Intravenous cereport (RMP-7) modifies topographic uptake profile of carboplatin within rat glioma and brain surrounding tumor, elevates platinum levels, and enhances survival.
Several experiments studied the effects of i.v. infusions of the bradykinin agonist, Cereport (RMP-7), on permeability of the blood-brain tumor barrier in rat gliomas. First, the ability of Cereport to increase uptake of two poorly blood-brain barrier-penetrating drugs (lypophilic paclitaxel and hydrophilic carboplatin) was directly compared to provide new information regarding the scope of delivery effects achieved with Cereport. Next, the increased uptake of platinum into tumor and brain surrounding tumor was shown to closely parallel that of radiolabeled carboplatin, confirming that delivery of a biologically active moiety is increased with Cereport. This study also demonstrated that the elevated tumor levels of platinum persisted for at least 2 h. The enhanced carboplatin uptake was then examined using a novel, high spatial resolution analysis of autoradiography. This revealed that the effects of Cereport were not uniform throughout the tumor, because it especially modified those areas normally impermeable to carboplatin. Finally, a range of i.v. Cereport doses (3.0 and 9.0 microg/kg) was tested in combination with carboplatin to determine whether increased survival might be achieved and to define the relationship between Cereport dose, plasma levels, uptake of carboplatin, and enhanced survival. Survival was enhanced only by the high dose of Cereport; the high dose also produced robust increases in carboplatin uptake and plasma concentrations of Cereport estimated to achieve the K(i), whereas the low dose did not. These data offer fundamental information regarding the effects of Cereport on delivery of chemotherapeutic agents to brain tumors and provide new insight into receptor-mediated permeability of the blood-brain tumor barrier.
Bartus
R T
RT
Alkermes, Inc., Cambridge, MA 02139-4136, USA. rtbartus@alkermes.com
Snodgrass
P
P
Marsh
J
J
Agostino
M
M
Perkins
A
A
Emerich
D F
DF
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D016190:Carboplatin / Q000493:pharmacokinetics*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D007262:Infusions, Intravenous; D008297:Male; D017239:Paclitaxel / Q000493:pharmacokinetics; D010984:Platinum / Q000493:pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344
D000970:Antineoplastic Agents; C089876:RMP 7; D010984:Platinum; D016190:Carboplatin; D017239:Paclitaxel; D001920:Bradykinin