Polyamine Inhibitors for Treatment of Feline Oral Squamous Cell Carcinoma: A Proof-of-Concept Study John R. Lewis, VMD; Thomas G. O’Brien, PhD; Katherine A. Skorupski, DVM; Erika L. Krick, VMD; Alexander M. Reiter, Dipl.Tzt., Dr. Med. Vet.; Michael W. Jennings, VMD; Carrie H. Jurney, DVM; Shofer FS, PhD; Karin U. Sorenmo, CMV Summary:

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 hematological toxicities. Further studies are warranted to explore pathophysiology of polyamine biochemistry and use of polyamine inhibitors in treatment of cats with oral SCC. J Vet Dent 30 (3); 140-145, 2013

Introduction

Squamous cell carcinoma (SCC) is the most common oral neoplasm affecting cats, accounting for 60 to 70 % of all feline oral tumors.1,2 Though the average age of onset is over 11-years, cats as young as 5-months of age have been affected by SCC.3 Common sites of occurrence include the tongue and sublingual tissues, alveolar mucosa, mucosa of the lips, cheek and palate, and maxillary or mandibular bone. Although wide surgical excision is the treatment of choice for resectable lesions, the cancer’s aggressive nature and advanced tumor size at the time of diagnosis have resulted in poor long-term success rates with surgery alone in most cases.4,5 Due to the small maxillofacial dimensions of the cat, postoperative function may be compromised after curative intent surgery,6 depending on the size and location of the SCC. Long-term success rates of chemotherapy and radiation therapy have been equally frustrating when treating feline oral SCC.7-12 Difluoromethylornithine (DFMO) appears to show promise for treatment of SCC based on previous research. Complete responses and apparent cures have been documented in a high percentage of mice with experimentally induced cutaneous SCC.13 Previous studies of human SCC cell lines indicated DFMO was very effective in inhibiting cell growth in vitro and in vivo of xenografts in athymic mice.14,15 DFMO works as a substrate 140

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analog to irreversibly inactivate its only cellular target, ornithine decarboxylase (ODC), the gatekeeper enzyme in the polyamine biosynthetic pathway. Polyamines are aliphatic polycations ubiquitous in all cells with the major polyamines being putrescine, spermidine, and spermine.16 DFMO inhibits synthesis of putrescine from ornithine, decreasing cellular polyamine levels, which in turn decreases cell proliferation. Known side effects of DFMO therapy in humans include gastrointestinal upset, thrombocytopenia, and ototoxicity.17 Human head and neck SCC cells exposed to DFMO showed depleted intracellular putrescine and spermidine levels (greater than 5-fold) and inhibition of cell proliferation.18 However, to the authors’ knowledge, DFMO has never been investigated as monotherapy for clinical treatment of cats or humans with head and neck SCC, nor have polyamineslevels been quantified in cats with oral SCC. The present study evaluated feasibility of oral administration of DFMO as a treatment for feline oral SCC in cases where neither surgery nor radiation therapy were pursued. Cellular effects of DFMO therapy were assessed by comparing polyamine levels of tumor tissue and adjacent normal oral mucosa before and after treatment.

Materials and Methods

All cats were evaluated in accordance with guidelines established by an Institutional Animal Care and Use Committee. Clients were made aware of potential risks and informed owner consent was obtained. The following inclusion criteria for this prospective study were applied: 1) cats had histologically confirmed, non-resectable oropharyngeal SCC; 2) cats were deemed to be in acceptable systemic health based on results of physical examination, thoracic radiographs, complete blood count (CBC), serum chemistry profile, urinalysis, serum thyroid hormone level, and FeLV/FIV tests; 3) cats had not received prior radiation therapy of the head/neck region or chemotherapy drugs; 4) cats had not received nonsteroidal anti-inflammatory (NSAID) medications or corticosteroids within 2-weeks prior to enrollment, or if they required these medications, the dose of NSAID or corticosteroid was unchanged for 2-weeks prior to enrollment with no appreciable decrease in tumor size during this 2-week period. Three-view thoracic radiographs, complete blood counts, chemistry screens and urinalyses were obtained in all cats, unless recently performed by the primary care veterinarian. All cats were placed under anesthesia at week 0 for biopsy of tumor and adjacent normal tissue, brainstem auditory evoked potential (BAEP) tests, and mandibular lymph node aspirates. Biopsy samples of tumor and adjacent normal mucosa ( > 1-cm away from clinically visible tumor) were obtained with a 4-mm biopsy punch and stored at -80° C. Tissues were treated with 0.2 N perchloric acid and polyamines were derivatized with dansyl chloride,

