Intracarotid infusion of RMP-7, a bradykinin analog: a method for selective drug delivery to brain tumors.
The bradykinin analog, RMP-7, was investigated for its ability to selectively increase uptake of molecular tracers in RG2 glial tumors. When infused in low doses (0.1 microgram/kg/min) through the intracarotid artery ipsilateral to RG2 gliomas in rats, RMP-7 significantly increased the permeability of tumor capillaries to methotrexate and to four other tracers of varying molecular weights, compared to intracarotid infusion of vehicle alone. Tracers used to examine permeability included radiolabeled alpha-aminoisobutyric acid (M(r) 103 D), sucrose (M(r) 342 D), methotrexate (M(r) 454.5 D), inulin (M(r) 5000 D), and dextran (M(r) 70,000 D). Permeability was expressed as the unidirectional transfer constant, Ki (microliters/gm/min). The permeability (Ki) of tumors in the RMP-7 group compared to the vehicle control group was as follows: alpha-aminoisobutyric acid, 35.3 +/- 9.11 versus 12.7 +/- 4.56 (p < 0.001); sucrose, 16.5 +/- 3.83 versus 9.28 +/- 3.12 (p < 0.05); methotrexate, 26.3 +/- 10.3 versus 8.98 +/- 6.78 (p < 0.005); inulin, 13.5 +/- 3.23 versus 6.55 +/- 4.32 (p < 0.005); dextran, 15.2 +/- 3.42 versus 1.47 +/- 1.24 (p < 0.001). The permeability of RG2 gliomas to high-molecular-weight dextran (70,000 D) was 10.3-fold higher in the RMP-7 group than in the vehicle control group. Intracarotid infusion of RMP-7 did not significantly increase the blood volume in tumor or brain tissue. The permeability of normal brain capillaries was unaffected by intracarotid infusion of 0.1 microgram/kg/min RMP-7 relative to that achieved in tumor. These data support the idea that intracarotid infusion of RMP-7 will be a useful technique for selective delivery of antitumor compounds to brain tumors.
Inamura
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Brain Research Institute, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Medical Center.
Nomura
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Bartus
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Black
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D000818:Animals; D001345:Autoradiography; D001794:Blood Pressure / Q000187:drug effects; D001810:Blood Volume / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002196:Capillaries / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002339:Carotid Arteries; D005260:Female; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007261:Infusions, Intra-Arterial; D051381:Rats; D017208:Rats, Wistar
C089876:RMP 7; D001920:Bradykinin