Edward G. Fey

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.

Serum amyloid P ameliorates radiation-induced oral mucositis and fibrosis

PurposeTo 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 DesignHamsters 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.ResultsSAP 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.ConclusionsSAP 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.

Attenuation of radiation‐ and chemoradiation‐induced mucositis using gamma‐d‐glutamyl‐l‐tryptophan (SCV‐07)

OBJECTIVE To evaluate the efficacy of a novel immunomodulating peptide (SCV-07) in attenuating the course of radiation-induced mucositis in an established animal model of oral mucositis (OM). MATERIAL AND METHODS In three separate experiments, golden Syrian hamsters received either an acute radiation challenge to the buccal mucosa of eight fractionated doses of 7.5 Gy of radiation over a 2-week-period, or a combination of acute radiation and cisplatin. In each experiment, animals were treated with varying doses or schedules of SCV-07 or placebo. OM was scored in a blinded fashion using digital images obtained during the experimental period. RESULTS We found that SCV-07 reduced the severity and duration of both acute and fractionated radiation-induced OM. Similarly, when radiation and chemotherapy were used to induce OM, treatment with SCV-07 significantly reduced the duration of ulcerative OM. The therapeutic benefit was dependent on both dose and schedule of administration. CONCLUSION Taken together, we found SCV-07 was able to modify the duration and severity of oral mucositis and was dependent on schedule and dose.

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.

SCV-07 treatment leads to alterations in VEGF, MIF, IL-1alpha, and MIP-1beta levels in patients with head and neck cancer

Introduction: Serum was collected before and after chemoradiation therapy from head and neck cancer (HNC) patients enrolled in a phase 2, randomized, double-blind, dose-ranging, placebo-controlled trial designed to test the safety, tolerability and efficacy of an immunomodulatory peptide, gamma-D-glutamyl-L-tryptophan (SCV-07) as an intervention for oral mucositis (OM). Results of the trial demonstrated that the high dose of SCV-07 (0.1 mg/kg daily on days of radiation) was safe and effective in attenuating the course of OM. The objective of this study was to determine if the administration of high dose SCV-07 affected detectable levels of peripheral blood cytokines that may be involved in the host response to chemoradiation therapy for HNC. Experimental Procedures: Samples were analyzed via multiplex (Affymetrix Procarta cytokine assay), evaluating 35 proteins expected to be affected by SCV-07, which has been shown to stimulate a Th1 cytokine profile and to inhibit IL-6 dependent STAT3 signaling. For each of the 35 proteins, the null hypothesis “average subject protein value in high-dose regimen subjects equals average subject protein value in placebo regimen subjects” was tested against the alternative hypothesis “average subject protein value in high-dose regimen subjects does not equal average subject protein value in placebo regimen subjects.” A two tail test (=0.05) was used as there was no a priori knowledge of a relationship between protein levels and treatment regimen. Unequal population variances were assumed as the samples were not assumed to be random draws from the same population. The dataset analyzed 26 subjects given the high dose SCV-07 regimen and 23 subjects given placebo. Summary of Results: MIF, MIP-1beta, and VEGF were found to be significantly higher (p Conclusions: SCV-07 treatment leads to increases in circulation of some immune-related cytokines (MIF, MIP-1beta, and VEGF) and leads to a decrease in another (IL-1alpha). These results can be used to better understand SCV-079s mechanism of action, and to follow biomarkers during future clinical trials evaluating SCV-07. Basic Research, Epigenetics, Immunology, Noncoding RNAs, Tumor Microenvironment, Metastasis, Target Identification, Validation, Lead Discovery, and Optimization

Abstract A28: A murine model for cancer treatment‐related fatigue

Objectives: Among patients being treated for cancer, cancer treatment‐related fatigue (CTRF) remains a poorly understood condition with a profound effect on quality of life. Our objective was to develop a murine model of CTRF, independent of anemia, in order to further understand its pathogenesis and provide a conduit for the development of mechanistically‐based therapeutic approaches. Methods: To determine the optimal dose of ionizing radiation to produce fatigue, female BALB/c mice were irradiated with 10 doses of fractionated total body irradiation (fTBI, 8, 9, and 10 Gy, cumulative dose) or 15 doses (fTBI, 10.5 and 13.5 Gy, cumulative dose). In a separate experiment, mice received 70, 60 or 50 mg/kg of etoposide sulfate to determine the optimal dose of chemotherapy to induce CTRF. Cage‐top activity sensors (Phillips Respironics) were used to evaluate daily activity patterns in animals up to 4 weeks following the completion of radiation or 12 weeks following etoposide sulfate administration. CTRF was induced by 15 doses of fractionated total body irradiation (fTBI, 10.5 Gy, cumulative dose) in female BALB/c mice or 60mg/kg etoposide sulfate administered as a single dose. Total daily animal activity and changes in wake/sleep cycles were compared to baseline levels. Systemic levels of IL‐6 and TNF‐α were measured and anemia and leukopenia were assessed using specimens obtained in the weeks following the last dose of radiation or etoposide sulfate administration. Results: fTBI resulted in animals with a significantly lower cumulative daily activity, disrupted sleep/wake cycles that continued up to forty days following the last dose of radiation. Administration of etoposide sulfate resulted in a significantly lower cumulative daily activity three weeks following chemotherapy administration and continued for the duration of the study. Reduced activity levels were not associated with laboratory parameters suggestive of anemia. Changes in the measured hematological parameters demonstrated a temporal, dose‐dependent and reversible pattern; consistent with those previously reported in human patients. Conclusions: Despite its frequency and impact, CTRF has been accepted as a cost of successful cancer treatment. This conclusion was largely based on the supposition that, aside for symptom control, there was no opportunity to develop an effective intervention. We report the development a novel mouse model of CTRF in which administration of fractionated TBI or etoposide sulfate was able to induce behaviors consistent with fatigue reported in humans. Our data supports the hypothesis that TBI and chemotherapy induce systemic effects that result in changes in daily activity patterns and sleep/wake cycles in the absence of anemia. Consistent with reports in humans with fatigue syndromes, radiation‐induced CTRF correlated with increased levels of TNF and IL‐6. Additional work is ongoing to further characterize the model. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A28.