Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Doxorubicin is metabolically activated by microsomal NADPH-dependent cytochrome P450 reductase as well as by intact nuclei forming semiquinone free radicals, which reoxidize to doxorubicin in the presence of oxygen. Nuclear activated doxorubicin became bound to DNA in a time-dependent fashion. The addition of microsomal protein to intact nuclei increased the amount of doxorubicin bound to DNA under aerobic conditions. In contrast, inclusion of microsomes virtually abolished DNA binding under anaerobic conditions. Disruption of the nuclear membrane by sonification increased the amount of drug bound to DNA, indicating that the nuclear envelope serves as a partial barrier to the diffusion of microsomal DNA-directed intermediates. The data indicate that under aerobic conditions metabolites produced by microsomes either traverse the nuclear membrane and bind to DNA or act indirectly by disrupting the nuclear membrane. In contrast, inhibition of DNA binding by doxorubicin under anaerobic conditions suggests either that the microsomal metabolites do not diffuse across the nuclear membrane or that the metabolites are not capable of binding to DNA. The decreased diffusibility of the anaerobic metabolites may represent either the generation of metabolites having lower diffusion constants or the formation of highly reactive intermediates which preferentially bind in the immediate vicinity to the site of generation on the microsomal surface. In conclusion, it appears that, under aerobic conditions, metabolic activation of doxorubicin on the surface of the endoplasmic reticulum can contribute to the amount of the drug which becomes closely associated with nuclear DNA. Consequently, the microsomal drug-metabolizing system may be important in affecting the therapeutic or cytotoxic properties of the drug.
Mol Pharmacol 1987 Mar
PMID:Oxygen-dependent effect of microsomes on the binding of doxorubicin to rat hepatic nuclear DNA. 356 86

Mouse NIH 3T3 cells were transformed to multidrug resistance with high-molecular-weight DNA from multidrug-resistant human KB carcinoma cells. The patterns of cross resistance to colchicine, vinblastine, and doxorubicin hydrochloride (Adriamycin; Adria Laboratories Inc.) of the human donor cell line and mouse recipients were similar. The multidrug-resistant human donor cell line contains amplified sequences of the mdr1 gene which are expressed at high levels. Both primary and secondary NIH 3T3 transformants contained and expressed these amplified human mdr1 sequences. Amplification and expression of the human mdr1 sequences and amplification of cotransferred human Alu sequences in the mouse cells correlated with the degree of multidrug resistance. These data suggest that the mdr1 gene is likely to be responsible for multidrug resistance in cultured cells.
Mol Cell Biol 1986 Nov
PMID:Multidrug resistance of DNA-mediated transformants is linked to transfer of the human mdr1 gene. 379 99

Purified bovine cardiac G-actin was interacted with doxorubicin (Adriamycin, ADR), in absence of potassium or magnesium to study ADR's effects on actin polymerization. Actin with ADR (10(-6) M) was incubated with polylysine-coated polystyrene beads and filaments formed were visualized by negative staining electron microscopy (NSEM). ADR-induced actin polymerization was assessed biochemically by ultracentrifugation and analysis of protein content of the supernatant solution. Kinetic assays of turbidity of actin were performed which showed that ADR induced formation of stubby actin polymers which bound to the beads and differed ultrastructurally from the longer actin filaments induced by KCl + MgCl2. Actin content in the supernatant solution decreased after centrifugation (0.8 mg/ml in G-actin to 0.45 mg/ml in actin incubated with 10(-4) M ADR). ADR (10(-4) M) caused increased turbidity of actin of similar magnitude to that induced by actin + KCl + MgCl2. Data support the hypothesis that ADR induces polymerization of cardiac actin in vitro but this polymerization has characteristics which are different from actin polymerization induced by salts.
Exp Mol Pathol 1986 Feb
PMID:Cardiac actin interactions with doxorubicin in vitro. 394 80

The mitochondrial mutation petite was induced in yeast cells by ethidium bromide (EB), Adriamycin (ADR) and 4-nitroquinoline-N-oxide (NQO). In the presence of aspirin in concentrations ranging from 0.1 to 1.0 mg/ml, the mutagenicity of EB and ADR was reversed but petite induction by NQO was unaffected. At these concentrations, aspirin also reversed mitochondrial inhibition by oligomycin, a non-mutagenic inhibitor of the organellar ATPase complex. Cells grown in the presence of aspirin alone showed a significantly higher rate of oxygen uptake than untreated control cultures when the drug concentration ranged from 0.05 to 1.0 mg/ml. At concentrations of 2 mg/ml and above, aspirin inhibited mitochondrial respiration.
Mol Gen Genet 1984
PMID:Effect of aspirin on mitochondrial mutagens in Saccharomyces cerevisiae. 637 78

