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

NEOPLASTIC MENINGITIS DUE to the dissemination of systemic cancer or p rimary central nervous system tumors through the cerebrospinal fluid c arries a very poor prognosis. Current treatments for this disease are ineffective, and new therapeutic modalities such as immunotoxins may b e beneficial. We created an animal model of human carcinomatous mening itis with LOX melanoma-derived tissue-culture cells in athymic rats fo r testing the efficacy of intrathecal therapy with transferrin-Pseudom onas exotoxin A (Tfn-PE) immunotoxin. An injection of 5 x 10(5) LOX ce lls 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 t he thoracic and lumbar spinal cord. A dose of 2.5 or 5 mug of intrathe cal Tfn-PE immunotoxin was neurotoxic and resulted in the deaths of 8 of 10 animals within 24 hours. Histological evidence of central nervou s system damage was seen as hemorrhagic degeneration around the centra l canal or a pathological cleft at the level of the cervical spinal co rd. Because no neurotoxicity was seen with 1 mug of intrathecal Tfn-PE immunotoxin, this dose was administered in treatment experiments. Twe nty-four hours after the intrathecal instillation of LOX cells, 10 ani mals received intrathecally either 1 mug of Tfn-PE or phosphate-buffer ed saline with 0.1% human serum albumin (control group). Control anima ls experienced lower-extremity paraplegia at 10.7 +/- 2.75 days compar ed with animals treated with Tfn-PE, which did not develop paralysis u ntil 15.5 +/- 4.58 days, representing a mean delay in the onset of par aplegia of 5 days or 31% (P = 0.015). This observed delay in the onset of paraplegia in treated animals with human neoplastic meningitis sup ports the use of intrathecal immunotoxins for Phase I/II clinical tria ls in patients with carcinomatous meningitis from systemic or central nervous system cancer.