After GlaxoSmithKline received final FDA approval for topotecan on 15 October 2007, it became the first topoisomerase I inhibitor for oral use.

UBE3A is located on chromosome 15 and the paternal copy for the gene is genetically imprinted and is silenced by an antisense RNA transcript.

Topotecan inhibits topoisomerase I restoring UBE3A levels to wild-type range in cultured mince neurons.

[15] When tested on mice in vivo, topotecan affected the hippocampus, striatum and cerebral cortex but not the cerebellum unless a higher dose was administered (21.6 micrograms/hour for five days).

Topoisomerase-I is a nuclear enzyme that relieves torsional strain in DNA by opening single strand breaks.

[20] Once topoisomerase-I creates a single strand break, the DNA can rotate in front of the advancing replication fork.

[21] Topotecan's active lactone form intercalates between DNA bases in the topoisomerase-I cleavage complex.

[22] The binding of topotecan in the cleavage complex prevents topoisomerase-I from religating the nicked DNA strand after relieving the strain.

Administration of topotecan down-regulates its target, topoisomerase-I; therefore, it is dosed to maximize efficacy and minimize related toxicity.