Tissue distribution, antitumour activity and in vivo apoptosis induction by MEN10755 in nude mice

MEN10755 is a disaccharide analogue of doxorubicin (DXR) endowed with a bro ader spectrum of activity compared with DXR in a panel of human tumour xeno grafts. In an attempt to investigate the pharmacological basis of the impro vement of therapeutic efficacy of the analogue, a comparative pharmacokinet ic (tissue and tumour distribution) and pharmacodynamic (antitumoral activi ty and ability to induce apoptosis) study of MEN10755 and DXR was performed in athymic nude mice bearing a human ovarian carcinoma xenograft (A2780). Drug level was quantified by high performance liquid chromatography (HPLC) with fluorimetric detection after a single intravenous (i.v.) injection of 7 mg/kg of MEN10755 or DXR. The results indicated a reduced accumulation of MEN10755 compared with DXR in all tissues investigated (tumour, heart, kid ney and liver). The reduction was more marked in normal than tumour tissues . Moreover, in spite of the reduced drug uptake by tumour tissues, the new disaccharide anthracycline given in its optimal regimen showed an enhanced antitumour efficacy, compared with DXR. The drug effects on tumour growth p aralleled a marked activation of apoptosis. In conclusion. the pattern of t issue distribution and the pharmacokinetic behaviour were consistent with a better tolerability of the novel analogue which allowed a higher cumulativ e dose to be delivered. The superior therapeutic efficacy of the analogue o ver DXR, in spite of a reduced tumour accumulation, supports an increased t umour selectivity. (C) 2001 Elsevier Science Ltd. All rights reserved.