alpha-difluoromethylornithine as treatment for metastatic breast cancer patients

DFMO (alpha-difluoromethylornithine) is an oral irreversible inhibitor of o rnithine decarboxylase, the first rate-limiting enzyme in polyamine synthes is, DFMO has been shown to have antiproliferative effects against several h uman cancers, and some studies have suggested that DFMO may have pro-apopto tic and anti-invasive properties as well. DFMO is well tolerated with minim al toxicity but has been associated with ototoxicity with prolonged daily a dministration. We conducted a Phase I/II tolerability, pharmacokinetic, and efficacy study of high-dose DFMO in metastatic breast cancer patients. Twe nty-one patients,were treated with 4800 mg of DFMO p.o, three times a day f or 14 days, followed by a 2-week drug holiday on a 28-day cycle. Urinary po lyamine and blood DFMO levels were measured at multiple time points during therapy. High-dose DF;MO 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 sp ermidine urinary levels were suppressed with DFMO treatment and remained lo w during the 2-week drug holiday. High-dose DFMO on a schedule of 2 weeks o n treatment followed by 2 weeks off is well tolerated, is not associated wi th ototoxicity, and leads to sustained suppression of urinary polyamine lev els. Although not an active cytotoxic agent for metastatic breast cancer, t he intriguing prolonged growth arrest of liver metastases in one patient hi ghlights the potential clinical growth inhibitory properties of DFMO, We be lieve that DFMO is worthy of study as adjuvant therapy in primary breast ca ncer patients and as a chemopreventive agent.