Tissue distribution, antitumour activity and in vivo apoptosis induction by MEN10755 in nude mice O. Gonzalez-Paz a,1 , D. Polizzi a , M. De Cesare a , F. Zunino a , M. Bigioni b , C.A. Maggi b , S. Manzini b , G. Pratesi a, * a Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy b Menarini Ricerche S.p.A., 00040 Pomezia, Rome, Italy Received 7 July 2000; received in revised form 4 October 2000; accepted 5 October 2000 Abstract MEN10755 is a disaccharide analogue of doxorubicin (DXR) endowed with a broader spectrum of activity compared with DXR in a panel of human tumour xenografts. In an attempt to investigate the pharmacological basis of the improvement of therapeutic ecacy of the analogue, a comparative pharmacokinetic (tissue and tumour distribution) and pharmacodynamic (antitumoral activity 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 quanti®ed by high performance liquid chromatography (HPLC) with ¯uorimetric 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, kidney 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 ecacy, compared with DXR. The drug eects on tumour growth paralleled a marked activation of apoptosis. In conclusion, the pattern of tissue distribution and the pharmaco- kinetic behaviour were consistent with a better tolerability of the novel analogue which allowed a higher cumulative dose to be delivered. The superior therapeutic ecacy of the analogue over DXR, in spite of a reduced tumour accumulation, supports an increased tumour selectivity. # 2001 Elsevier Science Ltd. All rights reserved. Keywords: Anthracyclines; Biodistribution; Topoisomerase inhibitors; Apoptosis; MEN10755 1. Introduction Doxorubicin (DXR) still remains one of the most eective antitumour agents in clinical use today [1]. The ecacyofDXRhasstimulatedseveralstructure±activity relationship studies aimed at identifying critical mod- i®cations that might improve the therapeutic pro®le. A series of disaccharide anthracyclines has recently been synthesised and investigated [2,3], and one of them, MEN10755, was selected for clinical development on the basis of its promising preclinical pro®le [4,5]. The novel analogue exhibits improved ecacy related to the induction of apoptosis [4] and an enlarged spectrum of activity in human tumour xenografts [5]. Cellular pharma- cologystudieshaveindicatedthatMEN10755,compared with DXR, despite a lower uptake and accumulation in tumour cells, is endowed with an increased ability to induce DNA breaks and eventually apoptosis [4,6]. In an attempt to investigate the pharmacological basis of the improvement in the therapeutic ecacy of the analogue, a comparative pharmacokinetic and tissue distribution study of MEN10755 and DXR was carried out. The aims of the present study were: (a) to compare the in vivo distribution and accumulation of the two anthracyclines in tumour tissues and in selected organs (heart, liver and kidneys) of athymic nude mice bearing the human ovarian carcinoma xenograft A2780; (b) to investigate the ability of the two anthracyclines to inhi- bit tumour growth and to promote in vivo apoptosis. The results indicated that, in spite of a reduced drug accumulation in tumour tissue, the new analogue has an increased ability, compared with DXR, to induce apop- tosis and growth inhibition of the A2780 tumour. The reduction of tissue accumulation of MEN 10755, com- pared with DXR, was more marked in normal, than in tumour tissues. The pattern of distribution of the two drugs is consistent with an improved tolerability of 0959-8049/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved. PII: S0959-8049(00)00414-7 European Journal of Cancer 37 (2001) 431±437 www.ejconline.com * Corresponding author. Tel:. +39-2-239-0626; fax: +39-2-239- 0692. E-mail address: pratesi@istitutotumori.mi.it (G. Pratesi). 1 Present address: Department of Pharmacology, IRBM, 00040 Pomezia, Roma, Italy.