Inability of dimethyl sulfoxide and 5-fluorouracil to open the blood-brain barrier.
The inability of most chemotherapeutic agents to adequately penetrate the blood-brain barrier (BBB), in either normal brain or tumor-infiltrated brain, is a major factor limiting the use of chemotherapy in central nervous system malignancy. This barrier, however, can be opened in a reversible manner by the intra-arterial administration of hyperosmotic agents such as mannitol. It has been suggested that the intravenous administration of dimethyl sulfoxide (DMSO) or 5-fluorouracil (5-FU) can accomplish the same thing in a less invasive manner. We have not been able to confirm these findings. DMSO was administered to 25 rats intravenously at concentrations ranging from 25 to 90% or into the internal carotid artery at a concentration of 30%. The penetration of methotrexate, Evans blue-albumin, and hexosaminidase A was then evaluated at intervals ranging from 1.5 to 3.5 hours after administration. Significant barrier opening was not observed in animals receiving intravenous DMSO. Barrier modification, albeit generally modest, was obtained in animals receiving intracarotid DMSO, but this may have been the result of grand mal seizures, inasmuch as 5 of 6 of these animals had such seizures. Several of the animals receiving i.v. DMSO also had seizures, and all animals developed varying degrees of hematuria. Similarly, 5-FU was administered at a dose of 30 mg/kg i.v. and the permeability of the BBB to either Evans blue-albumin or methotrexate was evaluated. No increased permeability of the BBB to these two markers was observed. In summary, osmotic BBB opening in our hands remains the most consistent and reliable means available to open the BBB in a reversible fashion. Neither intravenous DMSO nor 5-FU seems to increase the delivery of chemotherapy or protein tracer to the central nervous system, and the use of DMSO can result in seizures and hematuria.
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002199:Capillary Permeability; D002339:Carotid Arteries; D004121:Dimethyl Sulfoxide / Q000008:administration & dosage / Q000494:pharmacology*; D005070:Evans Blue / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D054818:Hexosaminidase A; D006596:Hexosaminidases / Q000378:metabolism; D007269:Injections, Intra-Arterial; D008727:Methotrexate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D001619:beta-N-Acetylhexosaminidases
D005070:Evans Blue; D006596:Hexosaminidases; D054818:Hexosaminidase A; D001619:beta-N-Acetylhexosaminidases; D005472:Fluorouracil; D008727:Methotrexate; D004121:Dimethyl Sulfoxide