Week 6 - Drug Resistance

Question 1

Name 3 cancers that are commonly cured chemosensitive

Answer 1

ALL, Burkitts Lymphoma, Germ cell tumour, Hodkins lymphoma

Question 2

Name 3 cancers that are moderately chemosensitive

Answer 2

Ovarian, Breast, AML

Question 3

Name 3 cancers that are resistant and not very chemosensitive

Answer 3

NSCLC, Melanoma, pancreatic, renal, glioma, mCRC

Question 4

What are some cellular mechanisms of drug resistance (7)

Answer 4

Decreased - intracellular drug concentration

Increase metabolism and detoxification

Altered expression of target proteins

Enhanced DNA repair

Decrease in drug activation

Salvage pathways

Failure to engage apoptosis

Question 5

What is the name of the protein that is associated with a decrease in intracellular drug concetration?

Answer 5

P-Gp … Permeability Glycoprotein.

it mediates resistance to anti-cancer drugs.. as it is a wide xenobiotic transporter. Resistance to methotrexate (DMARD) via RFC… the reduced folate carrier.

Question 6

in terms of increased metabolism and detoxification of drugs, what drugs does this happen to the most?

Answer 6

Platinum based therapy,

• Thiols (gluthathione transferasea and tripeptides)
• rubicins

Look at chlorambucil conjugation with GSH by GST alpha

Question 7

what are 3 actions of enhanced DNA repair in cancer?

Answer 7

DNA nucleotide excision repair

0^6alkylguanine repair

DNA MMR — causes resitance, and tolerance

Question 8

What are the name of the dimers that act to stabilise lesions and recruit DNA-Protein Kinase and help align and joing DNA back together?

Answer 8

Ku - dimers

Question 9

what 4 target proteins are mainly involved in the altered expression of anti-cancer agents

Answer 9

DHFR - dihydrofolate reductase

Thymidylate synthase

Altered tubulin

Altered topoisomerase

Question 10

Name some methods of decrease drug activation/slavage pathways

Answer 10

Cytochrome P450 deficiencyes, HGPRT deficeincey, Deoxycytidine kinase deficiency..

these basically dont allow for the correct metabolism of the drug.. its the cancers way of evading.

Question 11

name some mulitple resistant methods to single agents

Answer 11

Cisplatin - reduction in membrane transport, increase in DNA repair, Increase in GS, increase tolerance of teh drug

Methotrexate, defect in the RFC - reduced folate carrier. problem within FPGS

Etoposide - increase drug effux due to P-glycogrptein, and alrtered topoisomerase.

Question 12

it is important to note that there is aspects of multidrug resistance too. transporter efflux pumps, increased gluthathione, topoisomerase, loss of p53… less apoptosis.

Answer 12

.

Question 13

What ion on the Cis platin molecule leaves the cells in order for the groups to be displaced on Cisplatin intracellularly?

Answer 13

Chlorine ( chloride ions)

Question 14

How can we overcome drug resistance?

Answer 14

cytokinetic resitance
biochemical modulation of the drug resistance
reduce the host toxicity (has its errors)

Question 15

How can we overcome cytokinetic resistance?

Answer 15

Increase dose intensity… butneed densitisation regimes also

combination chemotherapy

change of Tx to Novel Tx

Question 16

Comibination chemo.. what are some of the principles?

Answer 16

• active when used alone
• have different mechanism of action
• minimally overlapping toxicities

Question 17

name some examples of combination chemotherapy

Answer 17

• BEP day case
• CHOP for diffuse large cell lymphoma
• FOLFIRINOX for pancreatic cancer

Question 18

• dont really go too much into detail on biomodulation.

Answer 18

.

Question 19

what examples can you give to reduce host toxicity?

Answer 19

altering the route of the drug administartion - e.g. Intraperitoneal cisplatin in Ovarian cancer.

Use of Haemopoetic growth factors

Peripheral stem cell rescue

Question 20

Name some novel approaches in tackling drug resistance

Answer 20

ADEPT, GDEPT… modulation of signal transduction pathways