A clinically translatable mouse model for chemotherapy-related fatigue.

Fatigue is a debilitating and pervasive complication of cancer and cancer care. Clinical research investigating potential therapies is hindered by variability in patient histories, different metrics for measuring fatigue, and environmental factors that may affect fatigue. The purpose of this study was to establish an animal model of chemotherapy-related fatigue. Female HSD:ICR mice were treated with doxorubicin (2.5 mg/kg) or saline in 2 cycles (days 1 through 3 and 10 through 12). After treatment, mice were individually housed in cages equipped with running wheels. Open-field activity and motor coordination were examined after each cycle of treatment and after each week of wheel running. In a separate cohort, modafinil (50 mg/kg) was assessed as a potential treatment for fatigue. Doxorubicin administration resulted in greater than 30% less wheel running compared with that of saline controls. Activity differences were specific to wheel running: neither distance traveled in the open field nor motor coordination according to the rotarod test differed between groups. Compared with control values, RBC counts in the doxorubicin group were decreased on days 15 and 22 but recovered to control levels by study completion. Modafinil was efficacious in increasing wheel running in the doxorubicin group. The current results establish an animal model of chemotherapy-related fatigue that recapitulates the physical symptoms of cancer-related fatigue as manifested as decreased voluntary activity. This model is sensitive to pharmaceutical intervention and can be used to screen potential treatments for fatigue.

Serum amyloid P ameliorates radiation-induced oral mucositis and fibrosis.

PURPOSE: To evaluate the effect of the anti-fibrotic protein serum amyloid P (SAP) on radiation-induced oral mucositis (OM) and fibrosis in a hamster cheek-pouch model. EXPERIMENTAL DESIGN: Hamsters received a single dose of radiation (40 Gy) to the left everted cheek pouch to induce significant OM. The protective therapeutic potential of SAP was evaluated using varying dosing regimens. The extent of OM was measured using a validated six-point scoring scheme ranging from 0 (normal tissue, no mucositis) to 5 (complete ulceration). Fibrotic remodeling was also visualized histologically and quantified at later time points using collagen gene expression. RESULTS: SAP treatment attenuated the profile of radiation-induced oral mucositis by delaying the time of onset, reducing the peak value, and enhancing the resolution of injury. The peak mucositis score was reduced by approximately 0.5 grade in SAP-treated animals. The number of animal days with a score of >/= 3 was reduced by 48% in the SAP-treated group, compared with the saline control group (P < 0.01). SAP also inhibited the extent of tissue remodeling and decreased radiation-induced increases in myofibroblast number. Attenuated collagen deposition and gene expression was also observed in the cheek pouches of hamsters treated with SAP at both 16 and 28 days post-radiation. CONCLUSIONS: SAP treatment significantly attenuated radiation-induced injury. In particular, SAP attenuated the severity of OM and inhibited pathogenic remodeling. This suggests that SAP may be a useful therapy for the palliation of side effects observed during treatment for head and neck cancer.

Efficacy of superoxide dismutase mimetic M40403 in attenuating radiation-induced oral mucositis in hamsters.

PURPOSE: M40403 is a small-molecule superoxide dismutase mimetic that has shown efficacy in animal model disease states in which superoxide anions are thought to play a key role. Radiation treatment and chemotherapy for cancer generate free oxygen radicals that are hypothesized to trigger unwanted side effects in healthy tissue. For some patients undergoing these antineoplastic treatments, one of the most prevalent side effects is oral mucositis, which is a painful, often dose-limiting condition. Preclinical and clinical studies of this condition have shown the positive effect of treatment with compounds that decrease free oxygen radicals. This study investigated the efficacy M40403 in a clinically relevant hamster model of acute, radiation-induced oral mucositis. METHODS: Oral mucositis was induced in hamsters by irradiation of the cheek pouch. The ability of i.p. administered M40403 to decrease the duration and severity of oral mucositis was assessed after treatment at different doses and dosing schedules. Oral mucositis was scored using the WHO grading scale. RESULTS: Compared with placebo-treated animals, those irradiated on day 0 and treated twice daily with 30 mg/kg M40403 had significantly less severe and shorter duration mucositis over a range of treatment schedules, including from days -1 to 3, day 0 to 3, and day 0 alone. Similar efficacy was achieved at doses of 10 and 3 mg/kg twice daily on days -1 to 3. CONCLUSIONS: These results implicate free oxygen radicals in the onset of oral mucositis and also provide the basis for further development of M40403 in the prevention of this condition in at-risk cancer patients.

