DNA-interactive anticancer agents - Alkylating agents

Question 1

How do alkylating agents work?

Answer 1

work by alkylating the N2 of guanine in the minor groove thus forming bulky adducts which block DNA processing

Question 2

Ecteinascidin-743 (Trabectidin) works in two ways…

Answer 2

they have a unique chemical mechanism, and a Biological mechanism

Question 3

what is Ecteinascidin-743 (Trabectidin) unique chemical mechanism

Answer 3

• Covalent binding to the N2 position of guanine in the minor groove of DNA causing double helix to bend towards the major groove. All other DNA binding agents cause a bend towards their site of action with DNA rather than away from it.

Question 4

Ecteinascidin-743 (Trabectidin) structure

Answer 4

3 fused tetrahydroisoquinoline rings (subunits A-C)
Subunits A and B: provide the structural framework for covalent interaction.
Subunit C: protrudes from the DNA complex and interacts with adjacent proteins – accounts for cytotoxicity

Question 5

Ecteinascidin-743’s Biological mechanism is split into two. It can either

Answer 5

Inhibit repair OR Induces apoptosis

Question 6

How does Ecteinascidin-743 inhibit repair biologically

Answer 6

Drug causes inhibition of transcription dependent repair pathways (TC-NER)

TC-NER pathway: recognizes DNA damage and recruits various nucleases at the site of DNA damage for repair.

Drug traps the nucleases in a malfunctioning adduct complex which induces irreparable single strand breaks in DNA.

Question 7

How does Ecteinascidin-743 induce apoptosis

Answer 7

Induces strong perturbation of cell cycle causing a delay of cell progression from G1 to G2, inhibition of DNA synthesis, cell cycle arrest in G2 phase which results in p53 independent apoptosis.

Can also cause selective inhibition of transcriptional activation of genes involved in cell proliferation.

Question 8

So, Ecteinascidin-743 can induce apoptosis, and inhibit cell repair. What other biological role can it perform?

Answer 8

Inhibits MDR1

Selectively inhibits transcriptional activation of multi-drug-resistance (MDR1) gene in human sarcoma cells.

Question 9

Ecteinascidin-743 indication in clinic, and adverse reactions

Answer 9

Treatment of sarcomas (soft tissue)
Mostly well tolerated
Adverse events: not severe/treatment limiting
non-cumulative haematological and hepatic toxicities
transient/reversible elevation of hepatic enzymes
nausea & vomiting