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Journal of Cellular and Molecular... Sep 2013Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and... (Review)
Review
Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin.
Topics: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Epithelium; Fibroblast Growth Factor 7; Humans; Protective Agents; Regeneration
PubMed: 24151975
DOI: 10.1111/jcmm.12091 -
Biology of Blood and Marrow... Aug 2016Clinical trials evaluating palifermin have enrolled few pediatric patients, precluding safety analyses in large groups of children. We compared hematopoietic cell...
Clinical trials evaluating palifermin have enrolled few pediatric patients, precluding safety analyses in large groups of children. We compared hematopoietic cell transplantation (HCT) outcomes among pediatric patients who did or did not receive palifermin as a preventive treatment for oral mucositis. Pediatric patients and controls, matched for HCT and donor type, disease, disease status, and age, were selected from the Center for International Blood and Marrow Transplant Research database and a 1:3 matched cohort analysis was performed. Stratified Cox proportional hazards models were built and propensity score adjustments were used to compare overall and disease-free survival outcomes between palifermin-treated and untreated patients. Three controls were identified for 90% of palifermin recipients. The remaining cases were matched with 2 (8%) controls or 1 (2%) control, for a total of 210 palifermin-treated patients matched with 606 controls. Median follow-up was 31 months in cases and 36 months in controls. Fifty-seven percent of patients underwent allogeneic HCT, mostly for acute leukemia, and 43% underwent autologous HCT, mostly for solid tumors. In univariate analyses, 2-year survival and disease-free survival rates after allogeneic HCT (58% versus 66%, P = .109; 49% versus 60%, P = .06) and after autologous HCT (73% versus 77%, P = .474; 60% versus 64%, P = .637) were similar between palifermin-treated patients and matched controls. In multivariate analysis, palifermin treatment did not significantly increase the risk of mortality (relative risk [RR], 1.20; 95% confidence interval [CI], .87 to 1.66) or of relapse (RR, 1.12; 95% CI, .78 to 1.62) compared with matched controls. No significant differences in rates of acute or chronic graft-versus-host disease (GVHD) were observed between palifermin-treated patients and matched controls. Among pediatric patients undergoing HCT, overall survival, disease-free survival, neutrophil recovery, and GVHD rates were similar between palifermin-treated patients and matched controls.
Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; Databases, Factual; Female; Fibroblast Growth Factor 7; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Propensity Score; Recurrence; Stomatitis; Survival Analysis; Treatment Outcome
PubMed: 27090960
DOI: 10.1016/j.bbmt.2016.04.008 -
International Journal of Cancer Sep 2005Mucositis is a common side effect of cancer chemotherapy for which there is currently no treatment. Irinotecan is a commonly used effective chemotherapeutic agent,...
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 x 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 x 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.
Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Camptothecin; Diarrhea; Female; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Irinotecan; Keratinocytes; Mammary Neoplasms, Animal; Rats; Survival Analysis
PubMed: 15800945
DOI: 10.1002/ijc.21082 -
Trends in Immunology Jul 2009Chronic thymus involution associated with aging results in less efficient T-cell development and decreased emigration of naïve T cells to the periphery. Thymic decline... (Review)
Review
Chronic thymus involution associated with aging results in less efficient T-cell development and decreased emigration of naïve T cells to the periphery. Thymic decline in the aged is linked to increased morbidity and mortality in a wide range of clinical settings. Negative consequences of these effects on global health make it of paramount importance to understand the mechanisms driving thymic involution and homeostatic processes across the lifespan. There is growing evidence that thymus tissue is plastic and that the involution process might be therapeutically halted or reversed. We present here progress on the exploitation of thymosuppressive and thymostimulatory pathways using factors such as keratinocyte growth factor, interleukin 7 or sex steroid ablation for therapeutic thymus restoration and peripheral immune reconstitution in adults.
