Our previous report has indicated that enhanced anti-tumor effect of liposome entrapped cancer drugs is brought about by the slow release rather than the selective delivery to the tumors. Besides, it is noteworthy that large amounts of the liposome entrapped drugs are selectively taken up by the reticuloendothelial system (RES), such as the spleen, liver and lung. These facts led us to examine the possibility to increase intra-tumor uptake of the liposome entrapped drugs by means of prior RES blockade in cancer bearing nude mice and consequently to accelerate their anti-cancer effect.
Experiment-1. The effect of RES blockade on pharmacokinetics of liposome entrapped Bleomycin (BLM).
Testicular tumor bearing nude mice were treated by intraperitoneal administration of Fesin (saccharated ferric oxide) or drug free liposome for 3 days prior to injection of free (control group) or liposome entrapped BLM (study group). Then the intra-tumor accumulation of BLM was bioassayed at 12 and 24 hours after the injection.
Table 1 shows the results obtained at 12 and 24 hours following intraperitoneal injection of free and liposome entrapped BLM. These results indicate that the concentration of intra-tumor BLM was remarkably increased by RES blockade in the study group. On the other hand, high accumulation of liposome entrapped BLM in the RES was not influenced by RES blockade.
Experiment-2. The effect of RES blockade on in vivo anti-cancer effect of liposome entrapped BLM.
Nine testicular tumor bearing nude mice were divided into two groups, RES blockade and nonblockade groups, which included five and four nude mice, respectively. In RES blockade group (group A), the nude mice were treated by intraperitoneal administration of Fesin 4.5mg/head/day for 3 days and followed by intraperitoneal injection of liposome entrapped BLM, 5mg/head 24 hours after the 3rd shot of Fesin. Then the tumor size was measured every day for 10 days and subsequently individual growth rate was calculated by the formula. In non-blockade group (group B), the nude mice were given a single shot of liposome entrapped BLM, 5mg/head without administration of Fesin in advance. Their tumor size and growth rate were measured for 10 days as with group A. Finally, the daily mean values of the growth rate were compared between the two groups. The average growth rates of groups A and B were 0.77±0.06 and 0.88±0.17, respectively, on day 1, thereby indicating a stronger effect on the tumor size in the former group (statistically not significant). This tendency was observed on day 2. However, it was reversed on day 3, when the average tumor growth rate of group A turned out higher than that of group B, thereby indicating a rebound phenomenon. In both groups, tumors continued to decrease their size by day 5. However, they showed a trend of re-growth from day 6 through day 10, during which period the growth rates of the group A were always higher than those of group B. The average tumor growth rates were 1.02±0.339 in the former and 0.862±0.138 in the latter group on day 10.
One of the five nude mice of group A died on day 6. Autopsy did not disclose the cause of death. The remaining four in either groups showed no clinical illness throughout the period of experiment. In conclusion, clinical application of our system is too early at this moment, considering the limited duration of the effect and the existence of rebound phenomenon. On the other hand, the major impact of RES blockade is likely to be altered pharmacokinetics and drug metabolism. Further efforts to revise the method of RES blockade and to solve the problem of adverse effects could make clinical application of RES blockade possible in the field of sophisticated anti-tumor chemotherapy.
View full abstract