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 micrograms 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 microgram 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 microgram of Tfn-PE or phosphate-buffered saline with 0.1% human serum albumin (control group).(ABSTRACT TRUNCATED AT 250 WORDS)
Hall
W A
WA
Department of Tumor Biology, Norwegian Radium Hospital, Oslo, Norway.
Myklebust
A
A
Godal
A
A
Nesland
J M
JM
Fodstad
O
O
D036002:ADP Ribose Transferases; D000818:Animals; D001427:Bacterial Toxins; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002460:Cell Line; D005098:Exotoxins / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage*; D007278:Injections, Spinal; D008297:Male; D008546:Melanoma, Experimental / Q000473:pathology / Q000628:therapy*; D008577:Meningeal Neoplasms / Q000473:pathology / Q000628:therapy*; D008578:Meninges / Q000187:drug effects / Q000473:pathology; D009368:Neoplasm Transplantation; D051381:Rats; D011923:Rats, Nude; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D014168:Transferrin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D000922:Immunotoxins; D014168:Transferrin; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A