Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A large body of experimental research supports the anti-neoplastic activity of cellular and humoral immunity. Disease and therapy-related immune suppression may be important on the treatment outcome or on the subsequent course of the malignant disease. The aim of the study was to investigate the efficacy of amifostine in preventing the immunological toxicity of post-operative radiotherapy (RT) in breast cancer patients. Using flow-cytometry, we examined comparatively the peripheral blood lymphocytic subpopulations in breast cancer patients undergoing conventional post-operative RT versus a hypofractionated accelerated RT scheme combined with amifostine (HypoARC) administration. Despite the higher radiation dose intensity delivered in the HypoARC group, a significant protection of CD4, CD8, CD19 and CD56 subtypes by amifostine was noted. We further focused on two interesting CD4/CD8 subpopulations involved in cellular apoptosis and trans-endothelial migration, namely the CD95/Fas and CD31 positive lymphocytes. Amifostine protected and induced expansion of these subtypes, which could contribute to the maintenance of a high burden of tumor infiltrating lymphocytes during therapy. It is suggested that amifostine effectively protects lymphocytes against RT, which may enhance the efficacy of the latter. The clinical impact of the CD95(+) and CD31(+) T-cell immunological modulation induced by amifostine requires further investigation.
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PMID:Amifostine protects lymphocytes during radiotherapy and stimulates expansion of the CD95/Fas and CD31 expressing T-cells, in breast cancer patients. 1259 77

Specific radioprotection of normal tissue represents a promising approach to improve radiotherapy. The ultimate feature of a normal tissue selective radioprotector is that tumor tissue is excluded from protection. Radioprotectors of the current generation, such as Ethyol, are not explicit normal tissue specific. In contrast, the Bowman Birk protease inhibitor, which is known to prevent in vitro and in vivo radiation-induced carcinogenesis, was found to be normal tissue specific. Moreover, the molecular restrictions for this specificity were identified. The radioprotective effect is dependent upon the presence of a functional wt. TP53. Since a high amount of tumors have lost TP53 function during tumor development, the clinical application of BBI to protect normal tissue from radiation damage would effectively improve the therapeutic outcome of radiation therapy. We succeeded to identify stimulation of DNA-repair mechanisms, such as nucleotide excision repair (NER) and nonhomologous end joining (NHEJ), as molecular mode of action. These results are in good agreement with the observations that BBI concomitantly exhibits anticarcinogenic effect and radioprotective effects. Taken together, BBI is recommended as a radioprotector for normal tissue expressing wild type TP53 during treatment of tumors characterized by a mutant TP53.
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PMID:Radioprotection of normal tissue to improve radiotherapy: the effect of the Bowman Birk protease inhibitor. 1287 Oct 82

Amifostine (Ethyol, WR-2721; MedImmune, Inc, Gaithersburg, MD) is a member of a sulfhydryl-containing class of compounds that protects normal tissue and organs against ionizing radiation damage by scavenging radiation-induced radicals. The goal of this study was to assess the preclinical and clinical data on the protective effect of amifostine in normal organs and tissue. The current literature was reviewed and assessed for progress in the pathogenesis of radiation-induced pulmonary injury. Preclinical and clinical data on the protective effect of amifostine in radiation-induced lung and esophageal injuries were also critically assessed. Significant progress has been made in understanding the pathogenesis of radiation pneumonitis. Preclinical studies have shown strong evidence of the protective effect of amifostine in radiation-induced toxicities in rodents and monkeys. However, available clinical data are not conclusive in showing the protective effect of amifostine in radiation pneumonitis and esophagitis. Amifostine has been well tolerated with a low incidence of toxicities, which included nausea and vomiting (3% to 5%) and transient hypotension during intravenous infusion (7%). Preclinical data are promising for amifostine in protecting thoracic organs from radiation-induced toxicities. Studies measuring the magnitude of gain in tumor control and survival as a result of the enhanced protective effect of amifostine on normal tissue over that of tumor tissue are lacking. Such data would help in designing new approaches to maximize outcome. Additional well-designed phase III studies are necessary to confirm the clinical benefit of amifostine in minimizing radiation- and chemoradiation-related toxicities in patients with lung cancer.
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PMID:Radioprotective effect of amifostine in radiation pneumonitis. 1472 36

