Modification of oral mucositis by keratinocyte growth factor: single radiation exposure

Dörr, Wolfgang; Noack, R.; Spekl, Kathrin; Farrell, Catherine L.

doi:10.1080/09553000010018873

Cited by 97 publications

(52 citation statements)

References 4 publications

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“…Oral loperamide works to slow diarrhea in many, 27 but there is still a significant incidence of grade 4 diarrhea and occasional mortality, leading to cessation of treatment. 4,5,28 Previous research has shown that palifermin is an effective antimucotoxic, reducing severity and duration of mucositis in both animal models 12,15,[20][21][22]29,30 and the clinical setting. [16][17][18][19] A drug that would reduce irinotecan-induced diarrhea would improve the clinical options, particularly in colon cancer, but also in other tumors.…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12][13][14][15][16][17][18][19] Farrell et al 12 have shown that palifermin is protective in some animal models of gastrointestinal mucositis, in ameliorating weight loss and improving crypt survival. Furthermore, Dorr et al 14,15,[20][21][22] have shown that palifermin offers significant protection to the oral mucosa of mice following radiation therapy. In the clinical setting, reports from recent trials (phases 1, 2 and 3) have shown that palifermin is effective in reducing oral mucositis.…”

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confidence: 99%

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Palifermin reduces diarrhea and increases survival following irinotecan treatment in tumor‐bearing DA rats

Gibson

Bowen

Keefe

2005

Intl Journal of Cancer

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Mucositis is a common side effect of cancer chemotherapy for which there is currently no treatment. Irinotecan is a commonly used effective chemotherapeutic agent, causing severe gastrointestinal mucositis and diarrhea. Previous research suggests that palifermin is potentially antimucotoxic. The primary aim of this study was to determine whether palifermin was effective in ameliorating irinotecan-induced gastrointestinal mucositis. We also determined the protective effects of single large and multiple small doses of palifermin. Tumor-bearing DA rats were treated with a single large (10 mg/kg) dose of palifermin 3 days prior to, or multiple small (3 mg/kg day for 3 days) doses of palifermin or vehicle control prior to, receiving 2 doses of 150 mg/kg irinotecan. Animals were killed at 6, 24, 48, 72, 96, 120, or 144 hr after treatment. The primary endpoints were diarrhea and mortality. Gastrointestinal morphometry, histopathology and apoptosis were assessed. Tumor weights and mitoses were measured to ensure palifermin did not promote tumor growth. Data were analyzed using Peritz' F-test, Student's t-test and Tukey-Kramer multiple comparison test. Animals pretreated with palifermin tolerated irinotecan treatment better than control animals with less severe diarrhea (5% in animals receiving 10 mg/kg palifermin, 11% in animals receiving 3 3 3 mg/kg palifermin and 28% in animals receiving irinotecan only) and reduced mortality (2% in animals receiving 10 mg/kg palifermin, 11% in animals receiving 3 3 3 mg/kg palifermin and 28% in animals receiving irinotecan only). Small and large intestinal weights were maintained. Intestinal morphometry was not maintained in palifermin-pretreated rats despite being increased prior to irinotecan treatment. Palifermin pretreatment did not prevent apoptosis that peaked at 6 hr in the jejunum or colon, but prevented apoptosis at 96 hr in the small intestine. Palifermin pretreatment in both treatment regimens significantly reduces diarrhea and mortality following irinotecan administration without adversely affecting tumor growth. This positive response warrants further investigation, particularly in humans. ' 2005 Wiley-Liss, Inc.Key words: mucositis; irinotecan; palifermin; diarrhea Mucositis is a major oncologic problem caused by the cytotoxic effects of cancer chemotherapy. The condition affects the entire gastrointestinal tract from the mouth to the anus and causes pain and ulceration in both the mouth and small and large intestines. In addition, it causes abdominal bloating, vomiting and diarrhea.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Palifermin reduces diarrhea and increases survival following irinotecan treatment in tumor‐bearing DA rats

Gibson

Bowen

Keefe

2005

Intl Journal of Cancer

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“…Palifermin has been found to markedly reduce chemotherapy-and radiation-induced injury to the mucosal lining of the oral cavity and the lower gastrointestinal tract in a variety of animal models. [11][12][13][14][15] In particular, palifermin induces cell growth, differentiation, and thickening of the epithelial tissues (squamous epithelium of the oral cavity and glandular tissue of the intestinal column), thereby helping to provide cytoprotective effects throughout the gastrointestinal epithelia.…”

Section: Introductionmentioning

confidence: 99%

Phase 1/2 randomized, placebo-control trial of palifermin to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT)

