Novel radioprotectant drugs for sparing radiation‐induced damage to the physis

Damron, Timothy A.; Spadaro, Joseph A.; Horton, Jason A.; Margulies, Bryan S.; Strauss, Judith A.; Farnum, Cornelia E.

doi:10.1080/09553000410001669524

Cited by 23 publications

(16 citation statements)

References 37 publications

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“…Radiotherapy for bone or soft-tissue sarcomas close to the growth plate can result in the development of growth arrest, angular deformity, and/or limb length discrepancy. Potential for postirradiation recovery exists in the growth plate, based both on the variability of clinical outcomes following growth plate irradiation and on our own work in the weanling Sprague-Dawley (SD) rat model [Damron et al, 2000[Damron et al, , 2004a.…”

Section: Introductionmentioning

confidence: 99%

Microarray Analysis of Irradiated Growth Plate Zones following Laser Microdissection Shows Later Importance of Differentially Expressed Genes during Radiorecovery

Pritchard

Horton²,

Keenawinna³

et al. 2010

Cells Tissues Organs

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Purpose: Potential targets for selective radiorecovery modulation were investigated via the identification of late upregulated genes and pathways during growth plate chondrocyte recovery. Methods and Materials: Three groups of six 5-week-old male Sprague-Dawley rats underwent fractionated irradiation to the right tibiae over 5 days totaling 17.5 Gy and were then killed at 7, 11, and 16 days following the first radiotherapy fraction. The growth plates were collected from the proximal tibiae bilaterally and subsequently underwent laser microdissection to separate reserve, perichondral, proliferative, and hypertrophic zones. Differential gene expression was analyzed between irradiated right and nonirradiated left tibiae using RAE230 2.0 GeneChip microarray, compared between zones and time points, and subjected to functional pathway cluster analysis with real-time polymerase chain reaction (PCR) to confirm selected results. Results: The reserve zone showed the greatest number of differentially expressed genes and enriched pathways: 259 and 134, respectively. Differentially expressed genes included: Timp3, Gpx1, Gas6, Notch2, VEGF, and HIF-1. Enriched pathways included the developmental processes of regeneration, antiapoptosis, developmental growth, tissue regeneration, mesenchymal cell proliferation, negative regulation of immune response, and determination of symmetry. The reserve zone late upregulation of genes was validated using real-time PCR for Mgp, Gas6, and Eef1a1. Conclusions: A significant difference in late upregulated genes between growth plate zones exists. The reserve zone shows the greatest change, containing a 10-fold increase in the total number of genes differentially expressed between days 7 and 16. These findings suggest that reserve zone chondrocytes may play a later role in growth plate recovery response following irradiation.

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Section: Introductionmentioning

confidence: 99%

Microarray Analysis of Irradiated Growth Plate Zones following Laser Microdissection Shows Later Importance of Differentially Expressed Genes during Radiorecovery

Pritchard

Horton²,

Keenawinna³

et al. 2010

Cells Tissues Organs

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“…In this study, pentoxifylline had been shown to partially protect growth plate from the effect of phototherapy in a skeletally immature rat model. Earlier studies have indicated that pentoxifylline reduces oxygen radical production and protects against tissue damage in vivo by the action of its metabolites (20,21). The effects of pentoxifylline on membranes may explain its effects on cell deformability, inhibition of neutrophils priming by TNF-␣, diminished adherence and aggregation, reduced superoxide production, and improved locomotor responses (22).…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Pentoxifylline on Growth Plate in Neonatal Rats Following Long-Term Phototherapy

