Amifostine reduces the seminiferous epithelium damage in doxorubicin-treated prepubertal rats without improving the fertility status

<p>Abstract</p> <p>Background</p> <p>Amifostine is an efficient cytoprotector against toxicity caused by some chemotherapeutic drugs. Doxorubicin, a potent anticancer anthracycline, is known to produce spermatogenic damage even in low doses. Although some studies have suggested that amifostine does not confer protection to doxorubicin-induced testicular damage, schedules and age of treatment have different approach depending on the protocol. Thus, we proposed to investigate the potential cytoprotective action of amifostine against the damage provoked by doxorubicin to prepubertal rat testes (30-day-old) by assessing some macro and microscopic morphometric parameters 15, 30 and 60 days after the treatment; for fertility evaluation, quantitative analyses of sperm parameters and reproductive competence in the adult phase were also carried out.</p> <p>Methods</p> <p>Thirty-day-old male rats were distributed into four groups: Doxorubicin (5 mg/kg), Amifostine (400 mg/kg), Amifostine/Doxorubicin (amifostine 15 minutes before doxorubicin) and Sham Control (0.9% saline solution). "Standard One Way Anova" parametric and "Anova on Ranks" non-parametric tests were applied according to the behavior of the obtained data; significant differences were considered when p < 0.05.</p> <p>Results</p> <p>The rats killed 30 and 60 days after doxorubicin treatment showed diminution of seminiferous epithelium height and reduction on the frequency of tubular sections containing at least one type of differentiated spermatogonia; reduction of sperm concentration and motility and an increase of sperm anomalous forms where observed in doxorubicin-treated animals. All these parameters were improved in the Amifostine/Doxorubicin group only when compared to Doxorubicin group. Such reduction, however, still remained below the values obtained from the Sham Control group. Nevertheless, the reproductive competence of doxorubicin-treated rats was not improved by amifostine pre-administration.</p> <p>Conclusions</p> <p>These results suggest that amifostine promotes a significant reduction of the doxorubicin long-term side effects on the seminiferous epithelium of prepubertal rats, which is reflected in the epidydimal fluid parameters in the adult phase. However, fertility status results suggest that such protection may not be effective against sperm DNA content damage. Further investigation of sperm DNA integrity must be carried out using amifostine and doxorubicin-treated experimental models.</p

Time-and concentration-dependent penetration of doxorubicin in prostate tumors

The penetration of paclitaxel into multilayered solid tumors is time- and concentration-dependent, a result of the drug-induced apoptosis and changes in tissue composition. This study evaluates whether this tissue penetration property applies to other highly protein-bound drugs capable of inducing apoptosis. The penetration of doxorubicin was studied in histocultures of prostate xenograft tumors and tumor specimens obtained from patients who underwent radical prostatectomy. The kinetics of drug uptake and efflux in whole tumor histocultures were studied by analyzing the average tumor drug concentration using high-pressure liquid chromatography. Spatial drug distribution in tumors and the drug concentration gradient across the tumors were studied using fluorescence microscopy. The results indicate that drug penetration was limited to the periphery for 12 hours in patient tumors and to 24 hours in the more densely packed xenograft tumors. Subsequently, the rate of drug penetration to the deeper tumor tissue increased abruptly in tumors treated with higher drug concentrations capable of inducing apoptosis (i.e., >5 μm), but not in tumors treated with lower concentrations. These findings indicate a time- and concentration-dependent penetration of doxorubicin in solid tumors, similar to that of paclitaxel. We conclude that doxorubicin penetration in solid tumors is time- and concentration-dependent and is enhanced by drug-induced cell death