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 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.
Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy.
O
O
Gonzalez-Paz
D
D
Polizzi
M
M
De Cesare
F
F
Zunino
M
M
Bigioni
C A
CA
Maggi
S
S
Manzini
G
G
Pratesi
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D004187:Disaccharides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D004187:Disaccharides; D004317:Doxorubicin; C107602:sabarubicin