Differential permeability of the blood-tumour barrier in intracerebral tumour-bearing rats: antidrug antibody to achieve systemic drug rescue.
The feasibility of utilizing the differential permeability of the blood-tumour barrier to low- vs. high-molecular-weight compounds is demonstrated in a brain tumour model. Nude rats (n = 27) with or without intracerebral tumours received intravenous [3H]methotrexate (M(r) 454), followed 60 min later by antimethotrexate antibody (M(r) 150,000) or nonspecific mouse antibody. Antimethotrexate antibody resulted in 93% binding of serum methotrexate. In contrast, the percentage of antibody-bound methotrexate in brain and intracerebral tumour was only slightly greater than preantibody protein binding. Methotrexate delivery to tumour was significantly greater than to brain adjacent to tumour and normal brain. The percentage delivery of [3H]methotrexate to all areas of brain was similar between animals receiving antimethotrexate antibody and nonspecific antibody. These findings support the theory that a drug rescue method may be developed that may permit the safe administration of increased dosages of chemotherapeutic drugs for the treatment of intracerebral tumours.
Kroll
R A
RA
Department of Neurology, Oregon Health Sciences University, Portland 97201, USA.
Pagel
M A
MA
Langone
J J
JJ
Sexton
G J
GJ
Neuwelt
E A
EA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000936:Antigen-Antibody Complex / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D018288:Carcinoma, Small Cell / Q000188:drug therapy; D005260:Female; D008727:Methotrexate / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D051381:Rats; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate