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Phase I/II Trial of Polyamine-Based Therapy in Cats with Oral Cancer

While there is no effective therapy for inoperable oral squamous cell carcinoma (SCC) in cats, recent research in a mouse model of SCC has been highly promising. Treatment of SCC-bearing mice with the ornithine decarboxylase (ODC) inhibitor 2-difluoromethylornithine (DFMO) and MQT 1569 (a spermine analog) can achieve complete responses and even apparent cures in a high percentage of mice. ODC is an important gatekeeper enzyme in the polyamine biosynthetic pathway. MQT 1569’s cellular target is the polyamine transporter, which cells use to take up polyamines from the extracellular environment. Polyamines are aliphatic polycations ubiquitous in all cells. The goal of combination therapy is to decrease intracellular polyamine levels and prevent extracellular uptake of polyamines by tumor cells.

This drug combination represents a novel treatment for cats with SCC. Based on a previous study, DFMO was well tolerated, though some hearing loss has been documented by post-treatment hearing tests. Addition of MQT 1569 will inhibit extracellular uptake of polyamines by tumor cells, thereby decreasing the amount of DFMO needed to affect tumor growth.

Bibliography & References Cited

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2. Reeves NCP, Turrel JM, Withrow SJ. Oral squamous cell carcinoma in the cat. J Am Anim Hosp Assoc 1993, 29: 438-441.

3. Chen Y, Hu J, Boorman D, Klein-Szanto A, and O'Brien TG, Therapy of murine squamous cell carcinomas with 2-diflouromethylornithine. J Carcinogenesis 2004, 3: 1-10.

4. Duda L, Lewis JR, Kagan SH, Evans SM. Letter to the editor: SPAREDEL-Spontaneous parallel reciprocol model. JAVMA 2009, 235(8): 933.

5. O'Brien TG, Megosh LC, Gilliard G, and Peralta Soler A (1997). Ornithine decarboxylase overexpression is a sufficient condition for tumor promotion in mouse skin. Cancer Res. 57: p. 2630-2637.

6. Chen, Y., Weeks, R.S., Burns, M.R., Boorman, D.W., Klein-Szanto, A. and O'Brien, T.G. (2006) Combination therapy with 2-difluoromethylornithine and a polyamine transport inhibitor against murine squamous cell carcinoma. Int J Cancer. 118:2344-9

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