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followed by extraction with methanol. Polyamine levels of all biopsy samples were determined via high-performance liquid chromatography (HPLC) equipped with fluorescence detection.19 Median polyamine levels (total combined value of putrescine, spermidine, and spermine) were compared in biopsies of tumor tissue and adjacent normal oral mucosa in cats with oral SCC prior to and after treatment. The signed rank test was used for statistical comparisons due to the nonparametric nature of the data, and p values < 0.05 were considered significant. DFMO was administered as a fish-flavored oral liquid, beginning 1 to 2-days after the week 0 anesthetic visit. Dose of DFMO varied from 12.5 mg/kg to 116.5 mg/kg PO BID depending on stage of enrollment, based on extrapolation from other species.17,20,21 Toxicities were graded based on Veterinary Co-operative Oncology Group (VCOG) guidelines.22 Owners were asked to monitor their pets for signs of toxicity. All patients received concurrent oral buprenorphineb (0.01 mg/ kg transmucosally) for pain starting at the week 0 visit. Cats returned for repeat physical examination, CBC, and chemistry profile at 2, 4, 6 and 8-weeks. After 8-weeks of twice daily DFMO administration, cats deemed sufficiently stable were anesthetized for biopsies and BAEP tests. If tumor progression and quality of life issues dictated the need for euthanasia prior to the 8-week visit, biopsy samples of the tumor and normal tissue were obtained immediately after euthanasia, though BAEP tests were not obtained in these cats. At the 8-week study completion date, cats who tolerated their current dose were eligible to have their dose increased if their current dose level had been tolerated by these cats at the time of re-enrollment. Ten cats had pretreatment BAEP tests performeda using a previously described protocol.23 Post-treatment BAEP tests were obtained from 6 cats after 8-weeks of DFMO treatment. Latency from stimulus was measured for Wave I and V peaks. A central conduction time was calculated by subtracting the Wave I latency from the Wave V latency.

Results

Animals- Fourteen feline patients of the Matthew J. Ryan Veterinary Hospital of the University of Pennsylvania were enrolled. Mean cat age ± SD was 13.5 ± 2.8-years (range, 9.3 to 19.3-years). Mean body weight was 4.5 ± 1.5 kg (range, 2.6 to 6.9 kg). There were 9 spayed females and 5 castrated males. Of the 14 cats, there were 10 domestic shorthair, 2 Himalayan, and 2 Maine Coon cats. Mean duration of clinical signs at the time of initial visit was 46.4 ± 46.7-days (range, 3 to 180-days). The most common clinical signs reported as part of the history or identified during initial physical examination were anorexia/ decreased appetite (6 cats), lethargy (3), sneezing (3), ocular and nasal discharge (3), ptyalism (2), decreased grooming (2), difficulty or decreased range of opening the mouth (2), and sanguineous oral discharge (2). One of 14 cats had no clinical signs of disease with oral SCC diagnosed as an incidental finding during a dental cleaning. Apparent site of origin of tumors in the enrolled cats were: maxilla (5 cats), sublingual/ lingual region (4), mandible (2), lower lip (1), buccal mucosa (1), and caudal pharynx (1). Surface ulceration of the primary lesion was noted in 14 of 14 cats. Three cats had been historically placed

