This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by O’Shaughnessy, J. A. Articles by Manni, A. Search for Related Content PubMed PubMed Citation Articles by O’Shaughnessy, J. A. Articles by Manni, A.

-Difluoromethylornithine as Treatment for Metastatic Breast Cancer Patients

Texas Oncology, Practice Association, US Oncology, Dallas, Texas 75246 [J. A. O., S. E. J., J. A., P. K., T. G., R. G.]; Departments of Medicine [L. M. D., A. M.] and Health Evaluation Sciences [D. M.], Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

DFMO (-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.

This article has been cited by other articles:

				M. J. Worsham, K. M. Chen, N. Tiwari, G. Pals, J. P. Schouten, S. Sethi, and M. S. Benninger Fine-mapping loss of gene architecture at the CDKN2B (p15INK4b), CDKN2A (p14ARF, p16INK4a), and MTAP genes in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg, April 1, 2006; 132(4): 409 - 415. [Abstract] [Full Text] [PDF]

				X. Hu, S. Washington, M. F. Verderame, and A. Manni Interaction between Polyamines and the Mitogen-Activated Protein Kinase Pathway in the Regulation of Cell Cycle Variables in Breast Cancer Cells Cancer Res., December 1, 2005; 65(23): 11026 - 11033. [Abstract] [Full Text] [PDF]

				W. Deng, M. J. Viar, and L. R. Johnson Polyamine depletion inhibits irradiation-induced apoptosis in intestinal epithelia Am J Physiol Gastrointest Liver Physiol, September 1, 2005; 289(3): G599 - G606. [Abstract] [Full Text] [PDF]

				A.-T. Vlastos, L. A. West, E. N. Atkinson, I. Boiko, A. Malpica, W. K. Hong, and M. Follen Results of a Phase II Double-Blinded Randomized Clinical Trial of Difluoromethylornithine for Cervical Intraepithelial Neoplasia Grades 2 to 3 Clin. Cancer Res., January 1, 2005; 11(1): 390 - 396. [Abstract] [Full Text] [PDF]

				V. A. Levin, J. L. Jochec, L. M. Shantz, P. E. Koch, and A. E. Pegg Tissue-based Assay for Ornithine Decarboxylase to Identify Patients Likely to Respond to Difluoromethylornithine J. Histochem. Cytochem., November 1, 2004; 52(11): 1467 - 1474. [Abstract] [Full Text] [PDF]

				A. L. Subhi, B. Tang, B. R. Balsara, D. A. Altomare, J. R. Testa, H. S. Cooper, J. P. Hoffman, N. J. Meropol, and W. D. Kruger Loss of Methylthioadenosine Phosphorylase and Elevated Ornithine Decarboxylase Is Common in Pancreatic Cancer Clin. Cancer Res., November 1, 2004; 10(21): 7290 - 7296. [Abstract] [Full Text] [PDF]

				J. P. Carson, N. Zhang, G. M. Frampton, N. P. Gerry, M. E. Lenburg, and M. F. Christman Pharmacogenomic Identification of Targets for Adjuvant Therapy with the Topoisomerase Poison Camptothecin Cancer Res., March 15, 2004; 64(6): 2096 - 2104. [Abstract] [Full Text] [PDF]

				Y. Huang, J. C. Keen, E. Hager, R. Smith, A. Hacker, B. Frydman, A. L. Valasinas, V. K. Reddy, L. J. Marton, R. A. Casero Jr., et al. Regulation of Polyamine Analogue Cytotoxicity by c-Jun in Human MDA-MB-435 Cancer Cells Mol. Cancer Res., February 1, 2004; 2(2): 81 - 88. [Abstract] [Full Text] [PDF]

				A. C. Wolff, D. K. Armstrong, J. H. Fetting, M. K. Carducci, C. D. Riley, J. F. Bender, R. A. Casero Jr., and N. E. Davidson A Phase II Study of the Polyamine Analog N1,N11-Diethylnorspermine (DENSpm) Daily for Five Days Every 21 Days in Patients with Previously Treated Metastatic Breast Cancer Clin. Cancer Res., December 1, 2003; 9(16): 5922 - 5928. [Abstract] [Full Text] [PDF]

				S. M. Fischer, C. J. Conti, J. Viner, C.M. Aldaz, and R. A. Lubet Celecoxib and difluoromethylornithine in combination have strong therapeutic activity against UV-induced skin tumors in mice Carcinogenesis, May 1, 2003; 24(5): 945 - 952. [Abstract] [Full Text] [PDF]

				V. A. Levin, K. R. Hess, A. Choucair, P. J. Flynn, K. A. Jaeckle, A. P. Kyritsis, W. K. A. Yung, M. D. Prados, J. M. Bruner, S. Ictech, et al. Phase III Randomized Study of Postradiotherapy Chemotherapy with Combination {alpha}-Difluoromethylornithine-PCV versus PCV for Anaplastic Gliomas Clin. Cancer Res., March 1, 2003; 9(3): 981 - 990. [Abstract] [Full Text] [PDF]

				S. A. Christopher, P. Diegelman, C. W. Porter, and W. D. Kruger Methylthioadenosine Phosphorylase, a Gene Frequently Codeleted with p16cdkN2a/ARF, Acts as a Tumor Suppressor in a Breast Cancer Cell Line Cancer Res., November 15, 2002; 62(22): 6639 - 6644. [Abstract] [Full Text] [PDF]

				P. P. Carbone, J. A. Douglas, J. Thomas, K. Tutsch, M. Pomplun, M. Hamielec, and D. Pauk Bioavailability Study of Oral Liquid and Tablet Forms of {{alpha}}-Difluoromethylornithine Clin. Cancer Res., October 1, 2000; 6(10): 3850 - 3854. [Abstract] [Full Text]