Toxicity of intrathecally administered cytotoxic drugs and their antitumor activity against an intrathecal Walker 256 carcinosarcoma model for meningeal carcinomatosis in the rat

K. L. Kooistra, M. Rodriguez, G. Powis

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19 Scopus citations

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 neuro-behavioral changes was bleomycin (80 μg), cytarabine (640 μg), dacarbazine (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-bis(2-chloroethyl)-1-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 anti-tumor 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.

Original languageEnglish (US)
Pages (from-to)977-982
Number of pages6
JournalCancer Research
Volume49
Issue number4
StatePublished - 1989

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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