comparable in inhibition of DNA synthesis.
more potent in producing direct DNA strand breaks and inhibiting both DNA topoisomerase II activity and RNA synthesis.
stronger in DNA binding and intercalation.
Daunomustine achieves these functions without the cardiotoxicity produced by doxorubicin and daunorubicin. The increased potency of daunomustine over doxorubicin and daunorubicin is significantly greater in multidrug-resistant cells.
In the murine xenograft tumor models utilizing both drug-sensitive and doxorubicin-resistant tumors, curative activity at or near 100% was achieved with single dose administration of daunomustine. Curative activity with daunomustine was achieved with only negligible leukopenia and no other evidence of toxicity. In these same in vivo model systems, the activity of daunomustine was also markedly superior to that of admixtures of daunorubicin with conventional chlorethylnitrosourea drugs (BCNU or CCNU). Thus, the antitumor activity of daunomustine is inherent in the structure and is not achievable by simply combining separate agents containing the individual mechanistic functions. Daunomustine circumvents cellular drug resistance arising from the overexpression of multidrug transport proteins, such as P-glycoprotein, reduced topoisomerase II activity, and enhanced MGMT-mediated DNA repair activity.
Paradox Pharmaceuticals has completed ADME and toxicology studies in preparation for IND application submission to the FDA.
Daunomustine is the lead compound of our hybrid anthracycline series, combining the anthracycline ring system with a nitrosoureido alkylating functionality. Biochemical studies have established that daunomustine intercalates with DNA to inhibit mammalian DNA topoisomerase II activity (anthracycline mechanistic properties) and also causes DNA direct strand breaks and DNA-DNA interstrand crosslinks mediated by the enzyme O6-methylguanine methyl transferase (alkylating mechanistic properties).
Relative to conventional anthracyclines, such as doxorubicin and daunorubicin, daunomustine is: