Amifostine: chemotherapeutic and radiotherapeutic protective effects

Amifostine (Ethyoltrade mark, Alza Pharmaceuticals) is an inorganic thiophosphate cytoprotective agent known chemically as ethanethiol, 2-[3- aminopropyl)amino]dihydrogen phosphate. It is a prodrug of free thiol (WR-1065) that may act as a scavenger of free radicals generated in tissues exposed to cytotoxic drugs and binds to reactive metabolites of such drugs. Amifostine was originally developed as a radioprotective agent in a classified nuclear warfare project. Following declassification of the project it was evaluated as a cytoprotective agent against toxicity of the alkylating drugs and cisplatin. Differences in the alkaline phosphatase concentration of normal versus tumour tissues can result in greater conversion of amifostine in normal tissues. Inside the cell, WR-1065 provides an alternative target to DNA and RNA for the reactive molecules of alkylating or platinum agents and acts as a potent scavenger of the oxygen free radicals induced by ionizing radiation and some chemotherapy agents. Preclinical animal studies have demonstrated that the administration of amifostine protects against a variety of chemotherapy-related toxicities including cisplatin-induced nephrotoxicity, cisplatin-induced neurotoxicity, cyclophosphamide- and bleomycin-induced pulmonary toxicity and the cytotoxicities (including cardiotoxicity) induced by doxorubicin and related chemotherapeutic agents. Amifostine has been shown to protect a variety of animal species from lethal doses of radiation. Amifostine gives haematological protection from cyclophosphamide, carboplatin, mitomycin C, fotemustine and radiotherapy; renal and peripheral nerve protection from cisplatin; mucosa, skin and salivary gland protection from radiotherapy. Multiple Phase I studies were carried out with amifostine in combination with chemotherapy for various neoplasms. Appropriate doses of amifostine were found to be 740 - 910 mg/m(2) in single-dose regimens and 340 mg/m(2) in multiple-dose regimens. In radioprotection, doses are generally 200 - 350 mg/m(2). For all these characteristics, amifostine has been recently approved and suggested in ASCO clinical practice guidelines as a radioprotector for head and neck cancer treatment and supportive agent during cisplatin-based chemotherapy, in lymphomas and solid tumours. Moreover, its spectrum of possible applications is enlarging. As data have been provided indicating that amifostine stimulates haematopoiesis, it has been employed with intriguing results in the treatment of myelodysplastic syndromes (MDS).     

阿米福汀对骨髓增生异常综合征患者红细胞寿命的影响

目的研究骨髓增生异常综合征(myelodysplastic syndrome,MDS)患者的红细胞寿命以及阿米福汀对红细胞寿命的影响。方法回顾性分析浙江省中医院血液科2017年1月-2018年7月期间81例MDS患者的临床资料,分为阿米福汀治疗组(49例)和支持治疗组(32例)。以同期9名正常志愿者为正常对照,采用内源性一氧化碳呼气试验法测定患者及志愿者的红细胞寿命,分析MDS患者红细胞寿命及阿米福汀对红细胞寿命的影响。结果 81例初发MDS患者(未经输血支持)平均红细胞寿命为(33.41±10.96)d,与正常对照红细胞寿命(121.11±32.59)d相比明显缩短(P<0.01)。阿米福汀治疗组:部分缓解1例,血液学改善13例,疾病稳定12例,总有效率53.1%。治疗后MDS患者的红细胞寿命(42.24±12.99)d,与治疗前相比明显延长(P<0.01)。支持治疗组:血液学改善2例,疾病稳定9例,总有效率34.4%,红细胞寿命(34.53±7.50)d,与治疗前相比未明显改善。红细胞寿命与疗效关系分析表明,血液学改善患者的红细胞寿命(45.92±9.24)d,较正常对照组红细胞寿命短(P<0.01),与治疗前比较明显延长(P<0.01)。其余患者红细胞寿命治疗前后无统计学意义。结论 MDS患者红细胞寿命缩短,阿米福汀治疗后可提高患者红细胞寿命。     

