A comparative study on the antitumor effect, cardiotoxicity and nephrotoxicity of doxorubicin given as a bolus, continuous infusion or entrapped in liposomes in the Lou/M Wsl rat

Abstract

Liposome encapsulation of doxorubicin (DXR) has been shown to increase the therapeutic index of the drug in several animal systems. The prevention of peak plasma concentrations of free drug might be a major factor contributing to the beneficial effects resulting from liposome encapsulation. If so, the administration of DXR as a continuous infusion should also lead to an improved therapeutic index. In the present paper, the administration of liposome-encapsulated DXR is compared with the infusion of DXR with regard to their potential to preserve antitumor activity, enhance survival and reduce cardiomyo- and nephropathy in IgM immunocytoma-bearing Lou/M Wsl rats. Plasma concentrations of DXR were determined to correlate the biological results with pharmacokinetic parameters. Liposomes containing phosphatidylcholine, phosphatidylserine and cholesterol (extrusion-multilamellar vesicles) were used. Bolus injections of free DXR (free DXR) and DXR liposomes (lip-DXR) in a multiple-dose regimen were compared with 24-h infusions of the same cumulative doses of DXR (inf-DXR). The antitumor activity of inf-DXR equalled that of free DXR as well as that of lip-DXR at doses of greater than 0.25 mg/kg. The overall survival of tumor-bearing animals treated with 2.0 mg/kg lip-DXR was significantly prolonged (P less than 0.01) in comparison with that of animals treated with 2.0 mg/kg free DXR; however, treatment with 2.0 mg/kg inf-DXR did not induce a significant prolongation of survival. At a cumulative dose of 12 mg/kg, inf-DXR appeared to be as effective as lip-DXR in reducing the severity of cardiomyopathy induced by free DXR. However, for the reduction of nephropathy, only therapy with lip-DXR was effective. Inf-DXR induced high nephropathy scores comparable with those obtained with free DXR. For the first 24 h after an injection of 2.0 mg/kg or after the start of a continuous infusion of 2.0 mg/kg given over 24 h, similar areas under the plasma concentration-time curves (AUC) were calculated for free DXR and inf-DXR. However, for lip-DXR a much higher value was calculated. The higher plasma levels of lip-DXR did not result in higher cardiac levels. After five daily doses of 2.0 mg/kg, a much lower DXR concentration was found in cardiac tissue after the administration of lip-DXR than after the administration of free DXR or inf-DXR. This suggests that an important parameter to be determined and correlated with biological results is the free (i.e. not bound to liposomes) circulating fraction of DXR in lip-DXR-injected animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Improved distribution and reduced toxicity of adriamycin bound to albumin-heparin microspheres

“…Nephrotic syndrome was probably the main cause of death in the animals in the free ADR treated group. This agrees with reports of Storm et al (1989) who concluded that ADR-induced nephropathy represents an important cause of death in experimental animals.…”

“…This maximum allowable dose, however, is related to the dose schedule. Storm et al (1989) found that reduction of cardiotoxicity induced by either continuous infusion or liposomal encapsulation of ADR is most likely related to the reduction of peak plasma levels. Moreover, it has been reported that damage to heart muscle cells is mainly related to peak ADR concentrations and that at lower concentrations higher cumulative doses are tolerated (Bielack et al, 1989).…”

Simultaneous generation of methane, carbon dioxide, and carbon monoxide from choline and ascorbic acid ‐ a defensive mechanism against reductive stress?

“…In particular, PC has been shown to increase tolerance in experimental ischemia and hypoxia (13,14). Similarly, it has been shown to reduce the toxicity of the redoxcycling drugs and the ulcerogenicity of nonsteroidal anti-inflammatory agents (15,16). In the light of the experiments presented here, these effects can also be interpreted in terms of a more efficient response to reductive stress.…”

Effects of phosphatidylserine-containing liposomes on odontogenic differentiation of human dental pulp cells

“…To investigate the effects of PS on human dental pulp cells, PS was provided as liposomes with PC and CH added to stabilize liposome structure 17) . Liposomes containing PS, PC and CH have been frequently used in various studies for drug delivery, tissue repair, and molecular imaging [18][19][20] . The calciumbinding activity of PS in PS-containing liposomes was identified previously 21) .…”