on meloxicamc at least 2-weeks prior to enrollment with no visible change in tumor size. Three-view thoracic radiographs were evaluated by a board-certified veterinary radiologist in 12 of 14 cats with 1 cat showing evidence of multiple pulmonary nodules. Fine needle aspiration was performed of mandibular lymph nodes in 13 cats, of which 4 had cytological evidence of regional metastasis. No treatment-related mortalities occurred during the study except those attributable to progression of oncologic disease or euthanasia due to declining quality of life. Two cats were eligible to re-enroll at a higher dose level after completing their first 8-weeks of treatment, and one re-enrollee received the highest dose at 116.5 mg/kg PO BID, which was well tolerated. Table 1 describes prevalence and grades of adverse events, based on VCOG criteria were recorded.22 No cats showed adverse events in the following categories: fever, cardiac arrhythmia, dermatologic, allergic/hypersensitivity, musculoskeletal, pulmonary, and ocular/ visual. Hematologic abnormalities- Hematological changes were minor and abnormalities were limited to platelet count and PCV. Neutrophil counts before and during treatment showed no evidence of toxicity. Grade 1 and Grade 2 toxicities were seen in PCV levels, which did not appear to be dose-dependent. PCV was below reference range in 8 of 14 cats. Seven of the 8 cats with low PCV were below reference range prior to starting DFMO therapy, and one cat that was initially not anemic was found to be anemic at week 2. Thrombocytopenia occurred in 6 of 14 cats and appeared to be dose-dependent. All three cats receiving 87.5 mg/kg DFMO PO BID and the sole cat receiving 116.5 mg/kg DFMO PO BID developed non-clinical decreases in platelet count. Only one cat developed grade 3 thrombocytopenia (platelet count of 43,000/µl) after 4-weeks of DFMO administration. The owner of this cat chose to continue the medication with close monitoring since no clinical bleeding issues were seen. Two weeks later, the cat’s platelet count was 100,000/µl despite no change in DFMO dose. Chemistry abnormalities- Comparison of ALT values before and during treatment revealed no toxicity in any cats. Pre-treatment creatinine values were slightly elevated in 5 of 14 cats (range 2.1 to 3.3 mg/dl), but post-treatment creatinine values did not exceed initial values in any of the cats with preexisting creatinine elevations. Grade 1 toxicity in creatinine was seen in 1 cat receiving 62.5 mg/kg DFMO BID (increase from 2.0 mg/ dl at week 0 to 2.9 mg/dl at week 4). Grade 1 toxicity was seen in serum glucose level of one cat receiving 12.5 mg/kg DFMO BID (increase from 133 mg/dl at week 0 to 190 mg/dl at week 4). No toxicity was noted in other chemistry screen values. BAEP testing- At the onset of the study, owners were made aware of the possibility of hearing loss, and some owners mentioned that they perceived decreased hearing in their pets after receiving the medication. One cat had markedly abnormal BAEPs prior to receiving DFMO, with a central conduction time of 5.48 ms in the left ear and 4.37 ms in the right ear. This cat was removed from BAEP testing outcome analysis so as not skew the results. The mean pretreatment latencies for all cats was 1.08 ms for Wave I, 3.64 ms for Wave II and central conduction average was 2.56 ms. These results are consistent with previously published data on BAEPs for normal cats using this protocol.23 Post-treatment J VET DENT Vol. 30 No. 3 Fall 2013