Topics: Aging; Animals; Cytokines; Fibroblast Growth Factor 7; Gonadal Steroid Hormones; Humans; Interleukin-7; T-Lymphocyte Subsets; Thymus Gland
PubMed: 19540807
DOI: 10.1016/j.it.2009.04.003 -
Annals of Oncology : Official Journal... May 2007Oral and intestinal mucositis are among the most significant dose-limiting toxic effects of intensive cancer treatment and are associated with adverse clinical and... (Review)
Review
Palifermin (recombinant keratinocyte growth factor-1): a pleiotropic growth factor with multiple biological activities in preventing chemotherapy- and radiotherapy-induced mucositis.
Oral and intestinal mucositis are among the most significant dose-limiting toxic effects of intensive cancer treatment and are associated with adverse clinical and economic outcomes. Palifermin (Kepivancetrade mark), an N-truncated recombinant human keratinocyte growth factor-1, is the first agent to be approved for prevention of oral mucositis. Keratinocyte growth factor, a potent epithelial mitogen, appears to play a major role in the healing process. Palifermin has multiple biological activities that appear to protect the mucosal epithelium and promote its early regeneration after irradiation- and chemotherapy-induced injury. These include inhibition of epithelial cell apoptosis and DNA damage, up-regulation of detoxifying enzymes and down-regulation of pro-inflammatory cytokines, as well as enhanced migration, proliferation and differentiation of epithelial cells. Palifermin reduces the incidence, severity and duration of oral mucositis in patients with haematological malignancies undergoing myelotoxic conditioning therapy and haematopoietic stem-cell transplantation. Clinical sequelae, including febrile neutropenia and resource use (opioid analgesia and parenteral feeding), are concomitantly reduced. Other potential applications being explored include use in the solid tumour setting, reduction of intestinal mucositis and reduction of GVHD in allogenic transplantation. Thus, the development of palifermin and other potential new agents for preventing chemotherapy- and radiotherapy-induced mucositis represents an important breakthrough in oncological supportive care.
Topics: Animals; Drug-Related Side Effects and Adverse Reactions; Fibroblast Growth Factor 7; Humans; Models, Biological; Mucositis; Radiotherapy
PubMed: 17030544
DOI: 10.1093/annonc/mdl332 -
Annals of Internal Medicine Sep 2010Mucositis can be a serious complication of cancer treatment. Palifermin reduces mucositis when given in multiple doses to patients undergoing hematopoietic stem-cell... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Mucositis can be a serious complication of cancer treatment. Palifermin reduces mucositis when given in multiple doses to patients undergoing hematopoietic stem-cell transplantation.
OBJECTIVE
To evaluate the efficacy of palifermin given as a single dose before each cycle in patients receiving multicycle chemotherapy.
DESIGN
Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00267046)
SETTING
The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
PATIENTS
48 patients with sarcoma were randomly assigned in a 2:1 ratio to receive palifermin or placebo. All patients received doxorubicin-based chemotherapy (90 mg per m(2) of body surface area over 3 days, by infusion).
INTERVENTION
Palifermin (180 µg per kg of body weight) or placebo was administered intravenously as a single dose 3 days before each chemotherapy cycle (maximum, 6 cycles). Patients who had severe mucositis received open-label palifermin in subsequent cycles.
MEASUREMENTS
Oral assessment of mucositis by using World Health Organization (WHO) oral toxicity scale (grades 0 to 4), with moderate to severe mucositis (grades 2 to 4) as the main outcomes; patient-reported outcome questionnaire; and daily symptom record diary.
RESULTS
A median of 6 blinded cycles (range, 1 to 6) were completed by the palifermin group and 2 (range, 1 to 6) by the placebo group. Compared with placebo, palifermin reduced the cumulative incidence of moderate to severe (grade 2 or higher) mucositis (44% vs. 88%; P < 0.001; difference, -44 percentage points [95% CI, -71 to -16 percentage points) and severe (grade 3 or 4) mucositis (13% vs. 51%; P = 0.002; difference, -38 percentage points [CI, -67 to -9 percentage points]). The main adverse effects were thickening of oral mucosa (72% in the palifermin group vs. 31% in the placebo group; P = 0.007) and altered taste. Seven of the 8 patients who had severe mucositis in the placebo group received open-label palifermin. None of these patients had severe mucositis in the subsequent cycles (a total of 17) with open-label palifermin.
