D. Deprez-De Campeneere

Rapid determination of doxorubicin and its fluorescent metabolites by high pressure liquid chromatography.

Abstract An original method for the separation and quantitation of doxorubicin (DOX) and its metabolites by high-pressure liquid chromatography and fluorometry is described. Doxorubicin and its derivatives are extracted from biological samples in a rapid, non-destructive manner, with a recovery close to 100%. The different compounds are rapidly separated by high-pressure liquid chromatography using an eluant system containing magnesium chloride, and detected quantitatively by fluorometry down to a concentration of 1.5 ng/ml in less than 5 min. Using this method, we have determined doxorubicin and its metabolites in plasma and urine, after an intravenous injection into DBA 2 and NMRI mice.

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

SummaryA 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 halflife 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.

Daunorubicin-DNA and doxorubicin-DNA a review of experimental and clinical data

SummaryExperimental 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.

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

SummaryWe 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 L 1210 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 drugmacromoleculare carrier entity.

Drug Targeting in Human Cancer Chemotherapy

Drug targeting aims to restrict the access of pharmacological agents to selected cells. Theoretically, such a method should on one hand, decrease unsuitable side effects resulting from an interaction of the drugs with non target cells and, on the other hand, enhance the pharmacological activity by increasing the proportion of the administered drug found within the target cells. Our conceptual approach to this problem consists in linking drugs through a covalent bond to macromolecular carriers which are recognized by receptors or antigens present at the cell surface of the target cells and thereafter endocytosed to allow the release of the drug after hydrolysis of the covalent linkage by lysosomal enzymes.

Accumulation and Metabolism of New Anthracycline Derivatives in the Heart After Iv Injection Into Mice

SummaryIn an attempt to establish a relationship between the pharmacokinetics in mouse heart of new anthracycline derivatives and their potential chronic cardiotoxicity and in this way to provide a useful and economical test for screening of new analogs, we followed the accumulation and metabolism of six anthracyclines in the mouse heart after single IV administrations of these drugs at equimolar doses. We found that the six drugs, i.e., daunorubicin (DNR), doxorubicin (DOX), rubidazone (RBZ), detorubicin (DET), N-l-leucyl-DNR (LEU-DNR) and N-l-leucyl-DOX (LEU-DOX), accumulate at various levels in the cardiac tissue and are metabolized to different extents, leading to the appearance in the heart of variable amounts of DNR or DOX. The total exposure of the mouse heart, as evaluated by calculation of the areas under the Cxt curves, can be correlated qualitatively with the chronic cardiotoxicity of the six anthracyclines, as recently determined in the rabbit model. We therefore think that our study provides a simple, rapid, and inexpensive predictive test for the screening of new analogs for potential cardiotoxicity. Moreover, it offers the advantage of using the same species for determining the most favorable ratio between therapeutic activity and toxic side-effects.

Plasma levels of doxorubicin after IV bolus injection and infusion of the doxorubicin-DNA complex in rabbits and man

SummaryWhen injected rapidly IV into rabbits, the plasma levels of free DOX decreased biphasically and the drug was distributed in a volume greater than the body volume. When given as a DNA complex, the area under the concentration versus time curve was increased 10-fold and the distribution volume reduced more than 100-fold. The DOX-DNA complex infused both in rabbits and in human patients reached steady state-concentrations 10 and 20 times higher, respectively, than free DOX infusion, and the distribution volumes were reduced accordingly. These results confirm that the observed lower cardiotoxicity of the DOX-DNA complex arises despite higher plasma concentrations of the drug.

DNA—Anthracycline complexes. II. Comparative study of the acute lesions induced in mice after intravenous administration of free and DNA bound adriamycin

Abstract We have compared in mice the overall toxicity of free adriamycin (ADR) or DNA bound adriamycin (ADR-DNA) after repeated i.v. injections of high drug doses ( 35–40 mg/kg ). Survival curves and variations in mean total body weight indicated that ADR-DNA is less toxic than ADR in mice. Histopathologic studies showed: (1) that ADR induced severe lesions in the hemopoietic organs (bone marrow, lymph nodes, spleen, thymus) and in the gastrointestinal tract. An important lipid overloading in liver and kidney was observed; (2) that the toxicity of ADR is reduced for bone marrow and stomach when the drug is associated with high mol. wt DNA. No lipid overloading has been seen in liver and kidney of the complex treated mice. The repair of the lesions induced in the tissues (lymphoid organs, thymus) which are not protected against the effect of ADR when using a DNA-complex, is significantly more rapid. Finally, in this subacute study in mice, no cardiomyopathy has been observed after treatment with either free or DNA bound drug.

Distribution and metabolism of rubidazone and daunorubicin in mice

SummaryA 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.

DNA—Anthracycline complexes. I. Toxicity in mice and chemotherapeutic activity against L1210 leukemia of daunorubicin—DNA and adriamycin—DNA☆

Abstract We report here comparative studies performed in mice on the toxic and therapeutic effects of free and DNA bound anthracyclines: daunorubicin (DNR) and adriamycin or doxorubicin (ADR). DNR-DNA is less toxic than DNR when given i.p., while a similar overall toxicity is observed when the drugs are given i.v. In contrast, ADR-DNA is significantly less toxic than ADR, both by the i.p. or the i.v. route. The better therapeutic effectiveness of DNR-DNA on L 1210 leukemia compared with free DNR is demonstrated; however, the activities of both DNR and DNR-DNA are dependent on the schedule of administration. The most striking chemotherapic effect is always obtained with ADR-DNA, due to the combination of a higher activity and a lower toxicity when the drug is associated to high mol. wt DNA. The results of the toxicologic and chemotherapic studies are discussed in view of the distinctive pharmacologic properties of free and DNA bound drugs.