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Title: Radioprotective effect of amifostine on parotid gland functioning is region dependent

Abstract

Purpose: To investigation the protective ability of amifostine during partial irradiation of the rat parotid gland. Methods and Materials: Single-dose X-ray irradiation was performed by use of collimators with conformal radiation portals for either the 100% volume (15 Gy) or the 50% cranial/caudal partial parotid gland volumes (30 Gy). Amifostine was administered intraperitoneally at a dose of 250 mg per kg body weight, 25 minutes before irradiation. Saliva flow rates, gland weights, and the tissues of the individual lobes were investigated up to 1 year after treatment. Results: A clear protective effect of amifostine was found against loss of saliva flow, the altered appearance of gross morphology, loss of gland weight, and histopathologic changes for the 100% volume gland irradiations and for the 50% volume cranial irradiations but not for the 50% volume caudal irradiations. Conclusions: The protective ability of amifostine is strongly dependent on the irradiated glandular region and observed for later damage only. The major effect of the drug seems to be the prevention of volume effects caused by secondary damage that occurs in shielded parts of the gland. The results of the present study show that understanding of the anatomy and physiology of organs that are tomore » be spared is necessary to ensure optimal preservation of function.« less

Authors:
 [1];  [2];  [3];  [2];  [4]
  1. Department of Radiation and Stress Cell Biology, University Medical Center Groningen and University of Groningen, Groningen (Netherlands). E-mail: a.w.t.konings@med.umcg.nl
  2. Department of Radiation and Stress Cell Biology, University Medical Center Groningen and University of Groningen, Groningen (Netherlands)
  3. Department of Oral and Maxillofacial Surgery, University Medical Center Groningen and University of Groningen, Groningen (Netherlands)
  4. (Netherlands)
Publication Date:
OSTI Identifier:
20788257
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 63; Journal Issue: 5; Other Information: DOI: 10.1016/j.ijrobp.2005.08.018; PII: S0360-3016(05)02385-0; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
61 RADIATION PROTECTION AND DOSIMETRY; ANATOMY; CARCINOMAS; COLLIMATORS; DAMAGE; DRUGS; GLANDS; HEAD; IRRADIATION; MORPHOLOGY; NECK; PHYSIOLOGY; RADIATION PROTECTION; RADIOPROTECTIVE SUBSTANCES; RATS; SALIVA

