Intrathecal administration of 4-hydroperoxycyclophosphamide in rhesus monkeys

Carola A.S. Arndt, O. Michael Colvin, Frank M. Balis, Cynthia M. Lester, Gloria Johnson

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

The preactivated cyclophosphamide analogue, 4-HC, does not require activation by hepatic microsomal enzymes to express Its cytotoxic activity and therefore, unlike cyclophosphamide, may be useful for the regional therapy of cancer. In the present study, the pharmacokinetics and toxicology of 4-HC were studied following intraventricular administration of 0.4 mg to rhesus monkeys with chronic indwelling Ommaya reservoirs. 4-HC was measured in cerebrospinal fluid (CSF) and plasma with a highperformance liquid chromatography assay utilizing a fluorometric detector following derivatization with m-aminophenol. The mean peak level of 4-HC in ventricular CSF was 100 μM 5 min after administration. The drug was cleared rapidly and the elimination was monoexponential with a mean half-life of 22 min. The mean clearance from CSF (033 ml/min) was 10-fold higher than CSF bulk flow. The drug was distributed throughout the subarachnoid space with lumbar levels approaching ventricular levels by 60 min. Neither acute nor chronic neurotoxicity or systemic toxicity was observed during the 6-wk observation period. Concentrations of 4-HC demonstrated to be cytocidal in vitro against human breast cancer, lymphoid leukemia, and rhabdomyosarcoma were readily achieved in CSF following intraventricular administration. This study demonstrates that intraventricular therapy with 4-HC is feasible and suggests that further study of this approach in the clinical setting should be considered.

Original languageEnglish (US)
Pages (from-to)5932-5934
Number of pages3
JournalCancer Research
Volume47
Issue number22
StatePublished - 1987
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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