A large body of experimental evidence suggests that amifostine (Ethyol, WR-2721; MedImmune, Inc, Gaithersburg, MD) is a selective cytoprotector of normal tissues. Nevertheless, several experimental studies, most of which were conducted in the early 1980s, suggest that amifostine may protect tumor tissues, although to a much lower degree than its protective effect on normal tissues. Based on a critical literature review, we conclude that any experimental evidence suggesting tumor protection is weak. The effects of anesthesia and hypotension on normal and tumor tissue oxygenation status of animals, the consequences of such events on amifostine activity, and the impact of this complex situation on host immunity and radiotherapy efficacy in the experimental setting do not reliably simulate the clinical setting. Analyses of radiobiologic and histologic results of the Canine Sarcoma Study show that, if any conclusion is to be made, amifostine protected normal tissues and preserved (or even enhanced) the antitumor activity of radiotherapy. The Ormaplatin Study clearly showed a 10-fold decreased concentration of platinum in tumor compared with normal tissues, and does not therefore support evidence of lack of amifostine selectivity. Finally, not one clinical study suggests tumor protection with amifostine. On the contrary, the majority of clinical data strongly suggest that patients who receive amifostine with radiotherapy and/or chemotherapy do better than controls. Rather than organizing large-scale, randomized clinical trials to exclude tumor protection by amifostine, it seems more useful to design trials that would measure amifostine benefits in terms of improved quality of life, tumor control, and survival rates in patients being treated with standard or novel chemotherapy/radiotherapy regimens.
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PMID:Amifostine: is there evidence of tumor protection? 1472 37

The chemo- and radioprotectant drug amifostine (Ethyol; MedImmune, Inc, Gaithersburg, MD) is approved for intravenous (IV) administration; however, the subcutaneous (SC) route is being explored as a practical alternative. We have previously reported equivalence between IV and SC administration using a rat model of radioprotection and active metabolite (WR-1065) tissue pharmacokinetics. To examine the more clinically relevant fractionated and hyperfractionated radiation schedules and the effects of variations in the time of amifostine administration, we expanded these studies to include radioprotection and pharmacokinetic studies of WR-1065 using multiple dosing. To measure radioprotection using a fractionated radioprotection model, rats were given amifostine over a 1-week period at various doses (25 mg/kg, 50 mg/kg, 100 mg/kg; or 162.5 mg/m(2), 325 mg/m(2), 650 mg/m(2), respectively) IV or SC daily 30 minutes before exposure to 7.5 Gy/dose. Rats were fully protected from mucositis at the highest amifostine dose, with protection diminishing as the amifostine was decreased. Equivalent protection was observed whether the drug was given IV or SC. When the number of days of amifostine administration was reduced, protection was diminished. Amifostine also protected against radiation delivered using a 1-week hyperfractionated schedule (4.5 Gy/exposure twice daily), with optimal protection occurring when the drug was administered bid 30 minutes before each exposure (50 mg/kg) or every day before the morning exposure (100 mg/kg). The need for daily dosing to achieve optimal radioprotection was consistent with the tissue pharmacokinetics of the active metabolite. We found that WR-1065 did not accumulate in tissues or in SC-implanted tumors when amifostine was administered daily for 3 weeks. In addition, tissue and tumor levels of WR-1065 declined to baseline 24 hours after each amifostine dose. In a monkey pharmacokinetic model, plasma levels of WR-1065 (characterized by a pronounced spike of WR-1065 immediately after IV administration that was absent when the drug was given SC) were similar to those of humans; however, levels of WR-1065 in the tissues were higher 30 minutes following SC administration and were equivalent 60 minutes following IV or SC administration. These results suggest that maximum tissue levels and protection occur when amifostine is given 30 to 60 minutes before radiation exposure, that treatment breaks reduce the radioprotection by amifostine, and that protection from hyperfractionated radiation is dependent on amifostine dose and schedule.
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PMID:Effects of dose and schedule on the efficacy of ethyol: preclinical studies. 1472 38

