LIPOSOMAL ENCAPSULATION INCREASES THE ACTIVITY OF THE TOPOISOMERASE-IINHIBITOR TOPOTECAN

Topotecan, a topoisomerase I poison and water-soluble derivative of ca mptothecin, has shown promise in treating solid tumors; however, the d rug is unstable under physiological conditions and converts to an inac tive form within 30 minutes. Encapsulating topotecan in liposomes (LIP -TPT) minimizes inactivation. The efficacy of LIP-TPT was examined wit h a novel in vivo bioassay called ICE for In vivo Complexes of Enzyme. This bioassay uses antibodies to probe DNA for the presence of topois omerase I covalent complexes and thereby allows direct quantification of topoisomerase I driven DNA adducts in living cells. We report that LIP-TPT was three- to fourfold more effective than free TPT in stabili zing covalent topoisomerase I-DNA intermediates inside tumor cells. Th ese findings reveal that liposomal wrapping permitted effective delive ry of camptothecin derivatives to active enzyme in the nucleus of the cell.