Identifying heritable genetic variants responsible for chemotherapeutic toxicities has been challenging due in part to its multigenic nature. To date, there is a paucity of data on genetic variants associated with patients experiencing severe myelosuppression or cardiac toxicity following treatment with daunorubicin. We present a genome-wide model using International HapMap cell lines that inte...

Cancer therapy with daunorubicin is limited by its cardiotoxicity. It has been suggested that daunorubicin-induced free radical generation can be involved. The precise molecular mechanism of daunorubicin-induced cardiotoxicity is still not well understood but it is believed that mitochondria play an important role in this process. It has been reported that flavonoids with antioxidant properties...

Anthracyclines are chemotherapeutic drugs known to induce heart failure in a dose-dependent manner. Mechanisms involved in anthracycline cardiotoxicity are an area of relevant investigation. Caveolins bind, organize and regulate receptors and signaling molecules within cell membranes. Caveolin-3 (Cav-3), integrins and related membrane repair proteins can function as cardioprotective proteins. E...

The cellular accumulation and disposition of the anthracycline antitumor antibiotic aclacinomycin A (ACM) were compared to those of daunorubicin. Although both drugs were avidly accumulated by cells, intracellular concentrations of ACM were two to three times those of daunorubicin. Whereas lowered temperature (0 degrees) reduced intracellular accumulation of both drugs, 10 mM sodium azide had n...

The multidrug-resistance associated protein MRP is a 180- to 195-kDa membrane protein associated with resistance of human tumor cells to cytotoxic drugs. We have investigated how MRP confers drug resistance in SW-1573 human lung carcinoma cells by generating a subline stably transfected with an expression vector containing MRP cDNA. MRP-overexpressing SW-1573 cells are resistant to doxorubicin,...

Two drugs, D-penicillamine and daunorubicin, were tested for their effect on proliferation and collagen synthesis of cultured conjunctival fibroblasts. This cell type is likely responsible for scar formation and ultimate filter surgery failure in glaucoma patients. Both drugs were antiproliferative; however, D-penicillamine required 2000 times the concentration of daunorubicin to achieve a simi...

PURPOSE To characterize daunorubicin-induced cell death in cultured human retinal pigment epithelial (RPE) cells and its modulation by CD95 ligand (CD95L). METHODS In situ DNA end labeling and an ELISA for histone-associated DNA fragments were used to assess apoptosis. CD95 and CD95L expression were examined by immunohistochemistry, flow cytometry, immunoblot, and RT-PCR. Cell death was measu...

PURPOSE The effect of CCl4-induced experimental hepatic injury (CCl4-EHI) on the pharmacokinetics of daunorubicin was investigated systemically in rats, in an attempt to elucidate the major determinants of the effect of CCl4-EHI on the pharmacokinetics of the drug. METHODS CCl4-EHI was induced in rats by a single intraperitoneal injection of CCl4 (1 mL/kg rat), and a 24 h fasting period. Daun...

BACKGROUND To improve the quality of care for patients with acute myeloid leukemia (AML), biomarkers predictive of response to the standard daunorubicin-based induction therapy are needed. Genetic variants affecting daunorubicin metabolism are attractive candidates for such biomarkers. METHODS We have previously shown that 13 of the naturally occurring nonsynonymous single-nucleotide polymorp...

The initial report of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group trial E1900 (#NCT00049517) showed that induction therapy with high-dose (HD) daunorubicin (90 mg/m(2)) improved overall survival in adults <60 years old with acute myeloid leukemia (AML); however, at initial analysis, the benefit was restricted to younger patients (<5...