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BAEPs were performed on six cats. Two cats showed a loss of all waveforms in both ears and one cat had only a discernable Wave V in one ear that showed an increased latency from the pretreatment value by 1.29 ms (Fig. 1). Two cats showed increased latencies in all waves ranging from an additional 0.24 to 0.79 ms for Wave I, 0.44 to 0.90 ms for Wave V, and a 0.11 to 0.53 ms increase in central conduction. One cat showed shorter latencies in all waves with Wave I latencies 0.15 and 0.09 ms shorter, Wave V latencies 0.39 ms and 0.08 ms shorter, and central conduction 0.24 ms and 0.01 ms shorter in the left and right ear, respectively. Other toxicities- No gastrointestinal toxicity was noted in any of the cats. Lethargy was reported in 4 cats (29.0 %). One cat showed mild post-anesthetic tremors that resolved without treatment within an hour of the anesthetic episode (Table 1). No cat discontinued DFMO therapy due to toxicity. Tissue polyamine levels- Pre- and post-treatment biopsies were obtained from all 14 cats. The median polyamine level of normal mucosa was 2.95 nmol/mg, and the median polyamine level of pre-treatment tumor tissue was 5.81 nmol/mg, though this difference was not significant. The difference between median pre-treatment (5.81 nmol/mg) and median post-treatment tumor polyamine levels (4.07 nmol/mg) was statistically significant (p = 0.0353). Median putrescine levels in tumor tissue were significantly lower after treatment (1.31 nmol/mg versus 0.62 nmol/mg, p = 0.0166). Median putrescine levels in normal mucosa were also significantly lower after treatment (0.79 nmol/mg versus 0.14 nmol/mg, p = 0.0327), though no significant difference was seen in median total polyamine levels of pre- and posttreatment normal mucosa (2.98 nmol/mg and 2.09 nmol/ mg, respectively). Spermidine and spermine levels were not significantly changed after DFMO treatment in either tumor tissue or normal mucosa (Fig. 2).

Discussion

The toxicity of DFMO has been extensively documented in both experimental animals and humans.17,20,21,24 A 1-year toxicity study in dogs receiving daily oral doses of 50-200 mg/kg reported alopecia, dermatitis, and conjunctivitis in a dose-dependent manner.20 At the highest dose, weight loss was observed due to decreased food consumption. In an early human study where DFMO was dosed up to 150 mg/kg orally QID for 28-days, observed toxicities were gastrointestinal upset, thrombocytopenia, and ototoxicity.17 None of these toxicities were life-threatening, and in most cases, toxicity resolved when treatment was stopped. A dose of approximately 200 mg/kg DFMO on a 2-week on/2-week off schedule was well tolerated by humans, and no clinically significant ototoxicity was reported.25 DFMO-related hearing loss, though not previously described in cats, has been reported in humans, gerbils, and guinea pigs.26-28 The clinical and electrophysiological findings in guinea pigs were correlated histologically with a loss of cochlear hair cells.26,29 Central conduction is used as a measurement of conduction time of the impulse from the initial stimulation of the cochlear nerve by the cochlear hair cells to the inferior colliculus in the brainstem.30 BAEPs are used clinically in domestic species to determine deafness and to investigate brainstem disease.31 In the present study, there was complete loss of evoked response or an increase in central conduction time in 5 of 6 cats. A dose-related effect on hearing was difficult to discern since only 6 cats received both pre- and post-treatment BAEP tests. However, all 5 cats with measurable hearing loss received a dose of 41.8 mg/kg BID or higher. One cat was noted to have faster BAEP latencies after receiving DFMO. It was noted on pre-treatment BAEP that this cat had debris in its right ear, and it is theorized that ear cleaning resulted in decreased conductive disturbance and

Figure 1 Image showing a brainstem auditory evoked potential (BAEP) test in a cat prior to receiving DFMO (A). Image showing a BAEP test in the same cat after receiving 87.5 mg/kg DFMO BID for 8-weeks (B). Five of 6 cats showed loss of all waveforms and/or increased latencies after 8-weeks of DFMO administration.