氨磷汀预防顺铂所致肾毒性

目的观察氨磷汀对顺铂所致肾毒性的预防性保护作用。方法随机将大鼠分成5组,即空白对照组,顺铂5mg·kg-1组,顺铂7.5mg·kg-1组,顺铂5mg·kg-1 氨磷汀200mg·kg-1组和顺铂7.5mg·kg-1 氨磷汀200mg·kg-1组,分别测定肾脏脏器系数、血尿素氮、肌酐水平,并做肾组织病理学检查。结果顺铂5mg·kg-1及7.5mg·kg-1组大鼠BUN、Cr值均明显高于对照组和加用氨磷汀组,差异有显著性(P<0.05或P<0.01);氨磷汀组肾脏脏器系数明显下降,病理分级显示氨磷汀肾损害保护率分别为61.5%和56.8%。结论氨磷汀能有效地预防顺铂所致肾毒性。     

氨磷汀在骨肉瘤大剂量联合化疗中的骨髓保护作用

目的 探讨氨磷汀在骨肉瘤大剂量多药联合化疗中使用对血液学毒性的影响。方法 42例骨肉瘤患者随机分为化疗加氨磷汀组(观察组)及单纯化疗组(对照组),各21例。行MTX-MTX-DDP-ADM化疗,比较化疗后血液学毒性的发生情况。结果 第3周期化疗后观察组Ⅳ°粒细胞减少为28.6%,对照组为66.7%,两组比较有显著性差异(P<0.05)。第4周期化疗后观察组Ⅳ°白细胞减少为33.3%,对照组为81.0%;观察组Ⅳ°粒细胞减少为33.3%,对照组为81.0%,两组比较均有显著性差异(P<0.01)。比较两组患者输红细胞的均次数,观察组明显低于对照组(P<0.01)。结论 氨磷汀在骨肉瘤大剂量联合化疗中使用后可以明显减少化疗后发生Ⅳ°白细胞及粒细胞减少的发生率,降低输红细胞的均次数。对生存率无明显影响,安全性好。     

氨磷汀对淋巴瘤化疗病人重要脏器保护作用临床观察

目的 观察氨磷汀（阿米福汀）对淋巴瘤化疗病人重要脏器保护作用及药物不良反应和安全性。方法 16例恶性淋巴瘤病人均接受单纯化疗（对照组）及化疗加阿米福汀（治疗组）两种方案治疗,作自身前后对照研究。化疗前后监测肝功能、肾功能、心功能及血常规、血钙浓度。结果 化疗相关肝功能损害对照组出现11例,治疗组出现2例（P〈0．01）;肾功能损害仅见对照组出现4例,心功能损害仅见对照组出现1例,治疗组未出现心肾功能损害（P〉0．05）;化疗后发生粒细胞缺乏症对照组11例,治疗组4例（P〈0.01）。结论 阿米福汀能明显减少化疗相关肝功能损害的发生,减少化疗后粒细胞缺乏症的发生。阿米福汀不良反应少见,主要是恶心呕吐、短暂的低血钙症。     

Arsenic trioxide for the treatment of myelodysplastic syndromes

The impressive activity of arsenic trioxide in acute promyelocytic leukaemia (APL) has renewed the interest in this old compound. Arsenic trioxide targets the sulfhydryl groups present in many proteins involved in oncogenesis and has a broad spectrum of biological activities. This article will review the mechanisms of action of the drug and their relevance to the treatment of myelodysplastic syndrome (MDS), a disease for which no standard treatment currently exists. The early clinical experience has confirmed the activity of arsenic trioxide in MDS. The preliminary results of ongoing Phase II studies conducted in patients with MDS suggest that arsenic trioxide produces haematological improvement including durable transfusion independence in ～ 30% of patients. The current data are presented and discussed in this review.     

Azacitidine and the beginnings of therapeutic epigenetic modulation

Background: Although originally developed as a cytarabine analog more than 40 years ago, azacitidine has been the subject of renewed interest in the era of cancer epigenetics. Objective: What is the history of the clinical development of azacitidine and how has it been applied successfully to the treatment of myelodysplastic syndromes (MDS)? Methods: We review the evolution of the use of azacitidine for the therapy of human disease and review the major studies that have laid the groundwork for its current clinical indication. Conclusion: The use of azacitidine has changed the approach to the treatment of MDS and has resulted in improved outcomes for patients.     

