title: Toxicity of intrathecally administered cytotoxic drugs and their antitumor activity against an intrathecal Walker 256 carcinosarcoma model for meningeal carcinomatosis in the rat.
abstract: Meningeal carcinomatosis in humans is refractory to most attempts at therapy and has a grave prognosis. As part of a search for new agents to treat meningeal carcinomatosis, the toxicity of a series of antitumor agents administered through an implanted catheter directly into the cerebrospinal fluid (CSF) of the lumbar spinal cord of 200-g rats has been examined. The highest non-toxic dose (HNTD) of the agents producing no signs of histological damage, motor dysfunction, or neurobehavioral changes was bleomycin (80 micrograms), cytarabine (640 micrograms), dacarbazine (1 microgram), doxorubicin (20 micrograms), 5-fluorouracil (150 micrograms), methotrexate (1000 micrograms), mitomycin C (10 micrograms), and triethylene phosphoramide (800 micrograms). No toxicity was observed at the highest dose that could be administered because of limited solubility of 1,3-bis(2-chloroethyl)-1-nitrosourea (100 micrograms), or diaziquone (70 micrograms). The rat model gave reasonable prediction of the toxicity of antitumor agents that have been administered intra-CSF to humans but with a tendency to underpredict toxicity. The antitumor activity of the agents administered intra-CSF at the HNTD against a Walker 256 carcinosarcoma model for meningeal carcinomatosis in the rat was examined. Diaziquone, doxorubicin, methotrexate, and mitomycin C gave a 25% or greater increase in lifespan and diaziquone and mitomycin C gave some long-term survivors. BCNU, bleomycin and 5-fluorouracil gave less than a 25% increase in lifespan. When mitomycin C was administered intra-CSF at the HNTD and diaziquone at the limit of solubility daily for 4 days there was no toxicity and an increase in survival of Walker 256 carcinosarcoma tumored animals compared to animals administered a single daily dose. Intrathecal diaziquone was more active against meningeal Walker 256 carcinosarcoma than i.v. diaziquone. Intravenous methotrexate had no activity against meningeal Walker 256 carcinosarcoma. We conclude that intra-CSF administration of some anticancer agents such as diaziquone and mitomycin C at doses that do not produce toxicity can significantly increase the survival of rats with experimental meningeal carcinomatosis.
authors.affiliation: Department of Pharmacology, Mayo Clinic and Foundation, Rochester, Minnesota 55905.
authors.forename: K L
authors.initials: KL
authors.lastname: Kooistra
authors.forename: M
authors.initials: M
authors.lastname: Rodriguez
authors.forename: G
authors.initials: G
authors.lastname: Powis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D002279:Carcinoma 256, Walker / Q000188:drug therapy*; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D008577:Meningeal Neoplasms / Q000188:drug therapy*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000970:Antineoplastic Agents