Dexamethasone decreases the delivery of tumor-specific monoclonal antibody to both intracerebral and subcutaneous tumor xenografts.
The effect of dexamethasone on the delivery of monoclonal antibody L6 IgG to intracerebral and subcutaneous LX-1 small cell lung carcinoma xenografts was evaluated in nude rats (n = 157). Dexamethasone (0, 8, or 24 mg/m2) was given 18 hours before infusion of L6 IgG, with or without osmotic disruption of the blood-brain barrier. Compared with controls, the 8 mg/m2 dose decreased delivery of L6 IgG (12-37%) to all tissues, but the only significant decrease (P < 0.001) was in the subcutaneous tumor (37%). In the 24 mg/m2 group, L6 IgG delivery was significantly (P < 0.001) decreased to all tissues (37-60%). Dexamethasone had no effect on plasma levels. Barrier disruption significantly (P < 0.0001) increased L6 IgG delivery to intracranial tumor and surrounding brain, but not to subcutaneous tumor or plasma. The percentage of decremental effect of dexamethasone on L6 IgG delivery was the same with and without barrier disruption and was not associated with the time the animals were killed (P > 0.05). Compared with controls, the ratio of intracranial tumor to normal brain showed no change with dexamethasone, but the ratios of both intracranial and subcutaneous tumors to plasma significantly (P < 0.002) decreased with both doses. The in vitro cell binding capacity of L6 IgG to LX-1 cells remained unchanged after incubation of cells with dexamethasone over a 3-log concentration for 4 days, demonstrating no effect on antigen expression. This study suggests that dexamethasone has a clinically relevant generalized (i.e., central nervous system and systemic) vascular effect on permeability to L6 IgG monoclonal antibody.
Neuwelt
E A
EA
Department of Neurology, Oregon Health Sciences University, Portland.
Barnett
P A
PA
Ramsey
F L
FL
Hellström
I
I
Hellström
K E
KE
McCormick
C I
CI
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000494:pharmacology; D000918:Antibody Specificity / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D001932:Brain Neoplasms / Q000473:pathology*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D018288:Carcinoma, Small Cell / Q000473:pathology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D008353:Mannitol / Q000494:pharmacology; D009368:Neoplasm Transplantation; D051381:Rats; D011923:Rats, Nude
D000911:Antibodies, Monoclonal; D008353:Mannitol; D003907:Dexamethasone