阿米福汀滴注速度与恶心呕吐的相关性分析

目的研究阿米福汀滴注速度的快慢与恶心呕吐分级和骨髓保护作用的相关性。方法采用随机的分组方法将35例化疗患者分为A组17例和B组18例,均接受相同周期的化疗。2组Ⅰ周期（对照组）,化疗前用阿米福汀时间严格控制在15min内;Ⅱ周期（实验组）,化疗前用阿米福汀时间控制在60min内。2个周期后评价恶心呕吐分级和血液毒性。结果 A组和B组患者在Ⅰ周期（对照组）出现恶心呕吐的人次、程度均明显高于Ⅱ周期（实验组）（P〈0.01）;而A组和B组患者在Ⅰ周期和Ⅱ周期化疗后的外周血毒性无显著性差异（P〉0.05）。结论阿米福汀滴注速度的快慢,对骨髓保护作用无明显差异,但适当延长阿米福汀使用时间,可以明显减少恶心呕吐的发生率。     

氨磷汀在肿瘤放化疗中保护作用的文献分析

目的了解氨磷汀在国人化疗、放疗中所起的保护作用,为临床更安全有效地使用该药提供有价值的信息。方法通过万方数据网收集有关氨磷汀的临床研究文献。筛选文献,进行汇总分析。结果共获得符合条件的文献22篇,涉及病例1026例。文献表明氨磷汀在肿瘤放化疗中对骨髓、唾液腺及口腔黏膜、胃肠道、肝功能、肾功能均有保护作用。结论肿瘤放化疗中氨磷汀的骨髓的保护作用确切,鼻咽癌的放疗中唾液腺及口腔黏膜的保护作用确切,对顺铂引起的肾脏毒性的保护作用确切。     

Systemic chemotherapy‐induced microsatellite instability in the mononuclear cell fraction of women with breast cancer can be reproduced in vitro and abrogated by amifostine

Objectives Microsatellite instability (MSI) induction by alkylating agent‐based chemotherapy (ACHT) may underlie both tumor resistance to chemotherapy and secondary leukaemias in cancer patients. We investigated if ACHT could induce MSI in tumor‐derived plasma‐circulating DNA (pfDNA) and in normal peripheral blood mononuclear (PBMN) cells. We also evaluated if amifostine could interfere with this process in an in‐vitro model. Methods MSI was determined in pfDNA, PBMN cells and urine cell‐free DNA (ufDNA) of 33 breast cancer patients before and after ACHT. MCF‐7 cells and PBMN from normal donors were exposed in vitro to melphalan, with or without amifostine. Results We observed at least one MSI event in PBMN cells, pfDNA or ufDNA of 87, 80 and 80% of patients, respectively. In vitro, melphalan induced MSI in both MCF‐7 and normal PBMN cells. In PBMN cells, ACHT‐induced MSI occurred together with a significant decrease in the expression of the DNA mismatch repair gene hMSH2. Amifostine decreased hMSH2 expression and also prevented MSI induction only in normal PBMN cells. Conclusions ACHT induced MSI in PBMN cells and in tumour‐derived pfDNA. Because of its protective effect against ACHT induction of MSI in normal PBMN cells in vitro, amifostine may be a potential agent for preventing secondary leukaemias in patients exposed to ACHT.     

广谱细胞保护药——氨磷汀

氨磷汀是第一个被认可的广谱细胞保护药。本文概述了氨磷汀的药动学、作用机制以及在肿瘤的放、化疗中所显示的与器官特异性细胞保护药不同的高效、低毒、全面的正常细胞保护作用 ,不影响抗癌治疗效果。氨磷汀在各人群的安全性已得到临床证实。     

氨磷汀对同步放化疗所致肺癌细胞杀伤作用的影响

目的探讨氨磷汀在多西他赛(TXT)和同步放射治疗非小细胞肺癌过程中对肺癌组织细胞的保护作用。方法使用MTT方法评价在TXT和同步照射(10 Gy)体外培养的SPC-A1肺癌细胞过程中,氨磷汀对SPC-A1肺癌细胞的影响;以Lewis肺癌荷瘤鼠模型评价在TXT同步放射(10 Gy)在体Lewis肺癌过程中,氨磷汀对Lewis肺癌的影响。结果体外实验表明同步放化疗加氨磷汀组和同步放化疗组的吸光度分别相当于对照组的22.8%和24.4%,2组之间比较,经过t检验P>0.05。体内实验表明,同步放化疗加氨磷汀组和同步放化疗组在实验观察的20 d内,相同时间点2组动物的肿瘤体积没有统计学上的显著差异。结论在TXT和放疗同步治疗肺癌过程中,氨磷汀无论是对离体还是在体的肿瘤细胞没有保护作用,TXT和同步放射治疗肺癌的疗效不会因为使用氨磷汀而减弱。     