Blazar¹,

Weisdorf²,

DeFor³

et al. 2006

Blood

135

109

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Palifermin, a recombinant human keratinocyte growth factor, was tested for potential benefits on acute graft-versus-host disease (GVHD) and hematopoietic recovery in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. This randomized, double-blind, placebocontrolled, dose-escalation study assessed the safety and tolerability of palifermin (n ‫؍‬ 69) as compared with placebo (n ‫؍‬ 31) in patients conditioned with cyclophosphamide and fractionated total-body irradiation (Cy/TBI) or busulfan and cyclophosphamide (Bu/Cy) and given methotrexate along with a calcineurin inhibitor (cyclosporine A, tacrolimus) for GVHD prophylaxis. All patients received 3 doses before conditioning and either 3 (cohort 1), 6 (cohort 2), or 9 (cohort 3) doses after HSCT. Palifermin doses were 40 g/kg per day (cohort 1 only) or 60 g/kg per day (all cohorts). Six patients (placebo ‫؍‬ 2, palifermin ‫؍‬ 4) experienced a total of 11 dose-limiting toxicities (most often skin, respiratory, or oral mucositis). The most common adverse events included edema, infection, skin pain, or rash. Times to neutrophil and platelet engraftment were similar. No significant differences in acute GVHD incidence or severity, survival, or day 100 relapse rates were observed between groups. Palifermin was associated with reduced incidence and mean severity of mucositis in patients conditioned with Cy/TBI but not Bu/Cy. We conclude that palifermin was generally safe in allogeneic HSCTs but had no significant effect on engraftment, acute GVHD, or survival in this trial. (Blood. 2006;108:3216-3222)

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“…Mucosal epithelial growth factors such as keratinocyte growth factor (KGF) have been shown to be efficacious in treating experimental animal models of chemotherapy or radiotherapy-induced oral mucositis, and is the first approved biologic therapy for human cancer patients with oral mucositis (14)(15)(16)(17)(18)(19)(20). However, KGF has been shown to enhance the growth of human epithelial tumor cell lines in vitro and to increase the rate of tumor cell growth in human carcinoma xenograft models, probably by binding to its receptor present on the surface of these cells (21).…”

mentioning

confidence: 99%

R-Spondin1 protects mice from chemotherapy or radiation-induced oral mucositis through the canonical Wnt/β-catenin pathway

Zhao¹,

Kim²,

Vera³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

108

100

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R-Spondin1 (RSpo1) is a novel secreted protein that augments canonical Wnt/␤-catenin signaling. We injected recombinant RSpo1 protein into transgenic Wnt reporter TOPGAL mice and have identified the oral mucosa as a target tissue for RSpo1. Administration of RSpo1 into normal mice triggered nuclear translocation of ␤-catenin and resulted in increased basal layer cellularity, thickened mucosa, and elevated epithelial cell proliferation in tongue. We herein evaluated the therapeutic potential of RSpo1 in treating chemotherapy or radiotherapyinduced oral mucositis in several mouse models. Prophylactic treatment with RSpo1 dose-dependently overcame the reduction of basal layer epithelial cellularity, mucosal thickness, and epithelial cell proliferation in tongues of mice exposed to whole-body irradiation. RSpo1 administration also substantially alleviated tongue mucositis in the oral cavity of mice receiving concomitant 5-fluorouracil and x-ray radiation. Furthermore, RSpo1 significantly reduced the extent of tongue ulceration in mice receiving a single fraction, high dose head-only radiation in a dose-dependent manner. Moreover, combined therapy of RSpo1 and keratinocyte growth factor resulted in complete healing of tongue ulcers in mice subjected to snout-only irradiation. In conclusion, our results demonstrate RSpo1 to be a potent therapeutic agent for oral mucositis by enhancing basal layer epithelial regeneration and accelerating mucosal repair through upregulation of Wnt/␤-catenin pathway.RSpo1 ͉ tongue ulceration ͉ head-only radiation ͉ TOPGAL ͉ 5-FU

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Modification of oral mucositis by keratinocyte growth factor: single radiation exposure

Cited by 97 publications

References 4 publications

Palifermin reduces diarrhea and increases survival following irinotecan treatment in tumor‐bearing DA rats

Palifermin reduces diarrhea and increases survival following irinotecan treatment in tumor‐bearing DA rats

Phase 1/2 randomized, placebo-control trial of palifermin to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT)

R-Spondin1 protects mice from chemotherapy or radiation-induced oral mucositis through the canonical Wnt/β-catenin pathway

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