This study assessed proof-of-concept for use of polyamine inhibitor 2-difluoromethylornithine (DFMO) as a treatment for oral squamous cell carcinoma (SCC) in client-owned cats. Polyamine levels in tumor tissue and normal oral mucosa were quantified before and after treatment. DFMO was administered orally to 14 client-owned cats with histologically confirmed oral SCC. Patients were monitored for gastrointestinal, dermatologic, auditory, hematological, and biochemical abnormalities. Total polyamine levels in tumor tissue decreased after treatment, as did the specific polyamine putrescine in both tumor tissue and normal mucosa. Ototoxicity was observed in 5 of 6 cats receiving pre- and post-treatment brainstem auditory evoked potential tests. Subclinical thrombocytopenia was observed in 6 of 14 cats. One cat showed mild post-anesthetic tremors that resolved without treatment. Oral administration of DFMO at doses used in this study resulted in significantly decreased tumor polyamine levels without life-threatening clinical or hema-tological toxicities. Further studies are warranted to explore pathophysiology of polyamine biochemistry and use of polyamine inhibitors in treatment of cats with oral SCC.
Get full access to this article
View all access options for this article.
References
1.
StebbinsKEMorseCCGoldschmidtMH. Feline Oral Neoplasia: A Ten-Year Survey. Vet Pathol1989; 26:121–128.
2.
HarveyCEEmilyP. Oral neoplasms. In: HarveyCEEmilyP, eds. Small animal dentistry. St. Louis, Mosby, 1993; 306.
3.
VosJHvan der GaagI. Canine and feline oral-pharyngeal tumours. Zentralblatt fur Veterinarmedizin1987; 34: 420–427.
4.
BradleyRLMacEwenEGLoarAS. Mandibular resection for removal of oral tumors in 30 dogs and 6 cats. J Am Vet Med Assoc1984; 184: 460–463.
5.
ReevesNC PostorinoTurrelJMWithrowSJ. Oral squamous cell carcinoma in the cat. J Am Anim Hosp Assoc1993; 29: 438–441.
6.
NorthrupNCSeltingKARassnickKM. Outcomes of cats with oral tumors treated with mandibulectomy: 42 cases. J Am Anim Hosp Assoc2006; 42: 350–360.
7.
CotterSM. Oral pharyngeal neoplasms in the cat. J Am Anim Hosp Assoc1981; 17: 917–920.
8.
EvansSMLaCretaFHelfandS. Technique, pharmacokinetics, toxicity, and efficacy of intratumoral etanidazole and radiotherapy for treatment of spontaneous feline oral squamous cell carcinoma. Int J Radiat Oncol1991; 20: 703–708.
9.
BregazziVSLaRueSMPowersBE. Response of feline oral squamous cell carcinoma to palliative radiation therapy. Vet Radiol Ultrasoun2001; 42: 77–79.
10.
FidelJLSellonRKHoustonRK. A nine-day accelerated radiation protocol for feline squamous cell carcinoma. Vet Radiol Ultrasoun2007; 48: 482–485.
11.
MarrettaJJGarrettLDMarrettaSM. Feline oral squamous cell carcinoma: An overview. Vet Med-US2007; June: 392–408.
12.
FulmerAKMauldinGEMauldinGN. Evaluation of plasma folate and homocysteine concentrations in cats with and without oral squamous cell carcinoma. Vet Comp Oncol2008; 6: 248–256.
13.
ChenYHuJBoormanD. Therapy of murine squamous cell carcinomas with 2-difluoromethylornithine. J Carcinogenesis2004; 3: 10.
14.
PetereitDGHarariPMContrerasL. Combining polyamine depletion with radiation therapy for rapidly dividing head and neck tumors: Strategies for improved locoregional control. Int J Radiat Oncol1994; 28: 891–898.
15.
LukGDAbeloffMDGriffinCA. Successful treatment with DL-alpha-difluoromethylornithine in established human small cell variant lung carcinoma implants in athymic mice. Cancer Res1983; 43: 4239–4243.
