Biochemical and biological activity of the anthracycline analog, 4-demethyl-6-0-methyl-doxorubicin

Summary The chromophore-modified derivative of doxorubicin, 4-demethyl-6-0-methyl-doxorubicin, has been tested for antitumor activity in a range of experimental murine tumor systems. In contrast to the inactive 6-0-methyl derivative of daunorubicin, 4-demethyl-6-0-methyl-doxorubicin provided antitumor effects comparable to that of the parent compound. In addition, detailed DNA-interaction studies showed that the doxorubicin derivative retains the ability to bind DNA by the intercalation mechanism. However, the binding affinity was appreciably reduced following structural modification in the anthraquinone chromophore. On the basis of the proposed models of intercalation, these results could be rationalized in terms of steric influence of the bulky methoxy group. The results of this study are in agreement with the correlation already observed between DNA binding and relative antitumor activity of anthracyclines.     

Physical performance in long-term survivors of acute leukaemia in childhood

The aim of this study was to assess the physical performance in long-term survivors of acute leukaemia in childhood and to evaluate the effects of anthracycline therapy. Electrocardiography, echocardiography and spiroergometry were carried out on 56 patients aged 9–28 years, of whom 44 patients had been treated with 15–483 mg/m² doxorubicin (or equivalent). Acute leukaemia had been diagnosed 1.5–16 years earlier. Of the patients 75% reached normal maximal oxygen uptake, 69% normal oxygen uptake at the anaerobic threshold and 95% normal maximal work rate. Of the patients 75% achieved adequate values for maximal heart rate and 78% normal blood lactate concentration. No difference was seen between patients treated with and without anthracyclines. Conclusion The results of this study provide little evidence for cardiopulmonary impairment in long-term survivors of ALL. Both the cardiac function, as evaluated by ECG and echocardiography, and the physical performance in spiroergometry are normal in a large number of these patients. Anthracycline treatment does not appear to have a negative effect on these parameters. Received: 30 October 1996 / Accepted in revised form: 7 October 1997     

Effect of anthracyclines and isoflurane on QTc interval

BackgroundAnaesthetics and anthracyclines can affect the QT interval of the electrocardiogram (ECG). This study investigated whether the use of isoflurane in anthracyclines pretreated patients may induce or augment the QT prolongation to an arrhythmogenic level.Materials and methodsFifty-four female patients with breast cancer scheduled for mastectomy were included in the study, 27 received anthracyclines based chemotherapy before surgery, whereas 27 did not. All patients received a standardized balanced anaesthetic in which 0.5% end tidal concentration of isoflurane was used. The QT and corrected QT intervals (QTc) were measured before anaesthesia, after 1, 5, 15, 30, 60 min, respectively, following intubation and during recovery from anaesthesia.ResultsStatistically significant QTc prolongation was observed in patients who received anthracycline chemotherapy even prior to the administration of anaesthesia. The comparison of QTc interval at different intervals of isoflurane anaesthesia also showed a statistically significant difference between the two groups namely anthracycline treated group (study group) versus control group.A sample size of 27 in each group was calculated in order to achieve a study power of 80% with type 1 error rate of 5%. For the purpose of calculation, values of QT and QTc interval (range, mean, standard deviation) from the study of Owczuk et al. were used. t-test and analysis of variance were employed using SPSS version 10. P < 0.05 was considered as statistically significant.ConclusionsAnthracycline chemotherapy can produce significant prolongation of QTc interval. In addition, use of 0.5% end tidal concentration of isoflurane can further augment the QTc interval significantly.     

Quantitation of the nucleophosmin/B23-translocation using imaging analysis

We have previously detected by immunofluorescent assay that the cellular localization of nucleophosmin/B23 (NPM) shifts from the nucleolus to the nucleoplasm (NPM-translocation) after exposure of cells to multiple agents. In order to improve the quantification of the NPM-translocation, we have developed a digital imaging technique. Human Lo leukemia cells, MCF-7 breast carcinoma cells, and fresh human leukemia cells were exposed to anthracyclines or actinomycin D for 4 h. The degree of NPM-translocation was determined and presented as the localization index (LI). Control cells had a LI of about 10, which indicates that the majority of NPM was localized in nucleoli. The LI for drug-treated cells decreased in a dosage- and time-dependent manner. The effect of two classes of anthracycline (daunomycin and aclacinomycin A) and different types of intercalators (daunomycin and actinomycin D) had additive effects on induction of NPM-translocation. The imaging procedure was easily applied to fresh leukemia cells, thus providing useful information regarding drug effects on cancer cells.     

