chemotherapy

Question 1

what is the mechanism of action for multi-drug resistance?

Answer 1

Multi-drug resistance be attributed to mdr1 gene, p170 protein
o This is a glycoprotein with multiple ATP binding sites and cause drug efflux

Question 2

what is the curative treatment for testicular cancer?

Answer 2

Bleomycin, etoposide and cisplastin

Question 3

what is combination therapy? and what are its requirements?

Answer 3

combination therapy aims to decrease the probability of resistant strains arising during treatment. it increases overall toxicity towards the tumour, without increasing overall toxicity. drugs used must be:

• all active against that tumour
• with different mechanism of actions
• with different toxicity profiles

Question 4

how does L-asparginase work? and what is it used to treat?

Answer 4

it exploits a biochemical difference. it breaks down the non essential amino acid L-asparginine in circulation, starving the cells from it. it is used in childhood lymphocyte leukaemia

Question 5

what is Imantib meyslate? what is it used for?

Answer 5

it is a selective tyrosine kinase inhibitor, used in the treatment of CBR-ABL positive CML

Question 6

what is Bortezomib?

Answer 6

this is a proteasome inhibitor used in the treatment of multiple myeloma. it prevents the breakdown of IKb, which inhibits NF-Kb (a potent anti-apototic highly expressed in MM)

Question 7

how do the plant alkaloids work?

Answer 7

Vincristine
• Inhibit microtubule polymerisation
• This stops spindle formation and inhibits mitosis
Taxanes: paclitaxel and docelatel (taxols)
• They increase microtubule size
• Cell undergoes apoptosis once tubules increase beyond a certain size

Question 8

how does bleomycin work and what is its mechanism of resistance?

Answer 8

• Binds in DNA major groove
• FeII pocket
• Breaks DNA phosphate backbone: forms hydroxyl and superoxide radicals
• Prevent DNA replication and transcription
• Resistance: increased DNA repair and superoxide repair mechanism

Question 9

how does dactinomycin work? what is the mechanism for resistance?

Answer 9

• Binds in DNA minor groove
• Interacts with RNA polymerase
• Inhibits protein transcription

Question 10

how does doxorubicin and actinomycin work?

Answer 10

• Stabilise DNA polyermase, Topoismoerase II and DNA complex – this prevents DNA replication and keeps DNA in open configuration liable to attack

Question 11

how does cytarabine work?

Answer 11

• Recognised as a nucleoside by deoxycytidine kinase
o Phosphorylated and eventually added to DNA chain via DNA polymerase
o Terminates DNA elongation, because of extra moiety
• Resistance: decreased deoxycytidine kinase and increase in dCTP

Question 12

how does FCU work?

Answer 12

• Converted by thymidine phosphorylase, the product then complexes with tetrahydrofolate to inhibit thymidylate kinase
• This prevents DNA replication
• Resistance: decreased phosphorylase enzyme or affinity

Question 13

how does methotrexate work?

Answer 13

• Inhibits dihydrofolate reductase
• Glutamate addition increased in tumour cells
• Inhibits purine synthesis (At two points)
• Resistance: decreased transport, decreased affinity of enzyme or increased enzymatic expression

Question 14

how do the alklyating agents work?

Answer 14

Alkalyting agents: cross link-DNA
• Depend on the formation of a carbonium ion, a positive rich unstable ion. Preferentially attacks guanine
• Most alkalyting drugs are bifunctional
• Cisplastin: cross links guanine and adenine within the same strand
o This increases the rate of mutation and drives towards cellular death
Nitrosurease:
• Comustine and carmustine
• Those form a carbomylated protein, cytotoxic effect
• Are lipophilic and can cross the BBB
Resistance:
• Decreased permeability
• Increased gluthione
• Increased DNA repair
• Increased Metabolism

Question 15

what is tumour lysis syndrome?

Answer 15

this is a syndrome of metabolic complications associated with the release of cellular content due to their death

Question 16

what is growth fraction and how is it relevant to chemotherapy?

Answer 16

this is the fraction of actively dividing cells within a tumour, smaller tumours have higher growth fractions. chemotherapy is more active in tumours with higher growth fractions. but most tumours are not diagnosed until they’re beyond their optimal treatable window