Locoregional recurrence remains a major obstacle to achieving cure of locally advanced head and neck cancers despite maximal resection and postoperative external beam radiation therapy (EBRT). Locoregional failure occurs in 30% to 40% of high-risk resected head and neck cancer patients after standard postoperative EBRT. In an effort to overcome this problem, a number of strategies have been designed to enhance the effectiveness of radiation including concurrent postoperative chemoradiation, accelerated radiation schedules, incorporation of targeted biologic therapies, and improved radiation delivery techniques such as intensity modulated radiation and high-dose rate (HDR) intraoperative radiation therapy. Intraoperative radiation therapy (IORT) represents an important approach to improve outcome in head and neck cancer patients treated with definitive surgery. High-dose rate IORT is defined as the delivery of a single, large dose of radiation at the time of surgery when the tumor bed is exposed. In conjunction with EBRT, HDR-IORT offers several advantages including: (1) conformal delivery of a large dose of radiation while the tumor bed is precisely defined, minimizing the risk of a geographic miss; (2) potential for subsequent dose reduction of EBRT; (3) shortening overall treatment time; and (4) dose-escalation. Because mucositis represents the dose-limiting acute toxicity and xerostomia ranks as the most common long-term quality-of-life complaint, a reduction of the EBRT dose may provide an important benefit in reducing toxicity, especially when combined with the radioprotectant amifostine (Ethyol, WR-2721; MedImmune, Inc, Gaithersburg, MD). The purpose of this article is to review the rationale for integrating HDR-IORT with a reduced dose of postoperative EBRT combined with amifostine to improve locoregional control and quality of life outcomes in advanced-stage resected head and neck cancer patients.
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PMID:Rationale for integrating high-dose rate intraoperative radiation (HDR-IORT) and postoperative external beam radiation with subcutaneous amifostine for the management of stage III/IV head and neck cancer. 1472 39

Concurrent cisplatin-based chemoradiation therapy is now considered the standard treatment for locally advanced cervical carcinoma. Available data also suggest that combined-modality therapy improves outcome compared with radiation therapy alone in disease with positive para-aortic lymph nodes. However, radiation therapy alone is associated with significant toxicity in cervical cancer, and toxicity is increased with chemoradiation therapy. The cytoprotectant/radioprotectant agent amifostine (Ethyol; MedImmune, Inc, Gaithersburg, MD) has been found to reduce toxicities associated with cisplatin, radiation, and combined modality approaches in the treatment of several tumor types. The limited available data on the use of amifostine in patients with cervical or pelvic cancers indicate a benefit in reducing chemoradiation toxicity, although cisplatin regimens used in the early investigations in cervical cancer are no longer considered optimal. In the Radiation Therapy Oncology Group C-0116 phase I/II trial, patients with cervical cancer with positive para-aortic or high common iliac nodes are to receive extended-field radiation and intracavitary brachytherapy plus weekly cisplatin in the first part of the study; in the second part of the trial, patients are also to receive amifostine. The trial should provide important information on the potential for adjunctive amifostine use in chemoradiation therapy for cervical cancer.
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PMID:Cytoprotection/radioprotection with amifostine: potential role in cervical cancer and early findings in the Radiation Therapy Oncology Group C-0116 trial. 1472 43

Most patients with locally advanced esophageal cancer die from their disease, despite complete surgical extirpation of tumor or institution of aggressive, multimodality treatment. Nevertheless, a favorable trend emerging in the management of such patients is that "more therapy is better." This review describes several studies indicating that aggressive, combined-modality therapy provides a survival advantage for patients with locally advanced esophageal cancer. An ongoing North Central Cancer Treatment Group trial further capitalizes on the concept of "more is better," and tests subcutaneous amifostine (Ethyol, WR-2721; MedImmune, Inc, Gaithersburg, MD) to balance the need for aggressive therapy with the need to mitigate associated toxicity.
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PMID:Aggressive multimodality therapy for patients with locally advanced esophageal cancer: is there a role for amifostine? 1472 44

