Iodinated derivatives of verapamil were synthesized and tested as P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) reversal agents. The ability of these compounds to revert MDR was evaluated on daunorubicin-resistant K562 cells, by measuring the intracellular accumulation of rhodamine 123, a fluorescent probe of Pgp transport activity. One of the investigated compounds (16c) was found t...

Anaerobic incubations of rat liver microsomes convert daunorubicin into at least six or seven aglycones in the presence of reduced nicotinamide adenine dinucleotide phosphate or a reduced nicotinamide adenine dinucleotide phosphate-generating system. The partial identification of some of the aglycones is based on cochromatographs of chemically synthesized derivatives by isocratic high-pressure ...

The influence of pH and temperature on the stability of N-[(piperidine)methylene]daunorubicin hydrochloride (PPD) was investigated. Degradation was studied using an HPLC method. Specific acid-base catalysis of PPD involves hydrolysis of protonated molecules of PPD catalyzed by hydrogen ions and spontaneous hydrolysis under the influence of water zwitterions, unprotonated molecules, and monoanio...

A number of new agents are being developed concurrently, including cytotoxins, hormonal agents, and biologic approaches (Table). There are a number of new anthracyclines, particularly liposomal anthracyclines. There are ongoing clinical trials with liposomal daunorubicin and liposomal doxorubicin. At M.D. Anderson, we developed liposomal anamycin, which is a new anthracycline that is not a p-gl...

I term survival without an apparent effect on the initial response rate. However, reports of improved disease-free surNDUCTION THERAPY for acute myeloid leukemia (AML) has been fairly standardized over the past two decades, with major controversies addressing the optimal vival attributable to intensified induction therapy need to be cautiously interpreted. Such benefit may be impossible to post...

The anthracycline daunorubicin is widely used in the treatment of acute nonlymphocytic leukemia. The drug has, of course, been the object of intense basic research, as well as preclinical and clinical study. As reviewed in this article, evidence stemming from this research clearly demonstrates that cell response to daunorubicin is highly regulated by multiple signaling events, including a sphin...

Drug resistance is a major cause of chemotherapy failure in cancer treatment. One reason is the overexpression of the drug efflux pump P-glycoprotein (P-gp), involved in multidrug resistance (MDR). In vivo pharmacokinetic analysis of P-gp transport might identify the capacity of modulation by P-gp substrate modulators, such as cyclosporin A. Therefore, P-gp function was measured in vivo with po...

Anthracyclines are widely used in patients for anticancer activity. However, one of the limitations for their clinical use is P-gp-mediated drug resistance in cancer therapy. We hypothesize that modified anthracyclines will retain their anticancer activity, avert P-gp binding, and thus overcome P-gp-mediated drug resistance. Twenty-five daunorubicin analogues were synthesized with slight struct...