Design and tumor targeting of anthracyclines able to overcome multidrug resistance: a double-advantage approach.
A novel, 'double-advantage approach' to developing more effective chemotherapies will be reviewed. This approach is based on a presumption that analogs designed on a sound hypothesis, and combined with a rationally selected drug delivery system, will optimize antitumor activity by creating drugs that are more active and that can be more specifically targeted to tumors. In the design of drugs superior to doxorubicin, we have focused on typical multidrug resistance and new anthracycline analogs, whose uptake is not affected by P-glycoprotein. Analysis of structural elements of anthracyclines affecting activity against multidrug resistant tumors and affinity for liposomes will be discussed. Annamycin, a lipophilic anthracycline analog, was selected for further preclinical development as a liposomal formulation and demonstrated, in the initial biological evaluation, high activity against tumors resistant to doxorubicin.
Priebe
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Department of Clinical Investigation, University of Texas, M.D. Anderson Cancer Center, Houston 77030.
Perez-Soler
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R
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D015195:Drug Design; D004351:Drug Resistance; D006801:Humans; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004317:Doxorubicin; C080315:annamycin