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Biomedical subjects

A Trouet

Publications and source records attributed to A Trouet.

At least 91 records · Page 5Linked to original sources
PubMed1980

Amino acid and dipeptide derivatives of daunorubicin. 1. Synthesis, physicochemical properties, and lysosomal digestion.

The synthesis of amino acid and dipeptide derivatives of daunorubicin (DNR) is described. The binding-affinity parameters for DNA of those derivatives were determined by a spectral titration method. The affinity constants of the amino acid and dipeptide derivatives are, respectively, three and ten times lower than that of DNR. The susceptibility of those derivatives toward lysosomal peptidases was studied. It was found that the Leu and the Ala-Leu derivatives are the most rapidly hydrolyzed into DNR. It is concluded that Leu-DNR and Ala-Leu-DNR could act as prodrugs of DNR, which could be activated inside or in the close vicinity of tumor cells which display a high aminopeptidase activity.

Animals↗
PubMed1980

Amino acid and dipeptide derivatives of daunorubicin. 2. Cellular pharmacology and antitumor activity on L1210 leukemic cells in vitro and in vivo.

The accumulation of amino acid and dipeptide derivatives of DNR has been studied in vitro on L1210 cells. Only Leu-DNR reaches accumulation levels close to DNR, while Val-DNR, Ile-DNR, and Leu-Leu-DNR reach intermediate values. Intracellular DNR was found when the L1210 cells were incubated in the presence of DNR, Leu-Leu-DNR, Leu-Ala-DNR, and Leu-DNR. The cytostatic activity of the derivatives in vitro on L1210 cells cannot be correlated with their uptake or conversion into DNR. At equitoxic doses given iv on the iv inoculated form of L1210 leukemia, all the derivatives are less active than DNR. When given iv on the sc inoculated L1210 leukemia, Leu-DNR, Ala-Leu-DNR and Leu-Leu-DNR are much more active than DNR with a striking increase in ILS and reduction of tumor progression. The superiority of those compounds could be due to their greater hydrophobicity and to their hydrolysis in situ by enzymes secreted by tumor cells or present on the tumor cells surface.

Animals↗
PubMed1980

Cardiotoxicity and comparative pharmacokinetics of six anthracyclines in the rabbit.

Six anthracycline antibiotics with demonstrated antitumor activity in human or experimental tumor systems were studied. The purpose of this investigation was to compare the cardiotoxic potential of these compounds and to characterize the myocardial pharmacokinetics in order to provide a possible explanation for differences in cardiotoxicity. Groups of rabbits received i.v. injections of drug at maximally tolerated treatment doses with respect to lymphohematopoietic toxicity for periods of 11 or 16 weeks and were evaluated histopathologically for the development of myocardial damage. Following a single i.v. administration of the different anthracyclines to rabbits, the amount of parent drug and metabolites accumulating in the heart at various times was determined by high-pressure liquid chromatography and fluorometry. Adriamycin (ADR), daunorubicin (DNR), and detorubicin produced similar severe cardiomyopathy with frequent congestive heart failure at approximately equal dose levels. Three additional antibiotics, rubidazone and the N-L-leucyl derivatives of ADR and DNR (N-L-leucyl-adriamycin and N-L-leucyl-daunorubicin), produced significantly less severe lymphohematopoietic toxicity, thus permitting the administration of 3 to 3.5 times the ADR and DNR treatment doses. Chronic treatment with these anthracyclines also resulted in significantly less cardiomyopathy, especially in the case of N-L-leucyl-daunorubicin and rubidazone. This reduced cardiomyopathy correlated with lower total myocardial drug accumulation but, more importantly, with lower amounts of DNR or ADR accumulation in the heart. These findings suggest that the degree of anthracycline myocardial toxicity may be directly related to the relative qualitative and quantitative accumulation of drug metabolites in the myocardium.

Animals↗
PubMed1979

Uptake of the daunorubicin-DNA complex in cultured fibroblasts.

The uptake and fate of the daunorubicin-DNA complex have been studied in cultured rat embryo fibroblasts. 125I-DNA was digested by the cells and appeared as low molecular weight fragments in the incubation medium. Subcellular fractionation of fibroblasts, previously incubated with the complex, showed that daunorubicin was localized to nuclei and lysosomes. At a high incubation concentration (17.5 microM), the accumulation of the free drug exceeded that of the complex. However, at a lower concentration (1.75 microM), the accumulation of the complex was as high as that of the free drug. The results are consistent with an uptake of the complex into cultured rat embryo fibroblasts by endocytosis. However, it cannot be excluded that the complex partly dissociates in the incubation medium, and that daunorubicin and DNA thereafter enter the cells separately.