Doxorubicin (adriamycin) forms molecular associations with other aromatic and planar molecules (hetero-association) and with other doxorubicin molecules (self-association) in aqueous solution. The ability of doxorubicin to form complexes was demonstrated in a nonbiological system by measuring the doxorubicin partition coefficient. A decreased apparent doxorubicin activity coefficient in the presence of complex formation was also demonstrated in a biological system by measuring the transmembranous doxorubicin transport and the doxorubicin distribution at equilibrium in human red blood cells and their suspending medium. Doxorubicin formed complexes in aqueous solution at 37 degrees (pH 7.3) with (a) DNA-derived bases, nucleosides, and nucleotides; (b) amino acids such as tryptophan; (c) proteins such as human serum albumin and hemoglobin; and (d) a broad range of biologically active compounds such as NAD, propanthelline, caffeine, chloroquine, imipramine, and propranolol. The apparent thermodynamic quantities of the complex formation with adenosine 5'-triphosphate were delta H0, -9.5 kcal . mole-1; delta S0, -19 eu . mole-1; and delta G0 (310 degrees K), -3.6 kcal . mole-1. The binding forces of the molecular associations were probably hydrophobic (short-range force), sometimes supported by electrostatic interaction (long-range force).
Mol Pharmacol 1982 Jul
PMID:Molecular association between doxorubicin (adriamycin) and DNA-derived bases, nucleosides, nucleotides, other aromatic compounds, and proteins in aqueous solution. 712 47

Adriamycin (doxorubicin) is a broad spectrum anti-tumor antibiotic used to treat cancer patients. However, the potential usefulness of this drug is currently limited by the development of a dose-dependent cardiomyopathic process terminating in severe heart failure. Although several mechanisms have been suggested to explain the pathogenesis of adriamycin-induced cardiomyopathy, free-radical induced oxidative stress appears to play an important role. A concise description of adriamycin-induced cardiomyopathy is provided. Various combination therapies which have been attempted in the past to modulate the adriamycin-induced cardiomyopathy are also discussed. Recently, it has been discovered that probucol, a lipid lowering agent and potent antioxidant, provides complete protection against adriamycin-induced cardiomyopathy in rats without interfering with the anti-tumor properties of this antibiotic. Clinical trials employing adriamycin therapy in combination with probucol are needed to determine the applied value of these laboratory findings.
J Mol Cell Cardiol 1995 Apr
PMID:Combination therapy with probucol prevents adriamycin-induced cardiomyopathy. 756 2

Adriamycin (AD)-Fe3+ caused the inactivation of Na(+)-, K(+)-ATPase and Ca(2+)-ATPase of erythrocyte membranes during lipid peroxidation. AD-Fe3+ also induced the formation of fluorescent substances from the membranes with lipid peroxidation. The fluorescent substances were little extracted by chloroform-methanol, indicating that they were retained in the membranes. Butylated hydroxytoluene and trolox strongly inhibited both the inactivation of these ATPases and the formation of fluorescent substances with lipid peroxidation. Another antioxidant, vitamin E, slightly prevented the damage of the membranes. However, p-nitrophenyl phosphatase activity and acetylcholine esterase have lower or no susceptibility to the membrane lipid peroxidation. These results indicated that the ATPases were very sensitive to lipid peroxidation and that the membranes were modified during the peroxidation reaction.
Res Commun Mol Pathol Pharmacol 1995 Feb
PMID:Adriamycin-Fe(3+)-induced inactivation of enzymes in erythrocyte membranes during lipid peroxidation. 774 51

