Toxicity of Intrathecally Administered Cytotoxic Drugs and Their Antitumor Activity against an Intrathecal Walker 256 Carcinosarcoma Model for Meningeal Carcinomatosis in the Rat

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 neuro-behavioral changes was bleomycin (80 µg), cytarabine (640 µg), dacar-bazine (1 µg), doxorubicin (20 µg), 5-fluorouracil (150 µg), methotrexate (1000 µg), mitomycin C (10 µg), and triethylene phosphoramide (800 µg). No toxicity was observed at the highest dose that could be administered because of limited solubility of 1,3-6/y(2-chloroethyl)-l-nitrosourea (100 µg), or diaziquone (70 µg). 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-fluo-rouracil 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.