Single-Dose Prevention or Short-Term Treatment with Fibroblast Growth Factor-20 (CG53135-05)Reduces the Severity and Duration of Oral Mucositis.

Oral mucositis (OM) is a treatment-limiting condition associated with myelosupressive chemotherapy and radiation therapy. The objective of this study was to evaluate the activity of recombinant human fibroblast growth factor-20 (FGF-20 or CG53135-05) in the prevention and treatment of OM in experimental animals. Oral mucositis was induced in hamsters with 5-fluorouracil (5-FU; 60 mg/kg) on days -4 and -2, followed by targeted irradiation with 30 Gy on day 0. Oral mucositis was scored every other day using severity scores of 0-5. To test for prevention of OM, animals received varying doses of FGF-20 on day 1 or days 1 and 2 after irradiation before the development of symptoms. To test the effects of FGF-20 on established mucositis, animals were allowed to develop early OM (score of 2) before treatment initiation. Animals then received FGF-20 by intraperitoneal (i.p.) administration (12 mg/kg) for 1, 2, 3, or 4 consecutive days. When prevention of OM was tested, administration of FGF-20 (12 mg/kg i.p.) on day 1 or days 1 and 2 resulted in significant reduction in duration of severe OM to 26% (P < 0.003) or 29.4% (P <0.018) of cumulative days, respectively, compared with untreated control animals, which spent 40.2% of cumulative days with OM scores >/= 3. When the effects of FGF-20 on established mucositis were tested, treatment of animals with FGF-20 for 2, 3, or 4 consecutive days resulted in significant reduction of severe OM to 27.4%, 29.2%, or 18.5% of days, respectively, compared with vehicle-treated control animals, which spent 41.1% of cumulative days with OM scores >/=3 (P < 0.05). These findings support the utility of FGF-20 as a single-dose agent in the prevention of OM. In addition, the positive effects of FGF-20 on established mucositis may permit treatment of patients with OM who may not benefit from prophylactic agents.

Preclinical characterization of CG53135 (FGF-20) in radiation and concomitant chemotherapy/radiation-induced oral mucositis.

PURPOSE: The purpose of this study was to evaluate the activity of CG53135 (FGF-20), a protein with in vitro mitogenic activity on epithelial and mesenchymal cells, in two in vivo models of oral mucositis (OM). EXPERIMENTAL DESIGN: Radiation or concomitant chemotherapy/radiation-induced OM was elicited in hamsters. Activity of CG53135 was assessed at different doses and regimens in the models. Bromodeoxyuridine (BrdUrd) incorporation and pharmacokinetic studies were also performed to correlate in vivo activity of CG53135 with exposure. RESULTS: In the hamster radiation model, administration of CG53135 (600 or 1200 micro g/day, i.p.) on days 3-15 resulted in a statistically significant (P < 0.001) reduction in days spent with severe mucositis. CG53135 administered at 12 mg/kg, i.p. (days 1-2 or 1-8) in the concomitant chemotherapy/radiation model resulted in a statistically significant (P < 0.001) reduction in severe mucositis. Maximal BrdUrd incorporation was observed in cheek pouch and jejunal tissues at 8 h, and peak plasma levels of CG53135 were reached 1 h after administration. CONCLUSIONS: CG53135 demonstrates potent, regimen-dependent activity in hamster models of OM. The activity was regimen dependent. BrdUrd incorporation studies confirmed that CG53135 had proliferative activity in vivo with a favorable pharmacokinetic profile. Based in part on work described herein, CG53135 has received approval from the United States Food and Drug Administration to be evaluated in a Phase I clinical trial of cancer patients at risk for developing OM.

Oral complications of cancer therapy.

The mouth is a frequent site of complications arising from drug or radiation cancer therapy, with mucositis, xerostomia, osteoradionecrosis, and local infections being the most common. From the stand-point of dose limitation, treatment breaks, quality of life, and health economic outcomes, mucositis is the most significant acute oral toxicity. Xerostomia, a chronic side effect of radiation, involves the salivary gland tissue, and results in changes in taste, tissue resilience, and an increased risk of caries and periodontal disease. While the incidence of osteoradionecrosis seems to be decreasing, the chronicity and symptoms of this festering bony condition are especially difficult for patients. Local oral infections resulting from the overgrowth of opportunistic organisms or the activation of latent viruses are so common as to warrant a prophylactic approach in many cases. A surge of investigational interest has been directed at understanding the mechanisms of these stomatotoxicities and at developing treatment strategies to combat them.