CDDP was administered (i.p) once a week for 3 weeks at 5 mg/kg (group 5) alone or in combination with TQ at 5 mg/kg (group 6), 10 mg/kg (group 7) and 20 mg/kg (group 8). No mortality was observed in groups 1-6 though mice in group 6 lost 20-40% of body weight. 50% of the mice in group 7 and 75% in group 8 died. Histological analysis was performed on kidneys, liver, lung and heart of treated mice. There were no pathological abnormalities noted in the lungs and
heart of any of the mice. In the analysis of the kidneys no pathological abnormality was observed Selleck Epoxomicin in groups 1-4 (TQ treated alone) except for the presence of 5% focal proximal tubular Selleckchem Caspase Inhibitor VI damage noted in group 4 (TQ
20 mg/kg). In group 5 (CDDP5 mg/kg alone) there was proximal tubular damage noted in 20-30% of the samples. In the combination groups [7, 8] diffuse tubular damage and acute tubular necrosis (ATN) was noted in 40-80% of samples. Mice in these groups also lost significant Mdivi1 body weight and appeared dehydrated. This enhancement of nephrotoxicity may be related to poor by mouth intake and dehydration resulting in ATN. On the basis of these studies MTD was determined to be as follows: CDDP 2.5 mg/kg i.p. weekly along with TQ at 5 mg/kg and 20 mg/kg subcutaneously Monday, Wednesday and Friday for the xenograft study. 6) Mouse xenograft study In the mouse xenograft study as described in methods section after 4 weeks of tumor growth no mortality occurred. However, the combination of TQ and CDDP had striking effects on tumor volume (Figure 10). TQ alone at 5 mg/kg was not active. The higher dose of TQ at 20 mg/kg demonstrated some activity and reduced tumor volume although the effect was marginally significant (p 0.075). Cisplatin alone at 2.5 mg/kg reduced tumor volume significantly (p < 0.001). The effect on tumor volume was greatest in the combination arms
with significant reduction of tumor volume by 59% with the combination of (5 mg/kg TQ and 2.5 mg/kg CDDP) (p = 0.036) and by 79% with combination of (20 mg/kg TQ and 2.5 mg/kg of CDDP) (p = 0.0016). Figure 10 Results of Mouse xenograft study. Tumor Epothilone B (EPO906, Patupilone) volume with time: Change in tumor volume is shown in various treatment arms over the study period. Mice were treated with either s.c. TQ every Monday, Wednesday and Friday or CDDP i.p. once a week or combination.Mice in combination treatment arms (TQ20 mg/kg + CDDP 2.5 mg/kg) had the smallest tumor volume at the end of 3 week study period. The decrease in tumor volume was mimicked by a similar decrease in tumor weight in all treatment arms except TQ alone at 5 mg/kg (Figure 11) Figure 11 Mean tumor weight at day 26 for each group. (*) means significant inhibition by addition of TQ (p < 0.05). 7) TQ suppresses NF-κB expression in vivo TQ by itself had no effect on basal luciferase activity and NF-κB expression.