On the basis of a structure-activity study of a new series of
anthracycline disaccharides, we recently identified a
doxorubicin analogue (
MEN 10755) with a promising antitumor activity. In the present study, to better support the pharmacological interest of
MEN 10755, we extended the preclinical evaluation of antitumor efficacy to a large panel of 16 human
tumor xenografts, which originated from different clinicopathological types.
Tumors with typical multidrug-resistant phenotype were excluded because
MEN 10755 was found unable to overcome resistance mediated by transport systems. In the
doxorubicin-responsive series,
MEN 10755 exhibited a higher activity in three of five
tumors, as documented by a more marked
tumor growth inhibition and an increased value of log-cell kill. In the series of
doxorubicin-resistant
tumors,
MEN 10755 was found effective in 6 of 11
tumors (1 breast, 3 lung, and 2 prostate
carcinomas). The overall response rates were 31% and 69% for
doxorubicin and
MEN 10755, respectively. The improvement in
drug efficacy was also supported by a substantial increase in the long-term survivor rate of animals implanted with responsive
tumors. Most of the
tumors refractory to
doxorubicin and responsive to
MEN 10755 were characterized by overexpression of the antiapoptotic
protein Bcl-2. In one of these
tumors (MX-1
breast carcinoma), we examined the ability of
MEN 10755 to induce phosphorylation of Bcl-2 after a single treatment with therapeutic doses. The results indicated that, unlike
doxorubicin,
MEN 10755 induced
protein phosphorylation. A similar modification was produced by
Taxol, which is known to be very effective against the
tumor. The correlation between
drug efficacy and Bcl-2 phosphorylation may underly a peculiar feature related to improvement of efficacy of the
disaccharide analogue. In conclusion, the present study supports some favorable features of the novel
doxorubicin analogue in terms of both efficacy and tolerability with comparison to
doxorubicin, although the improvement is somewhat
tumor- and schedule-dependent.