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excellent homeostatic autoregulation of blood flow .

Figure 3. Enhancement of macromolecular drug delivery to tumor (Walker carcinoma 256) in rats given angiotensin II by i.v. infusion. Rats also had the systemic blood pressure elevated for about IS min from about 100 to ISO mmHg by angiotensin II infusion. To albumin l4C-glycine was attached via amide bond chemically using carbodiimide to a putative macromolecular drug (bovine serum albumin) (From refs. 30, 31). Tu,s.c., tumor implanted subcutaneous location; Tu.om, tumor inoculated peritoneally and metastatic tumor nodule on the omentum; Drug concentration in; Sm. int., small intestine; B. marrow, bone marrow. Tu,sc/sm.int. indicates the ratio of drug concentration between that in tumor subcutaneous over the small intestine, a normal tissue. Solid bars show values obtained after angiotensin II induced hypertension procedure. White bars, normotensive state.

Figure 3. Enhancement of macromolecular drug delivery to tumor (Walker carcinoma 256) in rats given angiotensin II by i.v. infusion. Rats also had the systemic blood pressure elevated for about IS min from about 100 to ISO mmHg by angiotensin II infusion. To albumin l4C-glycine was attached via amide bond chemically using carbodiimide to a putative macromolecular drug (bovine serum albumin) (From refs. 30, 31). Tu,s.c., tumor implanted subcutaneous location; Tu.om, tumor inoculated peritoneally and metastatic tumor nodule on the omentum; Drug concentration in; Sm. int., small intestine; B. marrow, bone marrow. Tu,sc/sm.int. indicates the ratio of drug concentration between that in tumor subcutaneous over the small intestine, a normal tissue. Solid bars show values obtained after angiotensin II induced hypertension procedure. White bars, normotensive state.

We previously investigated whether this increased tumor blood flow would influence the EPR effect, i.e., if an angiotensin II-induced hypertensive state would improve macromolecular drug delivery. As shown in Figure 3, both radiolabeled bovine serum albumin and SMANCS, which binds to albumin in vivo, thereby becoming an apparent molecular mass of about 80 kDa, accumulated about 1.3 - 3 fold more when arterial blood pressure was elevated from 100 to 150 mmHg by infusion of angiotensin II, and was maintained for 15 min after i.v. injection of [51Cr] labeled SMANCS or the putative macromolecular drug (radiolabeled bovine serum albumin) 34. Drug delivery to normal organs such as the kidney and the bone marrow was reduced because of the induced vasoconstriction of normal organs, so that the tighter endothelial cell gap suppressed transvascular transfer of macromolecules (Figure 3). Consequently, the side effects such as diarrhea, bone marrow-cellularity, and body weight were decreased to a significant extent 34 Although the therapeutic dose of an anticancer agent cannot usually be increased 2-3 times more than the recommended dose because of the very narrow safety margin of any conventional anticancer agents, the angiotensin II-induced hypertensive state permits administration of higher dosages for macromolecular drugs. Thus, one may achieve a better therapeutic effect but with fewer and less severe side effects by this method. This therapeutic maneuver is valid only for macromolecular drugs, however.

3.2 Bradykinin

Bradykinin, which has been studied extensively in inflammation,

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infection and in cancer - , , is an important mediator of the EPR effect. It is well known that bradykinin mediates pain and increases vascular

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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