Anticancer Drug Adriamycin Research Articles

Method for the determination of 4′-deoxydoxorubicin, 4′-deoxydoxorubicinol and their 7-deoxyaglycones in human serum by high-performance liquid chromatography

4′-Deoxydoxorubicin (4′-DOX) is a new and structurally similar analogue of the anti-cancer drug adriamycin (ADR). Based on known pathways of metabolism of ADR a high-performance liquid chromatographic method for the separation and identification of 4′-DOX and five possible metabolites was developed. Sensitivity for serum is 10 ng/ml for 4′-DOX and its alcoholic product 4′-deoxydoxorubicinol (4′-DOL) and 2 ng/ml for four of its aglycone products with coefficients of variation in k′ of less than 5% throughout the day. An extraction step with better than 80% recovery of 4′-DOX and five reference metabolites from serum is described. Analysis of patient sera identified two metabolite peaks. These co-eluted with the reference metabolites of 4′-DOL and the 7-deoxyaglycone of 4′-DOX. Pharmacokinetics of the parent drug followed a two-compartment model. Both the metabolites were produced quickly and disappeared quickly.

Failure of liposomally encapsulated adriamycin to improve therapeutic efficacy for cancer cells in vitro.

The anticancer drug Adriamycin was tested in vitro both in free form and encapsulated in negatively charged liposomes. [3H]-thymidine incorporation and a 72-hour survival test were used for the evaluation of cytotoxicity in a phagocytic human melanoma cell line and a non-phagocytic human ovarian carcinoma cell line. In each case, free Adriamycin induced greater cell damage than did liposomal drug. Stability tests of the liposomes used for subsequent cytotoxicity studies under the exact conditions of the cell culture assay revealed that up to 45 per cent of the originally entrapped drug was released from the lipid vesicles over a 24-hour period.

Toxicity of free and liposome-encapsulated adriamycin following large volume, short-term intraperitoneal exposure in the rat

The effect of liposome encapsulation on toxicity of the anticancer drug adriamycin (ADR) was studied using large volume intraperitoneal (ip) administration. Concebtrations of 5, 20, and 75 μg/ml of free ADR, ADR encapsulated within lipid vesicles, or ADR in the presence of empty lipid vesicles were tested. The most prominent toxic effect was peritonitis, characterized by accumulation of peritoneal fluid, abdominal adhesions, and histologic evidence of inflammation. Two days after treatment, peritonitis was marginally less with encapsulated than with free ADR. Fourteen days after treatment, peritonitis was generally more severe in the encapsulated 20 μg/ml group than in the free ADR group. At 75 μg/ml the effects of encapsulation on local toxicity were mixed, although the systemic effects were less severe with encapsulation. A generalized hyperlipidemia (Day 14) and elevated LDH levels (Day 2) produced by the highest dose of free ADR were not observed in rats receiving encapsulated ADR. It is concluded that at the concentrations tested, encapsulation appears to offer minimal advantage in reducing local toxicity, but that it may be of benefit in reducing the incidence and severity of systemic toxicity resulting from large volume ip administration of ADR.

The effects of adriamycin in vitro and in vivo on hepatic microsomal drug-metabolizing enzymes: Role of microsomal lipid peroxidation

The quinone-containing anticancer drug adriamycin augments the reduction of dioxygen to reactive oxygen species and thereby stimulates (sixfold) NADPH-dependent microsomal lipid peroxidation. In vitro the extensive adriamycin-promoted peroxidation depleted (85%) rat liver microsomal cytochrome P-450, severely inhibited cytochrome P-450-dependent monooxygenation (70%), and glucose-6-phosphatase activity (80%), and activated (450%) UDP-glucuronyltransferase activity. When lipid peroxidation was blocked by EDTA, adriamycin selectively decreased cytochrome P-450 and aminopyrine N-demethylase activity; NADPH-cytochrome c reductase, UDP-glucuronyltransferase, and glucose-6-phosphatase activities were unchanged. Washing and resedimenting peroxidized microsomes to remove adriamycin and soluble lipid peroxidation products failed to restore enzyme activities to control values. Adriamycin administered subacutely (5 mg/kg × three doses) to rats significantly descreased hepatic microsomal cytochrome P-450 content and reduced aminopyrine N-demethylase and NADPH-cytochrome c reductase activities compared to saline-treated controls. Microsomal lipid peroxidation was increased following the above adriamycin treatment. Thus, these data suggested that adriamycin was capable of impairing hepatic drug metabolism in vitro by stimulating membrane lipid peroxidation in a manner similar to carbon tetrachloride; the mechanism by which adriamycin treatment in vivo decreased the activity of the drug monooxygenase system remains unclear.

Evidence for a plasma membrane redox system on intact ascites tumor cells with different metastatic capacity

A NADH-ferricyanide reductase of the external surface of intact mouse ascites tumor cells grown in culture was shown. The oxidation/reduction reaction was due to enzymatic rather than inorganic iron catalysis as demonstrated by the kinetics and specificity of the reaction. Activities of three markers for cytoplasmic contents were lacking with the intact tumor cells. The dehydrogenase activity was inhibited by p-chloromercuribenzoate, bathophenanthroline sulfonate, and the anticancer drug adriamycin. Sodium azide and potassium cyanide inhibited partially. The response to inhibitors resembled that of isolated plasma membranes rather than that of mitochondria. Concurrent with these findings, neither superoxide dismutase nor rotenone affected the redox activity. The findings provide evidence for the operation of a plasma membrane redox system at the surface of intact, living cells.

Transforming potential of the anticancer drug adriamycin.

A Fischer rat embryo cell system in vitro, which had been shown to be highly accurate in identifying chemical carcinogens and to have application in the study of chemicals having anticancer properties, was used to study the anticancer drug adriamycin. At a nontoxic dose adriamycin not only did not protect the cells from transformation by the carcinogen 3-methylcholanthrene, but was found in two separate experiments to act on its own as a transforming agent.