A 
CCCST
CC checkpoints
Compartmentalisation
CSCs
Stress/growth signalling
TSG inactivation/oncogen activation
26
Q

Explain compartmentalisation

A

Transporters compartmentalise drugs into VESICLES

27
Q

Examples of stress/growth signalling that can cause resistance

A

PI3K/MAPK signalling

28
Q

What are CSCs?

A

Cancer Stem Cells

Small popn of cancer cells with the ability to SELF-RENEW and REGEN tumor

29
Q

3 suggested ORIGINS of CSCs?

A
  1. SC undergoes mutation
  2. Progenitor undergoes mutation
  3. Normal cell undergoes de-differentiation
30
Q

2 models of how CSCs cause resistance

A
  1. INTRINSIC - CSCs resistant to Tx SURVIVE and regen the tumor
  2. ACQUIRED - CSCs develop MUTATIONS to regen the tumor
31
Q

Explain how tumor HETEROGENEITY can contribute to resistance

A

Heterogeneity WITHIN and ACROSS tumors

=some can survive by chance and regen

32
Q

Name PRE-target resistance mechanisms for Cisplatin

A

Influx - loss/inactive Cu transporter
Efflux - up-regulated P-glycoprotein transporter, etc
Sequestration by cytoplasmic “scavengers”

33
Q

Name ON-target resistance mechanisms for Cisplatin

A

⬆️DNA repair of intra-strand x-links, esp by NER

Impaired MMR proteins = KO apoptosis

34
Q

Name POST-target resistance mechanisms for Cisplatin

Cisplatin has created intra-strand x-link already

A

∆BALANCE of apoptotic proteins to favor SURVIVAL

INC MAPK signalling

MEDSCI302 (8 decks)

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