The mechanism of action of many antitumor agents involves DNA damage, either by direct binding of the drug to DNA or to DNA-binding proteins. However, most of the DNA-interacting agents have only a limited degree of sequence specificity, which implies that they may hit all the cellular genes. DNA minor groove binders, among which the derivs. of distamycin A play an important role, could provide significant improvement in cancer management, increasing gene specificity, due to high selectivity of interaction with thymine-adenine (TA) rich sequences. Here, the authors report and discuss the synthesis, in vitro and in vivo activities, and some mechanistic features of -haloacrylamido derivs. of distamycin A. The final result of this work was the selection of brostallicin (its HCl salt is PNU-166196). Brostallicin, presently in phase II clin. trials, shows a broad spectrum of antitumor activity and an apoptotic effect higher than distamycin deriv. tallimustine. An important in vitro toxicol. feature of brostallicin is the very good ratio between myelotoxicity on human hematopoietic progenitor cells and cytotoxicity on tumor cells, in comparison with clin. tested DNA minor groove binders. A peculiarity of brostallicin is its in vitro reactivity in the DNA alkylation assays only in the presence of glutathione. Moreover brostallicin's antitumor activity, both in in vitro and in vivo tumor models, is higher in the presence of increased levels of glutathione/glutathione-S-transferase. These findings contribute to the definition of brostallicin as a novel anticancer agent that differs from other minor groove binders and alkylating agents for both the profile of activity and the mechanism of action and to classify the -bromoacrylamido derivs. of distamycin as a new class of cytotoxics. Moreover, due to its interaction with glutathione, brostallicin may have a role for the tailored treatment of tumors characterized by constitutive or therapy-induced overexpression of glutathione/glutathione-S-transferase levels.
Cytotoxic alpha-halogenoacrylic derivatives of distamycin A and congeners
BARALDI, Pier Giovanni;ROMAGNOLI, Romeo
2004
Abstract
The mechanism of action of many antitumor agents involves DNA damage, either by direct binding of the drug to DNA or to DNA-binding proteins. However, most of the DNA-interacting agents have only a limited degree of sequence specificity, which implies that they may hit all the cellular genes. DNA minor groove binders, among which the derivs. of distamycin A play an important role, could provide significant improvement in cancer management, increasing gene specificity, due to high selectivity of interaction with thymine-adenine (TA) rich sequences. Here, the authors report and discuss the synthesis, in vitro and in vivo activities, and some mechanistic features of -haloacrylamido derivs. of distamycin A. The final result of this work was the selection of brostallicin (its HCl salt is PNU-166196). Brostallicin, presently in phase II clin. trials, shows a broad spectrum of antitumor activity and an apoptotic effect higher than distamycin deriv. tallimustine. An important in vitro toxicol. feature of brostallicin is the very good ratio between myelotoxicity on human hematopoietic progenitor cells and cytotoxicity on tumor cells, in comparison with clin. tested DNA minor groove binders. A peculiarity of brostallicin is its in vitro reactivity in the DNA alkylation assays only in the presence of glutathione. Moreover brostallicin's antitumor activity, both in in vitro and in vivo tumor models, is higher in the presence of increased levels of glutathione/glutathione-S-transferase. These findings contribute to the definition of brostallicin as a novel anticancer agent that differs from other minor groove binders and alkylating agents for both the profile of activity and the mechanism of action and to classify the -bromoacrylamido derivs. of distamycin as a new class of cytotoxics. Moreover, due to its interaction with glutathione, brostallicin may have a role for the tailored treatment of tumors characterized by constitutive or therapy-induced overexpression of glutathione/glutathione-S-transferase levels.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
