Enhanced delivery improves the efficacy of a tumor-specific doxorubicin immunoconjugate in a human brain tumor xenograft model.
OBJECTIVE
To evaluate dose intensification with osmotic blood-brain barrier disruption (BBBD) and the potential use of drug targeting with monoclonal antibody (MAb) BR96 conjugated to doxorubicin (BR96-DOX, now called SGN15) for treatment of intracerebral and subcutaneous human LX-1 small cell lung carcinoma xenografts in rats.


METHODS
LX-1 tumors with high, low, or heterogeneous levels of the Lewis(y) antigen for BR96 were evaluated. Rats were treated with intracarotid or intravenous BR96-DOX, with or without osmotic BBBD.


RESULTS
Both BR96-DOX and MAb BR96 treatment resulted in significant regression of subcutaneous tumors, in contrast to control groups including doxorubicin alone, saline, or nonbinding doxorubicin immunoconjugate. BR96-DOX delivered with BBBD to brain tumors with low antigen expression resulted in significantly (P < 0.001) increased rat survival time compared with animals that received intravenous or intra-arterial BR96-DOX.


CONCLUSIONS
The combination of an effective drug such as doxorubicin with a MAb to facilitate tumor-selective localization and osmotic BBBD to increase tumor delivery may have practical application in the clinic, because an increased delivery of drug to tumor can be obtained without increasing the dose of systemic drug.
Remsen
L G
LG
Department of Neurology, Oregon Health Sciences University, Portland 97201, USA.
Trail
P A
PA
Hellström
I
I
Hellström
K E
KE
Neuwelt
E A
EA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000032:analysis / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000276:immunology; D002339:Carotid Arteries; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000494:pharmacology; D007269:Injections, Intra-Arterial; D007275:Injections, Intravenous; D009368:Neoplasm Transplantation; D051381:Rats; D011923:Rats, Nude; D016019:Survival Analysis; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C092612:BR96-doxorubicin immunoconjugate; D000922:Immunotoxins; D004317:Doxorubicin