Neurotoxicity of chemotherapeutic agents after blood-brain barrier modification: Neuropathological studies

Authors

  • Edward A. Neuwelt MD,

    Corresponding author
    1. Departments of Neurosurgery and Biochemistry, Oregon Health Sciences University, Portland, OR 97201
    2. Department of Medicine, University of Texas Southwestern
    • Oregon Health Sciences University, Division of Neurosurgery, 3181 SW Sam Jackson Park Rd, Portland, OR 97201
    Search for more papers by this author
  • Mark Glasberg MD,

    1. Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX 75235
    Search for more papers by this author
  • Eugene Frenkel MD,

    1. Department of Medicine, University of Texas Southwestern
    2. Veterans Administration Hospitals, Dallas and Portland
    Search for more papers by this author
  • Peggy Barnett BS

    1. Departments of Neurosurgery and Biochemistry, Oregon Health Sciences University, Portland, OR 97201
    Search for more papers by this author

Abstract

We examined in 47 dogs the effects of 5-fluorouracil, Adriamycin (doxorubicin hydrochloride), cis-diamminedichloroplatinum cyclophosphamide, and bleomycin given in association with osmotic blood-brain barrier modification. The dose of drug ranged from 100% to as little as 5 to 10% of the conventional systemic dosage. Serial neurological observation and subsequent postmortem neuropathological evaluation at times varying from 2.5 hours to 52 days after drug administration showed that cis-platinum and Adriamycin were highly neurotoxic, as evidenced by neurological deficits and pathological changes in the central nervous system parenchyma; 5-fluorouracil and bleomycin had much less, but consequential neurotoxicity; and cyclophosphamide was not associated with substantial toxicity. Intracarotid cis-platinum, unlike the other drugs, damaged the blood-brain barrier and resulted in marked neurotoxicity in the absence of osmotic blood-brain barrier opening. The neural lesions produced by these agents were not specific but were manifested as foci of hemorrhagic necrosis and edema. In addition, secondary brainstem hemorrhage was observed in animals that developed transtentorial herniation. On the basis of these studies, of five drugs studied at a wide range of doses, only cyclophosphamide appears to be safe enough to evaluate in clinical trials that utilize blood-brain barrier modification to enhance drug delivery. These studies also suggest that the lack of neurotoxicity associated with the usual administration of most chemotherapeutic agents probably stems from limited entry of drug into the brain through an intact blood-brain barrier.

Ancillary