LIMITATIONS
Study limitations include smaller sample size for the control group, inclusion of only patients with sarcoma, and perceived unblinding of the treatment because of notable differences between the biologic effects of palifermin and placebo.
CONCLUSION
A single dose of palifermin before each cycle reduced the incidence and severity of mucositis. The drug was generally well tolerated, but most patients experienced thickening of oral mucosa. Further investigation is needed to determine whether palifermin use will facilitate greater adherence to chemotherapy regimens by reducing mucositis.
Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Doxorubicin; Female; Fibroblast Growth Factor 7; Humans; Male; Middle Aged; Mouth Mucosa; Sarcoma; Stomatitis; Young Adult
PubMed: 20855800
DOI: 10.7326/0003-4819-153-6-201009210-00003 -
Biology of Blood and Marrow... Jul 2016Currently, effective pharmacologic treatment to reduce severe oral mucositis (OM) resulting from high-dose myeloablative cytotoxic therapy in the pediatric population is...
Safety, Pharmacokinetics, and Efficacy of Palifermin in Children and Adolescents with Acute Leukemias Undergoing Myeloablative Therapy and Allogeneic Hematopoietic Stem Cell Transplantation: A Pediatric Blood and Marrow Transplant Consortium Trial.
Currently, effective pharmacologic treatment to reduce severe oral mucositis (OM) resulting from high-dose myeloablative cytotoxic therapy in the pediatric population is not available. Palifermin has been proven to decrease the incidence and duration of severe OM in adults with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT). In the pediatric population, however, data on palifermin treatment are limited. A phase I dose-escalation study of palifermin in pediatric patients with acute leukemias undergoing myeloablative HSCT with total body irradiation, etoposide, and cyclophosphamide was performed to determine a safe and tolerable dose and to characterize the pharmacokinetic (PK) profile and efficacy of palifermin. Twenty-seven patients in 3 age groups (1 to 2, 3 to 11, and 12 to 16 years) and 3 dose levels (40, 60, and 80 μg/kg/day) were studied. There were no deaths, dose-limiting toxicities, or treatment-related serious adverse events. Long-term safety outcomes did not differ from what would be expected in this population. PK data showed no differences between the 3 age groups. Exposure did not increase with increase in dose. The maximum severity of OM (WHO grade 4) occurred in 6 patients (22%), none of whom was in the 80-μg/kg/day dosing group. This study showed that all doses were well tolerated and a good safety profile in all 3 pediatric age groups was seen.
Topics: Acute Disease; Adolescent; Child; Child, Preschool; Cyclophosphamide; Etoposide; Female; Fibroblast Growth Factor 7; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infant; Leukemia; Male; Myeloablative Agonists; Stomatitis; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation
PubMed: 26968792
DOI: 10.1016/j.bbmt.2016.02.016 -
Transplantation and Cellular Therapy Feb 2021Regimen-related toxicities with high-dose therapy followed by hematopoietic cell rescue leads to considerable patient distress, morbidity, and high readmission rates....
Regimen-related toxicities with high-dose therapy followed by hematopoietic cell rescue leads to considerable patient distress, morbidity, and high readmission rates. Palifermin is a recombinant keratinocyte growth factor that is Food and Drug Administration-approved to decrease severe oral mucositis (OM) associated with autologous hematopoietic cell transplantation (ASCT) for hematologic malignancies. We added palifermin as a supportive care measure for patients with lymphoma undergoing ASCT with BEAM conditioning. We compared patients receiving palifermin (n = 35) with historical controls (n = 38) for toxicity and readmission outcomes. The cumulative incidence of OM of any grade was 23% in the palifermin-treated patients and 42% in the control group. Patients receiving palifermin were less likely to be readmitted (57% versus 82%; P = .04), had fewer hospital readmission days (median, 4 days versus 7 days; P < .01), and had fewer total days in the hospital through day +30 after ASCT (median, 12 days versus 15 days; P = .05). Fewer patients in the palifermin group had >20 days in the hospital through day +30 (9% in the palifermin group versus 23% of controls). Adverse events associated with palifermin were mild and transient. The addition of palifermin limits severe regimen-related toxicities and decreases readmissions and duration of hospital stay. This and other measures are needed to identify comprehensive and cost-effective approaches, possibly including palifermin, to prevent severe regimen-related toxicities and decrease health care resource utilization.
