Role of apoptosis and apoptosis-related genes in cellular response and antitumor efficacy of anthracyclines

Cellular resistance to anthracyclines is a major limitation of their clinic al use in the treatment of human tumors. Resistance to doxorubicin is descr ibed as a multifactorial phenomenon involving the overexpression of defense factors and alterations in drug-target interactions. Such changes do not a ccount for all manifestations of drug resistance, in particular intrinsic r esistance of solid tumors. Since anthracyclines can induce apoptotic cell d eath, an alternative promising approach to drug resistance has focused on t he study of cellular response to drug-induced DNA damage, with particular r eference to the relationship between cytotoxicity/antitumor efficacy and ap optotic response. The evidence that a novel disaccharide analog (MEN 10755) , endowed with an improved preclinical activity over doxorubicin, was also more effective as an inducer of apoptosis provided additional insights to b etter understand the cellular processes that confer sensitivity to anthracy clines. Although the presence or alteration of a single apoptosis-related f actor (e.g., p53, bcl-2) is not predictive of the sensitivity/resistance st atus, the complex interplay among DNA damage-activated pathways is likely a n important determinant of tumor cell sensitivity to anthracyclines.