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faster latencies on the post-treatment BAEP. However, this does not account for the decrease in the Wave V to I latency. It is possible that the faster post-treatment latencies in this cat were due to measurement error. It is uncertain whether the transient, post-anesthetic tremors seen in one patient were a manifestation of ototoxicity/vestibular disease. Thrombocytopenia is a known side effect of chronic DFMO administration in humans,17 though clinically significant thrombocytopenia does not occur in humans after shortterm administration (4-days) via oral or intravenous routes.24 Interestingly, in a 52-week study of oral administration of DFMO to rats, thrombocytosis was seen, where platelets increased by approximately 50 % in rats fed 1600 mg/kg/

day, starting at month 3.20 To the authors’ knowledge, DFMOassociated thrombocytopenia has not been documented in cats. Human patients receiving prior chemotherapy may have an increased risk of DFMO-associated thrombocytopenia.17 The results of the present study suggest that cats receiving DFMO should be closely monitored with frequent platelet counts, even cats who have not received prior chemotherapy. Lymph node metastasis has historically been considered to be uncommon in cats with oral SCC. Previous studies showed lymph node metastasis in 8 of 59 cases (13.6%).5,32 In the present study, cytological confirmation of mandibular lymph node metastasis was seen in 4 of 13 cats (30.8%). Since the lymph node aspirates were taken at the week 0 enrollment

Figure 2 Line graph plots of pre- and post-treatment tumor polyamine levels in 14 cats: total polyamines (A), spermidine (B), spermine (C), putrescine (D). Significant (*) decreases were seen between pre- and post-treatment tumor total polyamine levels and putrescine levels. Total polyamine levels of each individual cat are the sum of that cat’s putrescine, spermidine, and spermine levels.

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visit, the increased prevalence of lymph node metastasis seen in the present study was not due to increased longevity due to treatment. Mean duration of clinical signs prior to presentation was 46.4-days, and duration of clinical signs was similar in cats with metastatic lymph nodes and cats with negative lymph node aspirates (53.3 versus 45.5-days, respectively). Referral bias may explain this increased prevalence of regional metastasis, since the most severe cases might be seen at a tertiary clinical trial center. The mandibular lymph nodes of all study cats were aspirated, whether enlarged or normal on palpation. The results of the present study suggest regional metastasis of feline oral SCC may be more common than previously thought, especially considering that only the mandibular lymphocentrum was evaluated in the patients of the present study. Additional studies evaluating lymph node status of a larger patient population are warranted. Significant differences were found in pre- and posttreatment tumor total polyamine levels, tumor putrescine levels, and normal mucosa putrescine levels. It is notable that total polyamine levels were significantly decreased in tumor tissue whereas total polyamine levels in normal mucosa were not significantly decreased. These results suggest that DFMO, at doses used in this study, have a more profound effect on tumor tissue polyamine levels than on normal tissue polyamine levels. Wide variation was seen in pre-treatment tumor polyamine levels (range=1.61 to 160.61) compared to pre-treatment normal mucosa (range=0.28 to 21.08). Future studies with larger patient numbers will provide additional information regarding polyamine differences in tumor tissue compared with normal tissue in cats with oral SCC. Further evaluation of patients at varying dose levels may provide insight regarding relationships between dose of DFMO and percent decrease of polyamines. If a linear relationship is not seen between dose and percent decrease of polyamine levels, dose level may need to be tailored to the individual patient based on pre-treatment levels. The primary purpose of this study was to obtain proof of principle for use of DFMO in cats with oral SCC. Results of the present study are promising because significant toxicity was not observed, other than ototoxicity and non-clinical thrombocytopenia. Since post-treatment tumor polyamine levels were significantly less than pre-treatment levels, DFMO appears to be a rational therapy for feline patients with oral SCC. A recent study documented significant decreases in total polyamine levels and spermidine levels after combination treatment with DFMO and a polyamine transport inhibitor, with vestibular disease being the dose-limiting toxicity.33 Extracellular polyamines are known to be neurotoxic, as are many of their structural analogues used as transport inhibitors.34 The differences in severity of toxicity seen between DFMO monotherapy and combination therapy of DFMO with a transport inhibitor is likely due to the neurotoxic effects of the transport inhibitor or potentiation of DFMO-related side effects. Phase I/II trials are warranted to evaluate toxicity and effectiveness of DFMO as a single agent and in combination with other therapies. Combination therapy is likely warranted due to the complexities of polyamine metabolism.35 144