In vivo measurement of myocardial oxidative metabolism and blood flow does not show changes in cancer patients undergoing doxorubicin therapy

Purpose: The aim was to investigate in patients receiving doxorubicin whether any alteration in myocardial oxidative metabolism or blood flow as assessed by positron emission tomography (PET) could be observed either after the first dose of the drug, or during its chronic administration. Methods: Six female non-heart-failure cancer patients treated with doxorubicin were included in a longitudinal study. Resting radionuclide cineangiography and PET scanning with carbon-11 acetate were performed the day before the initiation of doxorubicin treatment at a dosage of 50 mg/m² every 3 weeks, and 3 weeks after the cumulative administration of 300 mg/m² (chronic toxicity). In addition, PET was performed 24 h after the first administration of doxorubicin (evaluation of acute toxicity). Myocardial oxidative metabolism and blood flow were assessed by PET (acute and chronic toxicity), and left ventricular ejection fraction was measured by radionuclide angiography (chronic toxicity). Results: Using PET for both acute and chronic toxicity evaluations, no significant effect of doxorubicin was observed either on the flux through the tricarboxylic acid (TCA) cycle or on myocardial blood flow. However, systolic left ventricular function showed a small but significant impairment after the administration of 300 mg/m² of doxorubicin. Conclusions: Other hypotheses should be explored to better explain the predominant mechanisms of the cardiotoxicity of anthracyclines in humans. Received: 18 August 1999 / Accepted: 3 December 1999     

Low concentrations of cytosine arabinoside, 6-thioguanine,actinomycin-d and aclacinomycin a stimulates the differentiation of normal human marrow myeloid progenitor cells

Myelosuppression is the major side effect of most anticancer cytotoxic drugs. Low concentrations of cytosine arabinoside (Ara-C), 6-thioguanine (6-Th), actinomycin-D (Act-D) and aclacinomycin A (ACM) have been reported to induce differentiation of leukaemic cell lines. With the proposed clinical trials of low-dosage of these four drugs, their effect on the differentiation of normal human myeloid progenitor marrow cells was studied. The four cytotoxic anticancer drugs at low concentrations stimulated normal human myeloid differentiation. Low dosage Ara-C has been used with great success in several clinical trials. The results suggest a similar therapeutic role for the other three anticancer drugs.     

Redox-cycling of anthracyclines by thioredoxin system: increased superoxide generation and DNA damage

Anthracyclines such as doxorubicin and daunomycin undergo bioreductive activation by redox-cycling, and this is associated with generation of reactive oxygen species. Toxicity of anthracyclines is attributed to DNA intercalation by an anthracycline semiquinone radical that is generated via redox-cycling. Flavoprotein enzymes catalyze the bioreductive activation of anthracyclines. Thioredoxin reductase (TR), which is also a flavoprotein enzyme, participates in bioreductive activation of anthracyclines. In the present study we showed that addition of E. coli thioredoxin (Trx) enhances the rate of superoxide production by E. coli TR in the presence of anthracyclines. The superoxide generated in this redox-cycling process induced DNA damage as determined by an in vitro plasmid DNA damage assay. In addition, Trx-SH enhanced the activity of cytochrome P450 reductase and the redox-cycling of anthracyclines independently of NADPH. Furthermore, when A549 cells were incubated with E. coli Trx followed by doxorubicin treatment, increased levels of ROS generation were observed. Taken together, these results show a novel property of the Trx system in bioreductive activation of anthracyclines.     

Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of chemotherapy

Pegylated liposomal doxorubicin (Doxil, Caelyx) is a formulation of doxorubicin in poly(ethylene glycol)-coated (stealth) liposomes with a prolonged circulation time and unique toxicity profile. We review the preclinical and clinical pharmacology as well as recent clinical data obtained in specific cancer types. Doxil liposomes retain the drug payload during circulation and accumulate preferentially in tissues with increased microvascular permeability, as often is the case of tumors. Doxil toxicity profile is drastically different from that of doxorubicin, and is characterized by dominant and dose-limiting mucocutaneous toxicities, mild myelosupression, minimal alopecia, and no apparent cardiac toxicity. Although the single maximum tolerated dose (MTD) of Doxil is actually lower than that of conventionally administered doxorubicin, the cumulative MTD dose of Doxil may be substantially greater than that of free doxorubicin. Doxil is probably one of the most active agents in AIDS-related Kaposi's sarcoma and has a definite role in management of recurrent ovarian cancer. The potential of Doxil in the treatment of other cancer types and the opportunities it offers in combination with other drugs and therapeutic modalities are under active investigation.     

Intertrigo-like eruption caused by pegylated liposomal doxorubicin (PLD)

Pegylated liposomal doxorubicin (PLD) is a drug whose use is increasingly common. It has been associated with a lower rate of haematologic and cardiac side effects than its nonencapsulated form. However, mucocutaneous toxicity is quite frequent and can be severe. Here we provide a case report of a patient who developed an intertrigolike eruption during treatment with PLD.