© 1998 by Oxford University Press
Journal Of The National Cancer Institute, Vol 90, 1212-1218, Copyright © 1998 by Oxford University Press
FL Meyskens Jr, EW Gerner, S Emerson, D Pelot, T Durbin, K Doyle and W Lagerberg
BACKGROUND: Polyamines (e.g., putrescine, spermidine, and spermine) are
required for optimal cell growth. Inhibition of polyamine synthesis
suppresses carcinogen-induced epithelial cancers, including colon cancer,
in animal models. In a short-term phase IIa trial, we determined that low
doses of alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine
decarboxylase (an enzyme involved in polyamine synthesis), reduced the
polyamine content of normal-appearing rectal mucosa of subjects with a
prior history of resected colon polyps. In a follow-up study, we have
attempted to determine the lowest dose of DFMO that can suppress the
polyamine content of rectal mucosa over a course of 1 year with no or
minimal side effects. METHODS: Participants were randomly assigned to daily
oral treatment with a placebo or one of three doses (0.075, 0.20, or 0.40
g/m2) of DFMO. Baseline and serial determinations of polyamine levels in
rectal mucosa and extensive symptom monitoring (including audiometric
measurements, since DFMO causes some reversible hearing loss at higher
doses) were performed over a 15-month period. RESULTS: DFMO treatment
reduced putrescine levels in a dose-dependent manner. Following 6 months of
treatment, doses of 0.20 and 0.40 g/m2 per day reduced putrescine levels to
approximately 34% and 10%, respectively, of those observed in the placebo
group. Smaller decreases were seen in spermidine levels and
spermidine:spermine ratios. Polyamine levels increased toward baseline
values after discontinuation of DFMO. Although there were no statistically
significant differences among the dose groups with respect to clinically
important shifts in audiometric thresholds and nonaudiologic side effects,
statistically significant higher dropout and discontinuation rates were
observed in the highest dose group. CONCLUSIONS: Polyamine levels in rectal
mucosa can be continuously suppressed by daily oral doses of DFMO that
produce few or no side effects. A dose of 0.20 g/m2 can be used safely in
combination phase IIb or single-agent phase III chemoprevention trials.
ARTICLES
Effect of alpha-difluoromethylornithine on rectal mucosal levels of polyamines in a randomized, double-blinded trial for colon cancer prevention
Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, USA. flmeyske@uci.edu
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. A. Zell, A. Ziogas, N. Ignatenko, J. Honda, N. Qu, A. S. Bobbs, S. L. Neuhausen, E. W. Gerner, and H. Anton-Culver Associations of a Polymorphism in the Ornithine Decarboxylase Gene with Colorectal Cancer Survival Clin. Cancer Res., October 1, 2009; 15(19): 6208 - 6216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Sporn and W. K. Hong Clinical Prevention of Recurrence of Colorectal Adenomas by the Combination of Difluoromethylornithine and Sulindac: An Important Milestone Cancer Prevention Research, June 1, 2008; 1(1): 9 - 11. [Full Text] [PDF]
|
|
|
|
|
|
F. L. Meyskens Jr., C. E. McLaren, D. Pelot, S. Fujikawa-Brooks, P. M. Carpenter, E. Hawk, G. Kelloff, M. J. Lawson, J. Kidao, J. McCracken, et al. Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial Cancer Prevention Research, June 1, 2008; 1(1): 32 - 38. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Simoneau, E. W. Gerner, R. Nagle, A. Ziogas, S. Fujikawa-Brooks, H. Yerushalmi, T. E. Ahlering, R. Lieberman, C. E. McLaren, H. Anton-Culver, et al. The Effect of Difluoromethylornithine on Decreasing Prostate Size and Polyamines in Men: Results of a Year-Long Phase IIb Randomized Placebo-Controlled Chemoprevention Trial Cancer Epidemiol. Biomarkers Prev., February 1, 2008; 17(2): 292 - 299. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. L. Meyskens Jr. Another Negative Chemoprevention Trial: What Can We Learn? Clin. Cancer Res., January 1, 2008; 14(1): 2 - 3. [Full Text] [PDF]
|
|
|
|
 |
|