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____________________________________________________ Nicolet Viking Quest, Nicolet Biomedical, Madison, WI Buprenex, Reckitt & Colman, Wayne, NJ c Metacam, Boehringer Ingelheim Vetmedica, St. Joseph, MO a

b

Author Information

From Mari Lowe Center for Comparative Oncology and the Department of Clinical Studies, Ryan Veterinary Hospital, University of Pennsylvania School of Veterinary Medicine, 3900 Delancey Street, Philadelphia, PA, 19104-6010; and, Lankenau Institute for Medical Research (O’Brien), 100 Lancaster Avenue, Wynnewood, PA, 19096. Dr. Skorupski’s present address is Department of Veterinary Surgical and Radiological Sciences, University of California, Davis, School of Veterinary Medicine, 2112 Tupper Hall, One Shields Avenue, Davis, CA 95616-8782. Dr. Jurney’s present address is Veterinary Surgical Associates, 251 N. Amphlett Blvd., San Mateo, CA 94401. Dr. Shofer’s present address is School of Medicine, University of North Carolina, 170 Manning Drive, Chapel Hill, NC 275997594. Email: [email protected]

Acknowledgements

This study was supported by a portion of National Institutes of Health grant, # RO1 CA094107-04A1 and the Penn Vet Squamous Cell Carcinoma Research Fund, founded by a gift from Ms. Kathleen Jack.

References

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5. Postorino Reeves NC, Turrel JM, Withrow SJ. Oral squamous cell carcinoma in the cat. J Am Anim Hosp Assoc 1993; 29: 438-441. 6. Northrup NC, Selting KA, Rassnick KM, et al. Outcomes of cats with oral tumors treated with mandibulectomy: 42 cases. J Am Anim Hosp Assoc 2006; 42: 350-360. 7. Cotter SM. Oral pharyngeal neoplasms in the cat. J Am Anim Hosp Assoc 1981; 17: 917-920. 8. Evans SM, LaCreta F, Helfand S, et al. Technique, pharmacokinetics, toxicity, and efficacy of intratumoral etanidazole and radiotherapy for treatment of spontaneous feline oral squamous cell carcinoma. Int J Radiat Oncol 1991; 20: 703-708. 9. Bregazzi VS, LaRue SM, Powers BE, et al. Response of feline oral squamous cell carcinoma to palliative radiation therapy. Vet Radiol Ultrasoun 2001; 42: 77-79. 10. Fidel JL, Sellon RK, Houston RK, et al. A nine-day accelerated radiation protocol for feline squamous cell carcinoma. Vet Radiol Ultrasoun 2007; 48: 482-485. 11. Marretta JJ, Garrett LD, Marretta SM. Feline oral squamous cell carcinoma: an overview. Vet Med-US 2007; June: 392-408. 12. Fulmer AK, Mauldin GE, Mauldin GN. Evaluation of plasma folate and homocysteine concentrations in cats with and without oral squamous cell carcinoma. Vet Comp Oncol 2008; 6: 248-256. 13. Chen Y, Hu J, Boorman D, et al. Therapy of murine squamous cell carcinomas with 2-difluoromethylornithine. J Carcinogenesis 2004; 3: 10. 14. Petereit DG, Harari PM, Contreras L, et al. Combining polyamine depletion with radiation therapy for rapidly dividing head and neck tumors: Strategies for improved locoregional control. Int J Radiat Oncol 1994; 28: 891-898. 15. Luk GD, Abeloff MD, Griffin CA, et al. Successful treatment with DL-alpha-difluoromethylornithine in established human small cell variant lung carcinoma implants in athymic mice. Cancer Res 1983; 43: 4239-4243. 16. Pegg AE, McCann PP. Polyamine metabolism and function. Am J Physiol 1982; 243: 212-221.

