DNA-interactive anticancer agents - Intercalating agents Flashcards
What do intercalating agents generally look like?
Consist of 3-4 fused aromatic rings
How does the intercalating agent subclass, Anthracycline, work?
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)
Doxorubicin - other possible mechanisms, in addition to general anthracycline mechanism. Mention indications, and PK profile
- 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
what else can doxorubicin generate that is important for its actiivity?
free radicals. They damage cancer DNA
what are Phenoxazines, and give an example. What problems accompanies the drug?
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.
