Intravenous Cereport (RMP-7) enhances delivery of hydrophilic chemotherapeutics and increases survival in rats with metastatic tumors in the brain

The following experiments determined whether intravenous infusions of Cereport enhance delivery of chemotherapeutics and prolong survival in rats with metastatic tumors in the brain. Autoradiography and scintillation were used to examine uptake of the lipophilic (paclitaxel and carmustine) and the h...

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Bibliographic Details
Published in:Pharmaceutical research 2000-10, Vol.17 (10), p.1212-1219
Main Authors: EMERICH, Dwaine F, DEAN, Reginald L, MARSH, Joanne, PINK, Melissa, LAFRENIERE, Denise, SNODGRASS, Pamela, BARTUS, Raymond T
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Autoradiography
Biological and medical sciences
Blood-Brain Barrier - drug effects
Bradykinin - analogs & derivatives
Bradykinin - pharmacology
Brain - metabolism
Brain cancer
Brain Neoplasms - drug therapy
Brain Neoplasms - metabolism
Brain Neoplasms - secondary
Carboplatin - pharmacokinetics
Carboplatin - pharmacology
Carmustine - pharmacokinetics
Carmustine - pharmacology
Chemotherapy
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacokinetics
Deoxycytidine - pharmacology
Drugs
Effectiveness
Male
Medical sciences
Metastasis
Permeability
Pharmacology. Drug treatments
Rats
Rats, Inbred F344
Tumors
Vinblastine - analogs & derivatives
Vinblastine - pharmacokinetics
Vinblastine - pharmacology
Vinorelbine
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Summary:The following experiments determined whether intravenous infusions of Cereport enhance delivery of chemotherapeutics and prolong survival in rats with metastatic tumors in the brain. Autoradiography and scintillation were used to examine uptake of the lipophilic (paclitaxel and carmustine) and the hydrophilic (carboplatin) chemotherapeutic agents, as well as the large hydrophilic marker, 70 kDa dextran. Cereport was also tested in combination with the chemotherapeutic drugs carboplatin, vinorelbine, gemcitabine and carmustine to determine if Cereport could enhance the survival benefit beyond that provided by chemotherapy alone. Cereport enhanced the uptake of carboplatin and dextran, but not paclitaxel or carmustine. The pattern of Cereport's uptake effect with carboplatin revealed that Cereport selectively increased the proportion of highly permeable regions. Survival was significantly enhanced when Cereport was combined with either carboplatin, vinorelbine, or gemcitabine, but not carmustine, compared to each chemotherapeutic agent alone. These data provide the first evidence that Cereport, or any receptor-mediated approach intended to enhance the permeability of the blood-brain tumor barrier, can increase the delivery hydrophilic drugs to metastatic tumors in the brain, increasing survival in tumor-bearing rats.
ISSN:0724-8741
1573-904X