2007

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ABSTRACT:We demonstrated previously that receiving long-term phototherapy was associated with early impairment of growth plate structure in neonatal rats, and oxidative stress may be the main risk factor for growth plate injury. The purpose of this study was to examine the histomorphometric effects of pentoxifylline treatment on the growth plate. Sixty weanling Sprague-Dawley rats were randomly separated into three equal groups. Group A, the control group, did not receive phototherapy and pentoxifylline. Groups B and C were exposed to phototherapy for 7 d. In addition to phototherapy, group C was also given pentoxifylline during the study period. Compared with zonal lengths on d 7 after initiation of phototherapy, group B had significantly lower values than group A for all zonal lengths (p Ͻ 0.001). Zonal lengths of growth plate were increased significantly with pentoxifylline treatment in group C for 7 d compared with group B (p Ͻ 0.001). After phototherapy, group B had significantly higher values than groups A and C for plasma malondialdehyde levels (p Ͻ 0.001). The pentoxifylline was found here to have some potential to reduce the effects of phototherapy on growth plate in neonatal rats at a relatively low dose. T he growth plate is a highly organized cartilage structure located between the epiphyseal and metaphyseal bones at the distal ends of the long bones (1). Longitudinal bone growth is the result of chondrocyte proliferation and subsequent differentiation in the epiphyseal growth plates of the long bones. It is regulated by a multitude of genetic and hormonal factors, growth factors, environment, and nutrition (2-5). Regarding effects of radiation therapy on chondrocytes, Pateder et al. observed no change in transforming growth factor ␤ (TGF-␤) gene expression (6), whereas Margulies et al. found that TGF-␤ expression decreased and fibroblast growth factor 2 increased after irradiation (7). Moreover, there is evidence that growth plate chondrocytes, osteoclast precursors, and vascular endothelial cells are more sensitive to radiation than osteoblasts (8 -10). All these contribute to establishing the final height of an individual.Phototherapy administered to newborns with jaundice is considered to be a rather benign procedure with few side effects such as rash, loose stools, increased insensible water loss, and dehydration (11). Although phototherapy has been in use for a long time and its effects on the body have been studied extensively, so far, no studies have investigated the relationship between the growth plate and phototherapy. We previously showed the damaging effect of phototherapy by increased oxidative stress on growth plate in newborn rats. Moreover, we showed functional damage and a harmful effect on longitudinal growth of phototherapy on the SpragueDawley rat growth plate (12). Therefore, we hypothesized that pentoxifylline would ameliorate the adverse effects of phototherapy on the growth plate. METHODS Study groups.Sixty weaning Sprague-Dawley rats were randomized into three groups. As all...

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“…Thus, several approaches may be required and be complementary, or perhaps even seem synergistic. For example, preclinical data suggest that other agents, such as pentoxifylline, misoprostol, IL-1-α , or selenium, may have synergistic effects when combined with amifostine [59] . Considering the proposed sigmoidal shape of most normal tissue complication probability curves ( Figure 3 ), reductions in normal tissue dose can have markedly different effects depending on where along the curve one lies.…”

Section: Expert Opinionmentioning

confidence: 99%

Pharmacologic normal tissue protection in clinical radiation oncology: focus on amifostine

Mell

Movsas

2008

Expert Opinion on Drug Metabolism & Toxicology

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Background : Radiation toxicity is an important problem that limits treatment intensity and adversely affects patients' quality of life. Amifostine is a cytoprotector that can reduce toxicity and potentially improve the therapeutic ratio of radiotherapy. Objective : To discuss the role of amifostine in modern radiotherapy and compare and contrast with alternative approaches to reducing radiation toxicity. Methods : We conducted a literature search through Medline to identify randomized clinical trials pertaining to keyword 'amifostine'. We also consulted reviews, book chapters and selected articles regarding amifostine and normal tissue protection. Results/conclusion : Amifostine is an effective normal tissue protector with level I evidence supporting its use in head and neck and gynecologic cancers but studies in other disease sites, although promising, are inconclusive. Further study is needed to demonstrate conclusively the benefits of wider amifostine use.

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Novel radioprotectant drugs for sparing radiation‐induced damage to the physis

Abstract: Each drug reduced the amount of anticipated growth arrest in the animal model and some compared favourably in magnitude with that previously demonstrated for the established radioprotectant drug amifostine. Restoration of growth appears related to appearance of regenerative clones.

Cited by 23 publications

References 37 publications

Microarray Analysis of Irradiated Growth Plate Zones following Laser Microdissection Shows Later Importance of Differentially Expressed Genes during Radiorecovery

Microarray Analysis of Irradiated Growth Plate Zones following Laser Microdissection Shows Later Importance of Differentially Expressed Genes during Radiorecovery

Protective Effect of Pentoxifylline on Growth Plate in Neonatal Rats Following Long-Term Phototherapy

Pharmacologic normal tissue protection in clinical radiation oncology: focus on amifostine

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