and the brain was almost unaffected (Figure 6) . A similar effect, i.e., selective suppression (>90%) of tumor blood flow, was observed by using the prostaglandin I2 (PGI2) analogue beraprost (our unpublished data).

Injection of this PGI2 analogue, which has much longer in vivo t|/2 than resulted in much enhanced EPR effect as that seen with ACE

inhibitors in course of several hours: it increased 2-3 times extravasation of

Evans blue/albumin. Systemic blood pressure decreased only 10-20%, whereas blood flow in the tumor (AH136B) decreased 90-95%. We believe that this mechanism involves the opening of the tight junction of the endothelium at the postcapillary venule so that plasma components do leak out more effectively into the extravascular space before reaching the postcapillary venous side. As an incidental finding, these vasoactive mediators reduced blood flow downstream to an almost negligible amount

(to less than 10%). In this way, we may also achieve more selective accumulation of macromolecular anticancer agents in tumor as well as similar imaging agents though we need to demonstrate in clinical setting.

Therefore, one might improve tumor-selective drug delivery by using macromolecular drugs under angiotensin II-induced hypertensive conditions, together with appropriate vascular mediators such as ACE inhibitors. It should also be mentioned that when methylglucose, a representative of low-molecular-weight drug mimic, was studied, the EPR effect was only marginal and lasted no longer than 10 min. Such low-molecular-weight drugs seem to be washed out rapidly into the general circulation within 1033

min and excreted via the urine.

Figure 6. Effect of a second-generation ACE inhibitor, temocapril, on tumor blood flow. Note the great difference in flow rate in normal organs (A) vs that in tumor (B). Tumor blood flow was most affected by elevating blood pressure. The tumor used was LY80 in rats. (Adapted from ref. 39).

3.3 Other inflammatory mediators

Besides VPF (VEGF) and bradykinin system, many other factors involve in the EPR effect in solid tumor. Figure 4 shows various vascular mediators and their interaction for regulating tumor blood flow and vascular permeability.

Prostaglandin biosynthesis by cyclooxygenase (COX-1 and -2), particularly for prostaglandin E2 production, are markedly elevated in human and experimental tumors (40, 41), and many studies have shown that administration of prostaglandin synthesis inhibitors brought about a reduced risk of growth of tumor such as colon cancer, thus that they are beneficial for

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