IN-VIVO EFFICACY OF INTRATHECAL TRANSFERRIN-PSEUDOMONAS EXOTOXIN-A IMMUNOTOXIN AGAINST LOX-MELANOMA

NEOPLASTIC MENINGITIS DUE to the dissemination of systemic cancer or primary central nervous system tumors through the cerebrospinal fluid carries a very poor prognosis. Current treatments for this disease are ineffective, and new therapeutic modalities such as immunotoxins may be beneficial. We created an animal model of human carcinomatous meningitis with LOX melanoma-derived tissue-culture cells in athymic rats for testing the efficacy of intrathecal therapy with transferrin-Pseudomonas exotoxin A (Tfn-PE) immunotoxin. An injection of 5 x 10(5) LOX cells into the intrathecal space through an indwelling catheter resulted in the reproducible development of lower-extremity paraplegia at 9.24 +/- 1.77 days because of focal deposits of tumor growth adjacent to the thoracic and lumbar spinal cord. A dose of 2.5 or 5 mug of intrathecal Tfn-PE immunotoxin was neurotoxic and resulted in the deaths of 8 of 10 animals within 24 hours. Histological evidence of central nervous system damage was seen as hemorrhagic degeneration around the central canal or a pathological cleft at the level of the cervical spinal cord. Because no neurotoxicity was seen with 1 mug of intrathecal Tfn-PE immunotoxin, this dose was administered in treatment experiments. Twenty-four hours after the intrathecal instillation of LOX cells, 10 animals received intrathecally either 1 mug of Tfn-PE or phosphate-buffered saline with 0.1% human serum albumin (control group). Control animals experienced lower-extremity paraplegia at 10.7 +/- 2.75 days compared with animals treated with Tfn-PE, which did not develop paralysis until 15.5 +/- 4.58 days, representing a mean delay in the onset of paraplegia of 5 days or 31% (P = 0.015). This observed delay in the onset of paraplegia in treated animals with human neoplastic meningitis supports the use of intrathecal immunotoxins for Phase I/II clinical trials in patients with carcinomatous meningitis from systemic or central nervous system cancer.