Citation Formats

Konings, Antonius W.T., Faber, Hette, Vissink, Arjan, Coppes, Rob P., and Department of Radiation Oncology, University Medical Center Groningen and University of Groningen, Groningen. Radioprotective effect of amifostine on parotid gland functioning is region dependent. United States: N. p., 2005. Web. doi:10.1016/J.IJROBP.2005.0.
Konings, Antonius W.T., Faber, Hette, Vissink, Arjan, Coppes, Rob P., & Department of Radiation Oncology, University Medical Center Groningen and University of Groningen, Groningen. Radioprotective effect of amifostine on parotid gland functioning is region dependent. United States. doi:10.1016/J.IJROBP.2005.0.
Konings, Antonius W.T., Faber, Hette, Vissink, Arjan, Coppes, Rob P., and Department of Radiation Oncology, University Medical Center Groningen and University of Groningen, Groningen. Thu . "Radioprotective effect of amifostine on parotid gland functioning is region dependent". United States. doi:10.1016/J.IJROBP.2005.0.
@article{osti_20788257,
title = {Radioprotective effect of amifostine on parotid gland functioning is region dependent},
author = {Konings, Antonius W.T. and Faber, Hette and Vissink, Arjan and Coppes, Rob P. and Department of Radiation Oncology, University Medical Center Groningen and University of Groningen, Groningen},
abstractNote = {Purpose: To investigation the protective ability of amifostine during partial irradiation of the rat parotid gland. Methods and Materials: Single-dose X-ray irradiation was performed by use of collimators with conformal radiation portals for either the 100% volume (15 Gy) or the 50% cranial/caudal partial parotid gland volumes (30 Gy). Amifostine was administered intraperitoneally at a dose of 250 mg per kg body weight, 25 minutes before irradiation. Saliva flow rates, gland weights, and the tissues of the individual lobes were investigated up to 1 year after treatment. Results: A clear protective effect of amifostine was found against loss of saliva flow, the altered appearance of gross morphology, loss of gland weight, and histopathologic changes for the 100% volume gland irradiations and for the 50% volume cranial irradiations but not for the 50% volume caudal irradiations. Conclusions: The protective ability of amifostine is strongly dependent on the irradiated glandular region and observed for later damage only. The major effect of the drug seems to be the prevention of volume effects caused by secondary damage that occurs in shielded parts of the gland. The results of the present study show that understanding of the anatomy and physiology of organs that are to be spared is necessary to ensure optimal preservation of function.},
doi = {10.1016/J.IJROBP.2005.0},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 5,
volume = 63,
place = {United States},
year = {Thu Dec 01 00:00:00 EST 2005},
month = {Thu Dec 01 00:00:00 EST 2005}
}
  • Purpose: To detect volume effects and possible regional differences in radiosensitivity of the rat parotid gland. Methods and Materials: Parotid glands of male albino Wistar rats were locally X-irradiated, with collimators with conformal radiation portals used to supply 100% volume and 50% cranial/caudal partial volumes. High-resolution magnetic resonance imaging was used to provide the outlines of the parotid glands. Single doses of up to 40 Gy were applied, and the effects on saliva secretion, measured with the aid of miniaturized Lashley cups, were followed up to 365 days after the irradiation. Results: Under conditions of equal mean absorbed doses andmore » small variations in dose distribution, a pertinent volume effect was observed for late but not for early radiation damage. The late effects were different for the cranial part as compared with the caudal part of the parotid gland. The reduction in flow rate was much more severe after irradiation in the cranial part. After a single dose of 30 Gy, the reductions in flow rates were approximately 65% and 25% for the cranial and caudal parts, respectively. At that dose, no saliva flow was observed after irradiation of 100% of the gland. Conclusion: From the rat model studies presented, it is concluded that late radiation damage after partial irradiation of parotid glands shows region-dependent volume effects. This finding is expected to be relevant to the radiosensitivity of human salivary glands, and it implies that the predictive power of the mean dose concept in radiotherapeutic practice is limited. The finding of region-dependent late radiation damage also challenges the basic assumptions of most current normal tissue complication probability models for parotid gland function.« less
  • Changes in rat parotid salivary gland weight and functional parameters were evaluated at 8 to 10 days post irradiation in WR-2721 protected and non-protected animals following exposure to a single 15.3 Gy dose of Cs-137 radiation to the head. Glandular fluid secretory capacity was assessed by maximum flow rate, total volume of saliva and duration of secretion following pilocarpine stimulation. Protection against radiomucositis was also evaluated indirectly by daily monitoring of food and water intake, body weight and paraoral symptomatology. WR-2721 provided a significant degree of protection for all glandular functional parameters as well as gland weight. Relative protective factorsmore » (RPF) were computed for irradiated protected and non-protected animals compared to their sham-irradiated, pair-fed controls. Protection against radiomucositis and preservation of residual parotid gland secretory capacity as determined by functional parameters suggests that WR-2721 may be of significant benefit in alleviating oral symptoms and maintaining salivary gland function for patients receiving radiotherapy for head and neck tumors.« less
  • In permeabilized parotid cells and in isolated membrane vesicles from parotid endoplasmic reticulum (ER), Mg-ATP-dependent Ca{sup 2+} uptake was measured using a Ca{sup 2+}-specific macroelectrode and {sup 45}Ca{sup 2+}, respectively. Mg-ATP-dependent Ca{sup 2+} uptake was inhibited by vanadate by {approximately}45% in permeabilized cells and by {approximately}70% in membrane vesicles from ER during the initial 10 min. After this lag phase, Ca{sup 2+} uptake increased. Subsequent addition of inositol 1,4,5-trisphosphate (IP{sub 3}) caused a similar Ca{sup 2+} release compared with control. This indicates that in presence of vanadate an IP{sub 3}-sensitive Ca{sup 2+} pool was filled. However, when protonophores, such asmore » nigericin or carbonyl cyanide-m-chlorophenylhydrazone, were added in addition to vanadate, this low steady-state free (Ca{sup 2+}) was not reached. {sup 45}Ca{sup 2+} uptake was reduced by {approximately}70% within 60 min, and IP{sub 3} did not cause {sup 45}Ca{sup 2+} release when given subsequently, indicating that filling of an IP{sub 3}-sensitive Ca{sup 2+} pool was prevented. Mg-ATP-driven H{sup +} uptake into ER vesicles was abolished by protonophores and by the H{sup +}-ATPase blockers N-ethylmaleimide and Dio 9 but was unaltered by vanadate. Preincubation of ER vesicles in a medium without Ca{sup 2+}, but with vanadate and with Mg-ATP to generate an H{sup +} gradient, allowed demonstration of {sup 45}Ca{sup 2+} uptake from a medium that did not contain ATP. The data indicate that both a Ca{sup 2+} and a H{sup +} pump are located in a compartment of ER that is also sensitive to IP{sub 3}. Ca{sup 2+} uptake is coupled to an H{sup +} gradient that is generated by the H{sup +} pump and most likely occurs via Mg-ATP-driven Ca{sup 2+}-H{sup +} countertransport but to some extent can also operate in absence of ATP at the expense of the H{sup +} gradient.« less
  • To improve our understanding of hyperamylasemia secondary to parotid gland irradiation, serial serum amylase levels were measured from 12 consecutive patients who received incidental parotid irradiation during radiotherapy of their head and neck tumors. Rapid transient increases in enzyme activity, limited to the first days of radiotherapy, were consistently found. Awareness of the frequency and nature of this response may avoid unnecessary investigation and concern for abdominal pathology in this clinical setting.
  • Purpose: To discuss the implications of three examples of periparotid recurrence after definitive intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC). Methods and Materials: We present 3 patients with HNC who underwent definitive IMRT with concurrent chemotherapy and later had treatment failure in or near a spared parotid gland. Two patients had bilateral multilevel nodal disease, and all had Level II nodal disease ipsilateral to the site of recurrence. The patients were treated using dose-painting IMRT with a dose of 70 Gy to the gross tumor volume and 59.4 Gy or 54 Gy to the high-risk or low-risk clinicalmore » tumor volume, respectively. The parotid glands were spared bilaterally. The patients had not undergone any surgical treatment for HNC before radiotherapy. Results: All patients had treatment failure in the region of a spared parotid gland. Failure in the 2 patients with bilateral multilevel nodal involvement occurred in the periparotid lymph nodes. The third patient developed a dermal metastasis near the tail of a spared parotid gland. On pretreatment imaging, the 2 patients with nodal failure had small nonspecific periparotid nodules that showed no hypermetabolic activity on positron emission tomography. Conclusion: For HNC patients receiving definitive IMRT, nonspecific positron emission tomography-negative periparotid nodules on pretreatment imaging should raise the index of suspicion for subclinical disease in the presence of multilevel or Level II nodal metastases. Additional evaluation of such nodules might be indicated before sparing the ipsilateral parotid gland.« less