 X.-c. Chen, R. Wang, X. Zhao, Y.-q. Wei, M. Hu, Y.-s. Wang, X.-w. Zhang, R. Zhang, L. Zhang, B. Yao, et al. Prophylaxis against carcinogenesis in three kinds of unestablished tumor models via IL12-gene-engineered MSCs Carcinogenesis, December 1, 2006; 27(12): 2434 - 2441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. L. Meyskens Jr. American Society of Preventive Oncology Distinguished Career Achievement Lecture 2006--Enjoy the Journey: The Long and Winding Road of Chemoprevention Agent Development. Cancer Epidemiol. Biomarkers Prev., November 1, 2006; 15(11): 2038 - 2041. [Full Text] [PDF]
|
|
|
|
 |
|
 R. F. Souza and S. J. Spechler Concepts in the Prevention of Adenocarcinoma of the Distal Esophagus and Proximal Stomach CA Cancer J Clin, November 1, 2005; 55(6): 334 - 351. [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]
|
|
|
|
|
|
C. D. Lao, P. Backoff, L. I. Shotland, D. McCarty, T. Eaton, F. G. Ondrey, J. L. Viner, S. J. Spechler, E. T. Hawk, and D. E. Brenner Irreversible Ototoxicity Associated with Difluoromethylornithine Cancer Epidemiol. Biomarkers Prev., July 1, 2004; 13(7): 1250 - 1252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. W. Wattenberg, T. S. Wiedmann, and R. D. Estensen Chemoprevention of Cancer of the Upper Respiratory Tract of the Syrian Golden Hamster by Aerosol Administration of Difluoromethylornithine and 5-Fluorouracil Cancer Res., April 1, 2004; 64(7): 2347 - 2349. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. B. Armstrong, T. H. Taylor, and F. L. Meyskens Jr. Point: Surrogate End Point Biomarkers Are Likely To Be Limited in Their Usefulness in the Development of Cancer Chemoprevention Agents against Sporadic Cancers Cancer Epidemiol. Biomarkers Prev., July 1, 2003; 12(7): 589 - 592. [Full Text] [PDF]
|
|
|
|
|
|
C. J. Fabian, B. F. Kimler, D. A. Brady, M. S. Mayo, C. H. J. Chang, J. A. Ferraro, C. M. Zalles, A. L. Stanton, S. Masood, W. E. Grizzle, et al. A Phase II Breast Cancer Chemoprevention Trial of Oral {alpha}-Difluoromethylornithine: Breast Tissue, Imaging, and Serum and Urine Biomarkers Clin. Cancer Res., October 1, 2002; 8(10): 3105 - 3117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Doyle, C. E. McLaren, J. E. Shanks, C. M. Galus, and F. L. Meyskens Effects of Difluoromethylornithine Chemoprevention on Audiometry Thresholds and Otoacoustic Emissions Arch Otolaryngol Head Neck Surg, May 1, 2001; 127(5): 553 - 558. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. I. Shotland, F. G. Ondrey, K. A. Mayo, and J. L. Viner Recommendations for Cancer Prevention Trials Using Potentially Ototoxic Test Agents J. Clin. Oncol., March 15, 2001; 19(6): 1658 - 1663. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Simoneau, E. W. Gerner, M. Phung, C. E. McLaren, and F. L. Meyskens Jr. {{alpha}}-Difluoromethylornithine and Polyamine Levels in the Human Prostate: Results of a Phase IIa Trial J Natl Cancer Inst, January 3, 2001; 93(1): 57 - 59. [Full Text] [PDF]
|
|
|
|
|
|
J. A. O'Shaughnessy, L. M. Demers, S. E. Jones, J. Arseneau, P. Khandelwal, T. George, R. Gersh, D. Mauger, and A. Manni {{alpha}}-Difluoromethylornithine as Treatment for Metastatic Breast Cancer Patients Clin. Cancer Res., November 1, 1999; 5(11): 3438 - 3444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Erdman, N. A. Ignatenko, M. B. Powell, K. A. Blohm-Mangone, H. Holubec, J. M. Guillen-Rodriguez, and E. W. Gerner APC-dependent changes in expression of genes influencing polyamine metabolism, and consequences for gastrointestinal carcinogenesis, in the Min mouse Carcinogenesis, September 1, 1999; 20(9): 1709 - 1713. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Messing, R. R. Love, K. D. Tutsch, A. K. Verma, J. Douglas, M. Pomplun, R. Simsiman, and G. Wilding Low-Dose Difluoromethylornithine and Polyamine Levels in Human Prostate Tissue J Natl Cancer Inst, August 18, 1999; 91(16): 1416 - 1417. [Full Text] [PDF]
|
|
|
|
|
|
S. Gupta, N. Ahmad, R. R. Mohan, M. M. Husain, and H. Mukhtar Prostate Cancer Chemoprevention by Green Tea: In Vitro and in Vivo Inhibition of Testosterone-mediated Induction of Ornithine Decarboxylase Cancer Res., May 1, 1999; 59(9): 2115 - 2120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. L. Meyskens Jr. and E. W. Gerner Development of Difluoromethylornithine (DFMO) as a Chemoprevention Agent Clin. Cancer Res., May 1, 1999; 5(5): 945 - 951. [Abstract] [Full Text] [PDF]
|
|