Animals↗
PubMed1979

DNA-binding parameters of daunorubicin and doxorubicin in the conditions used for studying the interaction of anthracycline-DNA complexes with cells in vitro.

Affinity constants of daunorubicin and doxorubicin for DNA at 37 degrees C and in presence of 10% serum were determined by an optical method and calculated from Scatchard plots. Values from 0.10 to 0.12 and from 0.13 to 0.16 X 10(6) M-1 were obtained for daunorubicin and doxorubicin, respectively. According to these affinity constants, the amounts of free drugs were calculated for various concentrations of daunorubicin-DNA or doxorubicin-DNA and for various molar ratios. In a large range of concentrations there is rather stable concentration of both free drugs, and these concentrations are inversely proportional to the nucleotides/drug ratio. The amount of free drug present in the medium is low as long as the concentration of daunorubicin-DNA or doxorubicin-DNA is higher than 1 microgram/ml (expressed as drug concentration). At lower concentrations, however, the percentage of free drug increases very sharply.

Cells, Cultured↗
PubMed1979

Determination of daunorubicin, doxorubicin and their fluorescent metabolites by high-pressure liquid chromatography: plasma levels in DBA2 mice.

A rapid and nondestructive analytic method has been developed to separate and quantitate daunorubicin, doxorubicin, and their metabolites in biological fluids. This method combines the efficiency of high-pressure liquid chromatography and the sensitivity of fluorescence monitoring. The drug plasma levels achieved after IV administration of either daunorubicin or doxorubicin at 7 mg/kg into DBA2 mice were studied. The plasma disappearance curves are biphasic with a half-life of 1 min for the first elimination phase. In urine extracts, 13-hydroxy derivatives represent 80% of the fluorescence after injection of daunorubicin and only 4% after administration of doxorubicin.

Animals↗
PubMed1979

Comparative study in mice of the toxicity, pharmacology, and therapeutic activity of daunorubicin-DNA and doxorubicin-DNA complexes.

We have compared the toxicologic, pharmacologic, and therapeutic properties of the DNA complexes of daunorubicin and doxorubicin, after intravenous (IV) administration into mice. The overall toxicity of doxorubicin is significantly reduced after IV injection as a DNA complex while daunorubicin-DNA is as toxic as free daunorubicin. On hemopoietic stem cells, daunorubicin-DNA was found to be more cytotoxic than daunorubicin, while the opposite was observed with doxorubicin and doxorubicin-DNA. Both complexes are more effective than the corresponding free drugs on the L1210 murine leukemia, when given IV at equitoxic doses. The tissue uptake in mice, after IV administration, is generally lower when the drugs are given bound to DNA. The stability of the two DNA complexes is very different in the bloodstream: daunorubicin-DNA behaves more like a prodrug of daunorubicin, while doxorubicin-DNA, remaining stable in the bloodstream, meets much more the requirements of an ideal drug-macromoleculare carrier entity.

Animals↗
PubMed1979

Distribution and metabolism of rubidazone and daunorubicin in mice.

A comparative investigation of the distribution and metabolism of rubidazone and daunorubicin was conducted in NMRI mice, after a single IV dose of either rubidazone (8.4 mg/kg) or daunorubicin (7 mg/kg). The anthracyclines were analyzed by high-pressure liquid chromatography and fluorometry. Daunorubicin was the main compound found after daunorubicin administration, except in kidney and urine, where daunorubicinol was the main metabolite with trace amounts of aglycone. In contrast, rubidazone undergoes extensive metabolism into daunorubicin, daunorubicinol, and aglycone. The total drug level is significantly lower after rubidazone administration in kidney, heart, gastrointestinal tract, spleen, and urine, and the biliary excretion of rubidazone is more important than that of daunorubicin. When compared with daunorubicin, significantly less daunorubicinol is produced after rubidazone administration.

Animals↗
PubMed1979

Daunorubicin-DNA and doxorubicin-DNA. A review of experimental and clinical data.

Experimental data on the pharmacokinetic, toxic and therapeutic properties of daunorubicin-DNA and doxorubicin-DNA complexes are reviewed and summarized as well as the available reports on clinical trials performed with these anthracycline-DNA complexes. These results are discussed in view of the further development of the drug-carrier concept of cancer chemotherapy.

Animals↗