16.
PeggAEMcCannPP. Polyamine metabolism and function. Am J Physiol1982; 243: 212–221.
17.
AbeloffMDSlavikMLukGD. Phase I trial and pharmacokinetic studies of alpha-difluoromethylornithine–an inhibitor of polyamine biosynthesis. J Clin Oncol1984; 2: 124–130.
18.
BockJMPickartMAPinkJJ. Modulation of tumor cell proliferation and apoptosis by polyamine depletion in cells of head and neck squamous cell carcinomas. Radiat Res1999; 152: 604–610.
19.
KozaRAMegoshLCPalmieriM. Constitutively elevated levels of ornithine and polyamines in mouse epidermal papillomas. Carcinogenesis1991; 12: 1619–1625.
20.
CrowellJAGoldenthalEIKelloffGJ. Chronic toxicity studies of the potential cancer preventive 2-(difluoromethyl)-dl-ornithine. Fund Appl Toxicol1994; 22: 341–354.
21.
BrownAPMorrisseyRLCrowellJA. Difluoromethylornithine in combination with tamoxifen in female rats: 13-week oral toxicity study. Cancer Chemoth Pharm1999; 44: 475–483.
22.
Veterinary Co-operative Oncology Group (VCOG). Veterinary co-operative oncology group – common terminology criteria for adverse events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.0. Vet Comp Oncol2004; 2: 195–213.
23.
ViteCHDingWBryanC. Clinical, electrophysiological, and serum biochemical measures of progressive neurological and hepatic dysfunction in feline Niemann-Pick type C disease. Pediatr Res2008; 64: 544–549.
24.
GriffinCASlavikMChienSC. Phase I trial and pharmacokinetic study of intravenous and oral alpha-difluoromethylornithine. Invest New Drug1987; 5: 177–186.
25.
O'ShaughnessyJADemersLMJonesSE. Alpha-difluoromethylornithine as treatment for metastatic breast cancer patients. Clin Cancer Res1999; 5: 3438–3444.
26.
McWilliamsMLChenGDFechterLD. Characterization of the ototoxicity of difluoromethylornithine and its enantiomers. Toxicol Sci2000; 56: 124–132.
27.
DoyleKJ. Delayed, reversible hearing loss caused by difluoromethylornithine (DFMO). Laryngoscope2001; 111: 781–785.
SalzerSJMattoxDEBrownellWE. Cochlear damage and increased threshold in alpha-difluoromethylornithine (DFMO) treated guinea pigs. Hearing Res1990; 46: 101–112.
30.
BuchwaldJSHuangC. Far-field acoustic response: Origins in the cat. Science1975; 189: 382–384.
31.
DeLahuntaAGlassE. The neurologic examination. In: DeLahuntaAGlassE, eds. Veterinary neuroanatomy and clinical neurology. 3rd ed.St. Louis: Saunders Elsevier, 2009; 498.
32.
HutsonCAWillauerCCWalderEJ. Treatment of mandibular squamous cell carcinoma in cats by use of mandibulectomy and radiotherapy: Seven cases (1987–1989). J Am Vet Med Assoc1992; 201: 777–781.
33.
SkorupskiKAO'BrienTGGuerreroT. Phase I/II clinical trial of 2-difluoromethylornithine (DFMO) and a novel polyamine transport inhibitor (MQT 1426) for feline oral squamous cell carcinoma. Vet Comp Oncol2011; 9: 275–82.
34.
SeilerN. Thirty years of polyamine-related approaches to cancer therapy. Retrospect and prospect. Part 2. Structural analogues and derivatives. Curr Drug Targets2003; 4: 565–585.
35.
SeilerN. Thirty years of polyamine-related approaches to cancer therapy. Retrospect and prospect. Part 1. Selective enzyme inhibitors. Curr Drug Targets2003; 4: 537–564.
