α-Difluoromethylornithine as treatment for metastatic breast cancer patients

Joyce A. O'Shaughnessy, Laurence M. Demers, Stephen E. Jones, James Arseneau, Pankaj Khandelwal, Timothy George, Robert Gersh, David Mauger, Andrea Manni

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

DFMO (α-difluoromethylornithine) is an oral irreversible inhibitor of ornithine decarboxylase, the first rate-limiting enzyme in polyamine synthesis. DFMO has been shown to have antiproliferative effects against several human cancers, and some studies have suggested that DFMO may have pro-apoptotic and anti-invasive properties as well. DFMO is well tolerated with minimal toxicity but has been associated with ototoxicity with prolonged daily administration. We conducted a Phase I/II tolerability, pharmacokinetic, and efficacy study of high-dose DFMO in metastatic breast cancer patients. Twenty-one patients were treated with 4800 mg of DFMO p.o. three times a day for 14 days, followed by a 2-week drug holiday on a 28-day cycle. Urinary polyamine and blood DFMO levels were measured at multiple time points during therapy. High-dose DFMO was well tolerated, and no clinically significant ototoxicity was noted. No patient achieved an objective antitumor response; however, one patient with heavily pretreated liver metastases has achieved stable disease for 18 months to date on DFMO. Putrescine, spermine, and spermidine urinary levels were suppressed with DFMO treatment and remained low during the 2-week drug holiday. High-dose DFMO on a schedule of 2 weeks on treatment followed by 2 weeks off is well tolerated, is not associated with ototoxicity, and leads to sustained suppression of urinary polyamine levels. Although not an active cytotoxic agent for metastatic breast cancer, the intriguing prolonged growth arrest of liver metastases in one patient highlights the potential clinical growth inhibitory properties of DFMO. We believe that DFMO is worthy of study as adjuvant therapy in primary breast cancer patients and as a chemopreventive agent.

Original languageEnglish (US)
Pages (from-to)3438-3444
Number of pages7
JournalClinical Cancer Research
Volume5
Issue number11
StatePublished - Nov 1 1999

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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