| Abstract: |
Intrathecal (IT) administration of monoclonal antibodies (MAbs) represents a new therapeutic approach for the treatment of leptomeningeal (LM) cancer, which is presently rapidly fatal. In this study, we quantitated the accumulation of an intrathecally administered anti-ganglioside G(D2) MAb (3F8) within leptomeningeal neoplastic xenografts of G(D2) positive melanoma and neuroblastoma in nude rats by measuring concentrations of radiolabeled and unmodified MAbs and by immunohistochemistry. Intrathecal administration of 125I-3F8 resulted in area under the tissue concentration versus time curve (AUC) values in SK-MEL-1 melanoma xenografts (53.1 μCi*h/g) that were 14-fold greater than in corresponding blood (3.9 μCi*h/g), whereas IT administration of a control nonspecific MAb resulted in AUC values in tumors (7.1 μCi*h/g) that were less than those in blood (9.5 μCi*h/g). Administration of acetazolamide and furosemide, which slow the clearance of IgG MAb from rat cerebrospinal fluid resulted in a fivefold increase in AUC of 125I-3F8 in melanoma (262.9 μCi*h/g). The highest concentration of 125I-MAb in tumor after IT administration was seen at the first sampling time of 2 h, and this fell to 50% of maximum values at 8-16 h. Pharmacokinetic analysis of unmodified MAb demonstrated retention of MAb within the LM space of animals with tumor. The concentration of MAb 3F8 appearing in serum after IT administration was 10-fold lower in animals with melanoma xenografts than in those without tumor implants. Radiation dose estimates after intraventricular administration of a radiolabeled MAb indicated delivery to tumor of 1,870 rad/mCi of 125I-3F8 but only 40 rad/mCi of 125I-labeled control MAb. These results indicate that anti- ganglioside MAbs and other MAbs directed to tumor-associated antigens are excellent candidates for IT treatment of appropriate leptomeningeal cancers in humans. |
