Elsevier

European Journal of Cancer

Volume 37, Issue 3, February 2001, Pages 431-437
European Journal of Cancer

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

https://doi.org/10.1016/S0959-8049(00)00414-7Get rights and content

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 efficacy 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 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, 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 efficacy, compared with DXR. The drug effects on tumour growth paralleled a marked activation of apoptosis. In conclusion, the pattern of tissue distribution and the pharmacokinetic behaviour were consistent with a better tolerability of the novel analogue which allowed a higher cumulative dose to be delivered. The superior therapeutic efficacy of the analogue over DXR, in spite of a reduced tumour accumulation, supports an increased tumour selectivity.

Introduction

Doxorubicin (DXR) still remains one of the most effective antitumour agents in clinical use today [1]. The efficacy of DXR has stimulated several structure–activity relationship studies aimed at identifying critical modifications that might improve the therapeutic profile. 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 profile 4, 5. The novel analogue exhibits improved efficacy related to the induction of apoptosis [4] and an enlarged spectrum of activity in human tumour xenografts [5]. Cellular pharmacology studies have indicated that MEN10755, 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 efficacy 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 inhibit 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 apoptosis and growth inhibition of the A2780 tumour. The reduction of tissue accumulation of MEN 10755, compared 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 MEN 10755 as documented by the appreciable increase of tolerated doses of the analogue 4, 5.

Section snippets

Animals and drugs

Female athymic Swiss nude mice (Charles River, Calco, Italy), 10–12 weeks of age, were used throughout the study. Mice were maintained in laminar flow rooms, according to the United Kingdom Coordinating Committee on Cancer Research guidelines [7]. Experimental protocols were approved by the Ethics Committee for Animal Experimentation of the Istituto Nazionale Tumori.

DXR was supplied by Pharmacia-UpJohn (Milan, Italy). MEN10755 (7-(0-4′-0-alpha-l-daunosaminyl-2′-deoxy-alpha-l

Tissue distribution

Fig. 1 shows the time course of levels of DXR and MEN10755 in the tumour and selected organs (heart, kidney and liver). Calculated C max, area under the concentration curve (AUC) as well as T max are reported in Table 1. The tissue distribution of MEN10755 was markedly different from that of DXR. In particular, lower drug levels were achieved in the tumour and normal tissues at all times. With both anthracyclines, the greatest AUC was measured in the tumour. The T max in the tumour was achieved

Discussion

The present study provides further evidence that the improved preclinical profile of MEN10755 over DXR reflects an increased tumour selectivity of the disaccharide analogue. This interpretation is supported by the observation that, in spite of a reduced tumour accumulation, the novel drug given in its optimal regimen was more effective than DXR in inhibiting tumour growth and stimulating apoptosis of the A2780 ovarian carcinoma. The in vivo effects are reminiscent of the cellular behaviour,

Acknowledgements

This work was partially supported by the Associazione Italiana Ricerca sul Cancro, Milan and by the Ministero della Sanita', Roma, Italy and by IMI grant no. 63216. We wish to thank Ms L. Zanesi for editorial assistance, Ms M. Tortoreto for technical support and Dr A.E.G. Crea and V. D'Aranno for helpful discussion and comments on kinetic data.

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1

Present address: Department of Pharmacology, IRBM, 00040 Pomezia, Roma, Italy.

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