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17. Abeloff MD, Slavik M, Luk GD, et al. Phase I trial and pharmacokinetic studies of alpha difluoromethylornithine--an inhibitor of polyamine biosynthesis. J Clin Oncol 1984; 2: 124-130. 18. Bock JM, Pickart MA, Pink JJ, et al. Modulation of tumor cell proliferation and apoptosis by polyamine depletion in cells of head and neck squamous cell carcinomas. Radiat Res 1999; 152: 604-610. 19. Koza RA, Megosh LC, Palmieri M, et al. Constitutively elevated levels of ornithine and polyamines in mouse epidermal papillomas. Carcinogenesis 1991; 12: 1619-1625. 20. Crowell JA, Goldenthal EI, Kelloff GJ, et al. Chronic toxicity studies of the potential cancer preventive 2-(difluoromethyl)-dl-ornithine. Fund Appl Toxicol 1994; 22: 341-354. 21. Brown AP, Morrissey RL, Crowell JA, et al. Difluoromethylornithine in combination with tamoxifen in female rats: 13-week oral toxicity study. Cancer Chemoth Pharm 1999; 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 Oncol 2004; 2: 195-213. 23. Vite CH, Ding W, Bryan C, et al. Clinical, electrophysiological, and serum biochemical measures of progressive neurological and hepatic dysfunction in feline Niemann-Pick type C disease. Pediatr Res 2008; 64: 544-549. 24. Griffin CA, Slavik M, Chien SC, et al. Phase I trial and pharmacokinetic study of intravenous and oral alpha-difluoromethylornithine. Invest New Drug 1987; 5: 177-186. 25. O’Shaughnessy JA, Demers LM, Jones SE, et al. Alpha-difluoromethylornithine as treatment for metastatic breast cancer patients. Clin Cancer Res 1999; 5: 3438-3444. 26. McWilliams ML, Chen GD, Fechter LD. Characterization of the ototoxicity of difluoromethylornithine and its enantiomers. Toxicol Sci 2000; 56: 124-132. 27. Doyle KJ. Delayed, reversible hearing loss caused by difluoromethylornithine (DFMO). Laryngoscope 2001; 111: 781-785. 28. Pasic TR, Heisey D, Love RR. Alpha-difluoromethylornithine ototoxicity. Chemoprevention clinical trial results. Arch Otolaryngol 1997; 123: 1281-1286. 29. Salzer SJ, Mattox DE, Brownell WE. Cochlear damage and increased threshold in alpha difluoromethylornithine (DFMO) treated guinea pigs. Hearing Res 1990; 46: 101-112. 30. Buchwald JS, Huang C. Far-field acoustic response: Origins in the cat. Science 1975; 189: 382-384. 31. DeLahunta A, Glass E. The neurologic examination. In: DeLahunta A, Glass E, eds. Veterinary neuroanatomy and clinical neurology. 3rd ed. St. Louis: Saunders Elsevier, 2009; 498. 32. Hutson CA, Willauer CC, Walder EJ, et al. Treatment of mandibular squamous cell carcinoma in cats by use of mandibulectomy and radiotherapy: seven cases (1987-1989). J Am Vet Med Assoc 1992; 201: 777-781. 33. Skorupski KA, O’Brien TG, Guerrero T, et al. 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 Oncol 2011; 9: 275-82. 34. Seiler N. Thirty years of polyamine-related approaches to cancer therapy. Retrospect and prospect. Part 2. Structural analogues and derivatives. Curr Drug Targets 2003; 4: 565-585. 35. Seiler N. Thirty years of polyamine-related approaches to cancer therapy. Retrospect and prospect. Part 1. Selective enzyme inhibitors. Curr Drug Targets 2003; 4: 537-564.

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Polyamine inhibitors for treatment of feline oral squamous cell carcinoma: a proof-of-concept study.

This study assessed proof-of-concept for use of polyamine inhibitor 2-diluoromethylornithine (DFMO) as a treatment for oral squamous cell carcinoma (S...
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