Immunotoxins as cancer chemotherapeutic agents

Immunotoxins, composed of antibodies linked to protein toxins, are cell-specific cytotoxic reagents that have been constructed as both chemical conjugates and fusion proteins. A variety of different toxins derived from plants, such as ricin, saporin, and bryodin, and bacteria, including Diphtheria toxin and Pseudomonas exotoxin, have been utilized to construct extremely cytotoxic immunotoxin molecules. Single-chain immunotoxin fusion proteins composed of cloned antibody variable regions directly fused to toxins have several advantages over chemically conjugated forms, most importantly, enhanced in vivo antitumor activity. BR96 sFv-PE40 is a single-chain immunotoxin fusion protein that targets a Lewis-Y related antigen expressed on the surface of solid tumor cells. Complete regression and, in certain cases, cure of established tumor xenografts have been observed with BR96 sFv-PE40 administration into rodents. Clinical utility of immunotoxins has shown some promise but has been limited by many factors, most notably vascular leak syndrome (VLS). Our finding that rats serve as a model to study BR96 sFv-PE40 mediated VLS has led to identification of potential inhibitors of this dose-limiting toxicity. In summary, immunotoxins, especially single-chain forms, offer exciting possibilities for therapy of cancer. © 1995 Wiley-Liss, Inc.     

国产氨磷汀(WR-2721)对顺铂致肾毒性的保护作用

腹腔注射国产放化疗保护剂氨磷汀能明显减低由顺铂 ( cis- Pt)引起的正常小鼠或大鼠的肾脏毒性 ,氨磷汀各剂量组血清尿素氮与 cis- Pt组相比显著降低 ( P <0 .0 1 ) ,同时可见肾脏组织学损害明显逆转 ,与进口对照品 amifostine( AFT)相比无显著差异。对接受放化疗的腹水型肝癌和肉瘤 - 1 80荷瘤小鼠以及体外培养人肺腺癌肿瘤细胞加用氨磷汀均不影响放化疗的疗效 ,国产品与进口品无明显差异     

Inhibitors of inosine monophosphate dehydrogenase as potential chemotherapeutic agents

Inosine monophosphate dehydrogenase (IMPDH, E.C.1.1.1.205), an NAD-dependent enzyme that controls de novo synthesis of purine nucleotides, is an important target for the development of chemotherapeutic agents. The concentration of IMPDH is known to increase in tumour cells and activated lymphocytes. Thus, inhibition of IMPDH should result in anticancer and immunosuppressive activities. Since there is an increased demand for purine nucleotides in virus-infected cells needed for RNA and DNA synthesis, inhibition of IMPDH may also lead to antiviral activity. IMPDH enzymes from bacteria, parasites and mammalian sources differ significantly. Such differences can be exploited for the development of antibacterial or antiparasitic agents. A review, which covers the development of the field up to 1998, was published in this Journal [Pankiewicz KW, Expert Opin. Ther. Patents (1999) 9(1):55-65]. This article describes recent studies of molecular structure, mechanism of action and interactions of the enzyme with the co-factor and inhibitors. Perspectives on the development of a new generation of potent and specific inhibitors of IMPDH based on these accomplishments are discussed.     

Azacitidine for myelodysplastic patients aged > 65 years: a review of clinical efficacy

Introduction: Therapeutic strategies for elderly patients affected by myelodysplastic syndromes (MDS) are scarce and only few patients have an advantage in performing allogeneic bone marrow transplant.

Areas covered: Primary endpoints for treatment of elderly MDS patients were not curative, but rather allowing to maintain a good quality of life through prolongation of overall survival. In this context, azacitidine showed to improve responses in this subset of patients compared to conventional established regimens, such as intensive or low-dose chemotherapy and best supportive care. Good safety profile of the drug was reported either when it was used inside or outside clinical trials. Improved quality of response was observed when the drug was administered beyond the first response, and it is now usually recommended to continue it at the same dose and schedule in responding patients.