The major salivary glands produce about 90% of salivary secretions; the minor salivary glands produce the remainder. Standard conventional radiation therapy for advanced oropharyngeal tumors typically involves administering high radiation dose to the major salivary glands bilaterally. In most cases, this causes a marked reduction in oral saliva output. Xerostomia is the most prevalent late side effect of radiation for head and neck malignancies and is cited by patients as the major cause of decreased quality of life. The degree of xerostomia has been reported to depend on the radiation dose and salivary gland volume irradiated. Several studies show dose volume response relationships in the salivary glands, suggesting the possibility of significant improvement in saliva production post radiation as well as quality of life if radiation techniques can spare the salivary glands. In recent years, conformal radiation techniques have evolved, which may allow radiation of tumor targets in the head and neck area while sparing substantial portions of salivary glands. It has been shown that in using these techniques, adequate irradiation of the targets while sparing major salivary glands is feasible. Early clinical experience showed substantial sparing of salivary flow following radiation and suggested an improvement of tumor control and of xerostomia over that achieved with standard radiation techniques. We hypothesize that the addition of a radioprotector may further improve salivary function over that obtained with intensity modulated radiation therapy alone. To test this hypothesis, we initiated a pilot clinical trial whose principal objective is to compare measurements of unstimulated and stimulated salivary flow rates 6 months after intensity modulated radiation therapy plus amifostine (Ethyol; MedImmune, Inc, Gaithersburg, MD) (study patients) with those obtained in historical controls treated with intensity modulated radiation therapy alone.
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PMID:Pilot study of subcutaneous amifostine in patients undergoing postoperative intensity modulated radiation therapy for head and neck cancer: preliminary data. 1472 49

This study was conducted to define a new maximum tolerated dose and the dose-limiting toxicity (DLT) of melphalan and autologous hematopoietic stem cell transplantation (AHSCT) when used with the cytoprotective agent amifostine. Fifty-eight patients with various types of malignancy who were ineligible for higher-priority AHSCT protocols were entered on a phase I study of escalating doses of melphalan beginning at 220 mg/m(2) and advancing by 20 mg/m(2) increments in planned cohorts of 4 to 8 patients until severe regimen-related toxicity (RRT) was encountered. In all patients, amifostine 740 mg/m(2) was given on 2 occasions before the first melphalan dose (ie, 24 hours before and again 15 minutes before). AHSCT was given 24 hours after the first melphalan dose. Melphalan was given in doses up to and including 300 mg/m(2). Hematologic depression was profound, although it was rapidly and equally reversible at all melphalan doses. Although mucosal RRT was substantial, it was not the DLT, and some patients given the highest melphalan doses (ie, 300 mg/m(2)) did not develop mucosal RRT. The DLT was not clearly defined. Cardiac toxicity in the form of atrial fibrillation occurred in 3 of 36 patients treated with melphalan doses >/=280 mg/m(2) and was deemed fatal in 1 patient given melphalan 300 mg/m(2). (Another patient with a known cardiomyopathy was given melphalan 220 mg/m(2) and died as a result of heart failure but did not have atrial fibrillation.) Another patient given melphalan 300 mg/m(2) died of hepatic necrosis. The maximum tolerated dose of melphalan in this setting was thus considered to be 280 mg/m(2), and 27 patients were given this dose without severe RRT. Moreover, 38 patients were evaluable for delayed toxicity related to RRT; none was noted. Tumor responses have been noted at all melphalan doses and in all diagnostic groups, and 21 patients are alive at median day +1121 (range, day +136 to day +1923), including 16 without evidence of disease progression at median day +1075 (range, day +509 to day +1638). Amifostine and AHSCT permit the safe use of melphalan 280 mg/m(2), an apparent increase over the dose of melphalan that can be safely administered with AHSCT but without amifostine. Further studies are needed not only to confirm these findings, but also to define the antitumor efficacy of this regimen. Finally, it may be possible to evaluate additional methods of further dose escalation of melphalan in this setting.
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PMID:Amifostine and autologous hematopoietic stem cell support of escalating-dose melphalan: a phase I study. 1520 68


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