DNA-interactive anticancer agents - Intercalating agents

Question 1

What do intercalating agents generally look like?

Answer 1

Consist of 3-4 fused aromatic rings

Question 2

How does the intercalating agent subclass, Anthracycline, work?

Answer 2

Planar anthraquinone nucleus attached to an amino sugar (4 fused rings)

• The planar system inserts itself between DNA base pairs perpendicular to the long axis of double helix
• The amino acid portion gives the adduct stability through hydrogen bonding interactions with sugar phosphate backbone.
• Other side chains that are rich in H bonding functionalities are also positioned in the DNA minor or major groove to give further stability to the adduct
• This intercalation process can interfere with DNA processing (transcription)

Question 3

Doxorubicin - other possible mechanisms, in addition to general anthracycline mechanism. Mention indications, and PK profile

Answer 3

• Anthracyclines can form complexes with topoisomerase enzymes and DNA which can lead to strand breaks
• Drugs can also bind to cell membranes which might alter membrane fluidity, ion transport and biochemical equilibria.
• Treat acute leukemia, lymphomas, solid tumors (breast, lung, thyroid), soft tissue carcinoma
• Given by injection into fast running infusion
• At 21 day intervals
• Take care to avoid local extravasation : severe tissue necrosis
• Toxic effects: GI effects, myelosuppression, alopecia, mucositis
• Largely excreted by biliary tract

Question 4

what else can doxorubicin generate that is important for its actiivity?

Answer 4

free radicals. They damage cancer DNA

Question 5

what are Phenoxazines, and give an example. What problems accompanies the drug?

Answer 5

They have 3 fused 6 membered rings. Central ring has oxygen and nitrogen heteroatoms

E.g Dactinomycin - exhibits a Preferential intercalation between GC base pairs interacting with N2-amino groups

IV: paediatric cancers

Side effects:

• Cardiotoxicity less prominent
• GI effects
• Myelosuppression

Tumor resistance: reduced uptake and active transport of drug out of tumor cells.