Expert opinion: Evaluation of baseline prognostic factors and comorbidities may help to identify patients who can benefit from the prolonged administration of the drug. Real life data regarding efficacy and safety of azacitidine in MDS elderly patients are required in order to confirm the results of clinical trials.     

Focal adhesion kinase: a promising target for anticancer therapy

Focal adhesion kinase (FAK) is a protein tyrosine kinase acting as an early modulator of the integrin signalling cascade, thus regulating various basic cellular functions. In transformed cells, upregulation of FAK protein expression and uncontroled signalling were held responsible for the promotion of malignant phenotypic characteristics, as well as resistance to chemotherapy and radiotherapy. Direct FAK targeting resulted in the inhibition of the malignant phenotype of cancer cells, whereas increased apoptotic rates of cancer cells, either used alone or in combination with conventional chemotherapeutic agents, radiotherapy or hormonal therapy. Furthermore, drugs used in cancer chemotherapy, besides their basic mode of action, were also shown to act through altering FAK signalling. Finally, positive results were noted by the transfection of cancer cells with fak mutants or genes that suppress FAK expression or activity, such as phosphatase and tensin homolog deleted on chromosome Ten (PTEN), ribonucleotide reductase M1 polypeptide (RRM1) and melanoma differentiation-associated gene-7 (mda-7). The purpose of this article is a comprehensive review of the existing data on the possible use of FAK targeting in anticancer therapy.     

结直肠癌患者化疗后肝功能异常的分析

目的:分析结直肠癌患者化疗后肝功能异常的特点和易感因素。方法:回顾性分析2013年6月—2014年5月中国医学科学院肿瘤医院内科住院治疗的结直肠癌患者化疗后肝功能异常的特点,对化疗后肝功能异常与临床参数进行相关因素分析。结果:580例患者共接受了3 033周期的化疗,平均5.23周期/例,有170例在化疗过程中出现不同程度的肝功能异常,占29.3%。有140例为1度肝损伤,23例为2度损伤,6例为3度损伤,1例为4度损伤。相关因素分析显示肝功能异常与化疗总周期数、治疗类型及化疗药物相关(P<0.05)。结论:化疗所致肝功能异常的易感因素为化疗总周期数、治疗类型及化疗药物。化疗后肝功能异常的程度多为1度,化疗所致的肝损伤以肝细胞型为主。     

骨髓增生异常综合征感染原因及治疗策略

骨髓增生异常综合征 （MDS） 是一组起源于造血干细胞的恶性克隆性肿瘤。由于患者外周血白细胞持续低下, 较高危患者还会接受去甲基化药物、 常规药物化疗、 造血干细胞移植等治疗, 且MDS多为老年患者, 感染的风险相对较高。MDS患者感染的主要原因是中性粒细胞减少, 此外, 淋巴细胞亚群平衡异常、 铁过载、 高龄、 合并症等也是易感染的相关因素。基于上述危险因素, 对患者的感染风险进行评估, 给予早期预防及制定合适的抗感染治疗策略, 可以提高患者治疗效果及延长生存时间。     

三种化疗方案治疗进展期胃癌的成本效果分析

目的:总结探讨不同化疗方案治疗进展期胃癌的成本效果比。方法:收集上海长海医院普外科2003年6月至2004年6月间收治的96例进展期胃癌患者的治疗数据。根据用药方案的不同,分成3组:A组32例(多西他赛 顺铂 5-氟尿嘧啶 亚叶酸钙);B组30例(盐酸表柔比星 顺铂 5-氟尿嘧啶 亚叶酸钙);C组34例(奥沙利铂 5-氟尿嘧啶 亚叶酸钙),运用成本效果分析方法对三种化疗方案进行经济学评价。结果:在三种化疗药物治疗方案中,多西他赛组有效率为56．25%,1个疗程的治疗成本为9979元,成本效果比177．40(元/百分之一有效率);盐酸表柔比星组有效率为40．00%,1个疗程的治疗成本为4158元,成本效果比103．95(元/百分之一有效率);奥沙利铂组有效率为52．94%,1个疗程的治疗成本为4498元,成本效果比84．96(元/百分之一有效率)。增量成本效果分析表明,A组的(⊿C/⊿E)为358．22;C组的(⊿C/⊿E)为26．28。结论:C方案是三种化疗方案治疗进展期胃癌的最合理方案。