Dosing time dependency of doxorubicin-induced cardiotoxicity and bone marrow toxicity in rats

Abstract

Cardiac toxicity caused by doxorubicin (adriamycin) is a serious dose-limiting factor in the clinical situation. However, the influence of doxorubicin dosing time has not been clarified from the viewpoints of cardiotoxic development and its mechanism. In this study, we have investigated the dosing time dependency of doxorubicin-induced cardiotoxicity and bone marrow toxicity after repeated administration of doxorubicin in rats. When doxorubicin (5 mg kg(-1), i.p.) was administered every seven days (total of 30 mg kg(-1)) at 3, 9, 15 or 21 h after the light was turned on (HALO), toxic death was significantly higher in the 9 HALO treated group than the other groups. When doxorubicin was injected every seven days for 28 days at 9 or 21 HALO, we measured the levels of creatine kinase, malondialdehyde (MDA; an index of lipid peroxide), and glutathione peroxidase (GPx) as markers of cardiotoxicity. On days 14 and 28, creatine kinase levels were significantly higher in the 9-HALO group compared with the 21-HALO group (P< 0.01, respectively). On day 14, MDA levels increased significantly in the 9 HALO group compared with the 21 HALO group (P< 0.01). A single dose of doxorubicin was administered at 9-h or 21-h after the light was turned on to investigate the dosing-time-dependent difference of the pharmacokinetics. The area under the plasma time-concentration curve showed a significant increase at 9 HALO compared with 21 HALO (P< 0.05). These results suggested that the dosing-time-dependent difference of cardiotoxicity induced by doxorubicin was closely related to the daily variation of doxorubicin pharmacokinetics. In conclusion, the choice of optimal dosing time based on the chronopharmacokinetics of doxorubicin may decrease the cardiotoxicity and enable the practice of effective and safe chemotherapy of doxorubicin.

Influence of Dosing Schedule on Toxicity and Antitumor Effects of a Combination of Adriamycin and Docetaxel in Mice

“…Oxygen radical-induced injury of membrane lipids was suggested to be the most important factor responsible for the development of ADR-induced cardiotoxicity. We also reported that the concentration of lipid peroxide (LPO), which is a factor in ADR-induced congestive heart failure, differs with dosing time and that the daily variation in LPO coincides with that in ADR-induced toxic death (13). In the preliminary study, an increase in LPO was observed in mice treated repeatedly with both ADR and DOC at the same time compared with mice treated repeatedly with ADR alone.…”

“…ADR concentrations were quantified by a high-performance liquid chromatography system according to a previously published method (13). Plasma (100 l) or myelocyte cells (1 ϫ 10 7 cells) were mixed with 1 ml of Colthoff buffer, 0.1 ml of solution buffer [0.01 M phosphate buffer (pH 3.0):methanol (1:1, v/v)], 0.1 ml of the internal standard (epirubicin), and 4 ml of extraction solvent ethyl acetate:n-butanol (4:1, v/v).…”

Inactivation of NF-κB by 3,3′-diindolylmethane contributes to increased apoptosis induced by chemotherapeutic agent in breast cancer cells

“…6). However, the combination treatment may result in different levels of systematic toxicities (58,59). Thus, optimization of combination chemotherapy based on molecular mechanism may improve therapeutic indexes that are critically needed for the treatment of patients with breast cancer.…”

Chronopharmacologic Cancer Treatment with an Angiogenic Vessel-Targeted Liposomal Drug

“…11) To et al 30) examined the dosing time dependency of doxorubicin-induced cardiotoxicity and bone marrow toxicity after repeated administration in rats. They reported that the toxic effects were significantly high in the 9 HALO-treated group, corresponding to ZT 9 and that the reason was the increased AUC of the drug.…”