We have investigated the effect of doxorubicin (Adriamycin) on the yeast Saccharomyces cerevisiae. Drug treatment was found to be cytotoxic to wild-type strains, in a concentration-dependent manner, whereas a petite mutant lacking the cytochrome oxidase (EC 1.9.3.1) subunit IV gene was resistant to doxorubicin. Transformation of the doxorubicin-resistant mutant with a yeast in vivo expression vector harboring the cytochrome oxidase subunit IV gene restored both respiration and sensitivity to doxorubicin. Another petite strain, with a mutation in the mitochondrial adenine nucleotide translocator (pet9), did not display doxorubicin resistance. However, in contrast to the subunit IV mutant, it possesses a functional respiratory chain. We also compared the cytotoxic effect of doxorubicin with those of daunorubicin and mitoxantrone in yeast. We found comparable levels of cytotoxicity for doxorubicin and daunorubicin, which were significantly greater than that for mitoxantrone. Finally, we constructed a yeast strain that overexpresses manganese superoxide dismutase (EC 1.15.1.1), an antioxidant enzyme present in mitochondria. Overexpression of manganese superoxide dismutase protected significantly against doxorubicin and daunorubicin cytotoxicity but only slightly against mitoxantrone cytotoxicity. Collectively, our results provide direct in vivo evidence that superoxide radicals participate in doxorubicin- and daunorubicin-induced cytotoxicity in yeast. Furthermore, these results indicate that mitochondrial respiration is a crucial factor in anthracycline, and perhaps mitoxantrone, cytotoxicity in yeast.
Mol Pharmacol 1994 Dec
PMID:Doxorubicin, daunorubicin, and mitoxantrone cytotoxicity in yeast. 780 47

Doxorubicin (Dox) is a widely used antineoplastic agent. Irreversible cardiomyopathy is a serious and dose-limiting side effect after chronic administration. The iron chelating bispiperazinedione ICRF-187 is currently the only drug which affords protection against Dox-induced cardiotoxicity. To compare the protective value of structurally unrelated iron chelators, isolated mice atria were exposed to Dox (30 microM) and either the hydroxamate desferrioxamine (DFO, 200 and 500 microM), EDTA (200 microM) or the hydroxypridones CP44 (200 microM), CP51 (200 microM), and CP93 (200 microM) and ICRF-187 (200 and 500 microM). The nitroxide TEMPO (5 mM) lacks iron chelating properties but was used to prevent redox cycling or iron and scavenge superoxide. All iron chelators, except EDTA. CP93 and CP44, were modestly protective against a Dox-induced decrease in contractile force. As a single agent the hydroxypridones decreased atrial contractile force. At a concentration of 200 microM, DFO was the most effective protector of the chelators tested. However, this effect disappeared when a concentration of 500 microM was used. This in contrast to ICRF-187 for which a concentration-dependent inhibition of Dox-induced decrease in contractile force was observed. TEMPO exerted a biphasic response consisting of a two-fold increase in contractile force, followed by a decrease in force and irregular contractions. In this model TEMPO lacked any perspective as a cardioprotectant. We conclude that at 200 microM. DFO was the most effective agent to afford protection against Dox-mediated atrial malfunction. However, at 500 microM, DFO was not effective whereas ICRF-187 afforded partial protection. Hydroxipyridones were found to be of limited value because of a negative inotropic effect on the isolated atria.
J Mol Cell Cardiol 1994 Sep
PMID:Comparison of different iron chelators as protective agents against acute doxorubicin-induced cardiotoxicity. 781 60

The genotoxic and cytotoxic effects of etoposide (VP-16), a topoisomerase II inhibitor, on male rat spermatogenic cells were studied by analysing induction of micronuclei during meiosis. Micronuclei (MN) were scored in early spermatids after different time intervals corresponding to exposure of different stages of meiotic prophase. Etoposide had a strong effect on diplotene-diakinesis I cells harvested 1 day after exposure, and a significant effect also on late pachytene cells harvested 3 days after exposure. The effect at 18 days corresponding to exposure of preleptotene stage of meiosis (S-phase) was weaker but also statistically significant. Adriamycin was used as a positive control in this study. The results indicate a different mechanism of action of etoposide compared with adriamycin and other chemicals studied previously with the spermatid micronucleus test. DNA flow cytometry was carried out to assess cytotoxic damage at the same time intervals (1, 3, and 18 days after treatment) at stages I and VII of the seminiferous epithelial cycle allowing a study of cytotoxicity to different spermatogenic cell stages. Damage of differentiating spermatogonia was observed by a decrease in the cell numbers of the 2C peak 1 and 3 days after treatment and by a reduction of the number of 4C cells (primary spermatocytes) 18 d after etoposide treatment. Adriamycin also killed differentiating spermatogonia. Since the cell population which showed a high induction of MN by etoposide was not reduced in number, the genotoxic effect is remarkable. We conclude that etoposide is a potent inducer of genotoxicity and patients treated with this agent during cancer chemotherapy are at a risk of genetic damage.
Environ Mol Mutagen 1994
PMID:Etoposide (VP-16) is a potent inducer of micronuclei in male rat meiosis: spermatid micronucleus test and DNA flow cytometry after etoposide treatment. 795 23


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>