Topics: Fibroblast Growth Factor 7; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Patient Readmission; Transplantation, Autologous; United States
PubMed: 33830033
DOI: 10.1016/j.jtct.2020.11.005 -
Current Opinion in Rheumatology Nov 2009The lung in systemic sclerosis (scleroderma) is susceptible to fibrosis and the ensuing respiratory insufficiency contributes to significant morbidity and mortality in... (Review)
Review
PURPOSE OF REVIEW
The lung in systemic sclerosis (scleroderma) is susceptible to fibrosis and the ensuing respiratory insufficiency contributes to significant morbidity and mortality in this disease. The lack of effective therapies for pulmonary fibrosis has spurred a re-evaluation of pathobiological paradigms and therapeutic strategies in scleroderma-associated interstitial lung disease and in idiopathic pulmonary fibrosis. The purpose of this review is to examine emerging new therapeutic targets that modulate pro-fibrotic phenotypes of tissue-resident cells and the associated aberrant tissue remodeling responses in fibrotic disorders.
RECENT FINDINGS
Progressive forms of tissue fibrosis, including scleroderma, are characterized by an accumulation of activated mesenchymal cells and their secreted extracellular matrix proteins in association with dysrepair of epithelial and endothelial cells. Recent studies suggest that emergence of cellular phenotypes that perpetuate loss of cellular homeostasis is characteristic of many fibrosis-related clinical syndromes.
SUMMARY
Therapeutic strategies that modulate the fate/phenotype of reparative structural cells, including epithelial, endothelial, and mesenchymal cells, offer new opportunities for the development of more effective drugs for the treatment of fibrosis.
Topics: Eukaryotic Initiation Factor-4E; Fibroblast Growth Factor 7; Fibrosis; Hepatocyte Growth Factor; Homeostasis; Humans; Idiopathic Pulmonary Fibrosis; NADPH Oxidase 4; NADPH Oxidases; Nitric Oxide; PPAR gamma; Phenotype; Protein Kinase Inhibitors; Scleroderma, Systemic; Signal Transduction; Stem Cell Transplantation
PubMed: 19667993
DOI: 10.1097/BOR.0b013e328330da9b -
BioMed Research International 2016Fibroblast growth factors (FGFs) are a family of growth factors critically involved in developmental, physiological, and pathological processes, including embryogenesis,... (Review)
Review
Fibroblast growth factors (FGFs) are a family of growth factors critically involved in developmental, physiological, and pathological processes, including embryogenesis, angiogenesis, wound healing, and endocrine functions. In the liver, several FGFs are produced basally by hepatocytes and hepatic stellate cells (HSCs). Upon insult to the liver, expression of FGFs in HSCs is greatly upregulated, stimulating hepatocyte regeneration and growth. Various FGF isoforms have also been shown to directly induce HSC proliferation and activation thereby enabling autocrine and paracrine regulation of HSC function. Regulation of HSCs by the endocrine FGFs, namely, FGF15/19 and FGF21, has also recently been identified. With the ability to modulate HSC proliferation and transdifferentiation, targeting FGF signaling pathways constitutes a promising new therapeutic strategy to treat hepatic fibrosis.
Topics: Animals; Cell Differentiation; Cell Movement; Cell Proliferation; Fibroblast Growth Factor 1; Fibroblast Growth Factor 7; Fibroblast Growth Factor 9; Fibroblast Growth Factors; Fibrosis; Gene Expression Regulation; Hepatic Stellate Cells; Hepatocytes; Humans; Liver; Mice; Protein Isoforms; Signal Transduction
PubMed: 27699175
DOI: 10.1155/2016/8323747