MST-16, a novel derivative of bis(2,6-dioxopiperazine), synergistically enhances the antitumor effects of anthracyclines

MST-16, a derivative of bis(2,6-dioxopiperazine), is a newly developed anticancer agent that is potentially effective in combination with anthracyclines. It has a structural similarity to ICRF-187. The effects of MST-16 and its active form, ICRF-154, on the cytotoxic activities of six anthracyclines were investigated both in␣vitro and in vivo. Adriamycin (ADM), therarubicin (THP) and ME2303 (ME) showed synergistic cytotoxicity against colon 26 cells, when combined with MST-16. Epirubicin (EPI) and menogaril (TUT-7) and daunomycin (DM) all had a combination index of less than 1.0 only in the lower fraction affected range and, so there were probably no synergistic interactions between these drugs and MST-16. In colon 26 tumor-bearing mice, a significant delay in tumor growth was noted in the mice treated with ADM (7.5 mg/kg) and MST-16 (750 mg/kg) compared with mice given either drug alone. Similarly, tumor growth in mice treated with THP (10 mg/kg) or ME (10 mg/kg) with MST-16 (750 mg/kg) was significantly delayed. To elucidate the mechanism of synergy between these anthracyclines and MST-16, the concentration of anthracyclines in the treated cells was measured by flow cytometry. No increased intracellular accumulation of ADM, THP or ME was evident even when combined with MST-16. Cell cycle analysis revealed that MST-16 enhanced the accumulation of cells in G₂M induced by ADM, THP and ME 1.6, 1.4, and 1.5 times, respectively. We thus conclude that the administration of ADM, THP and ME combined with MST-16 is synergistic and that the mechanism may not include an increase in the intracellular drug uptake but rather an increase in G₂M accumulation. Received: 27 December 1996 / Accepted: 1 December 1997     

Evaluation of anthracycline cardiotoxicity with the model of isolated,perfused rat heart: comparison of new analogues versus doxorubicin

We have compared the cardiotixicity of 3 anthracyclines in a model of isolated perfused rat heart using the Langendorff technique. The contractile state and ventricular compliance were studied. Doxorubicin, epirubicin and pirarubicin were perfused at concentrations of 10^–6 and 10^–5 M during 70 min. The cardiac accumulation of the drugs was studied by HPLC. No significant alteration of cardiac functional parameters was observed at 10^–6 M. At 10^–5 M, epirubicin produced a significantly greater alteration of cardiac contractility than doxorubicin, whereas pirarubicin exerted first an inotropic effect followed by a recovery to initial values at the 60th min. Anthracycline accumulation in the heart was dose-dependent; epirubicin accumulated to a 30% greater extent than doxorubicin and pirarubicin heart concentrations were 4–5 times higher than those of doxorubicin at the end of the perfusion. These results suggest that doxorubicin and epirubicin have the same intrinsic cardiac toxicity, and that their distinct clinical cardiotoxicity must be explained by pharmacokinetic differences, whereas pirarubicin is much less cardiotoxic than the other anthracyclines because of different pharmacodynamic properties.     

血清中肌钙蛋白与蒽环类药物累积量的相关性研究

目的 探讨血清中肌钙蛋白（cTnT）与蒽环类药物累积量的相关性。方法 收集使用蒽环类药物化疗后的肿瘤患者41例，统计患者所用蒽环类药物的累积量，检测患者血清中cTnT的值，分析血清中cTnT与蒽环类药物累积量的相关性。结果 蒽环类药物累积量0～180mg，血清中cTnT 0～1．36μg／L，蒽环类药物累积量与血清中cTnT并无线性相关（P〉0．05）。结论 不能推荐使用血清中cTnT来检测葸环类药物心毒性累积的严重程度。     

表观遗传修饰在蒽环类药物导致心脏毒性中的作用机制研究

蒽环类药物如阿霉素(DOX)可用于多种癌症的治疗,但其引起的心脏毒性限制了其临床应用。了解阿霉素心脏毒性机制,对肿瘤心脏病学这一新兴领域的发展至关重要,如何预测、诊断和防治这种不良反应需引起高度重视和思考。由于DOX与线粒体功能障碍有关,以线粒体代谢物为底物的表观遗传修饰酶最有可能受到影响。文章对表观遗传修饰,即DNA甲基化、组蛋白修饰和非编码RNA表达进行综述,以了解DOX引起心脏毒性的表观遗传学机制。     

Pharmacological and molecular characterization of intrinsic and acquired doxorubicin resistance in murine tumor cell lines

We have studied the pharmacological parameters of doxorubicin resistance in three lines of murine cells selected by long-term culture in the presence of this drug or vincristine. A line originating from rat hepatoma spontaneously presented an intrinsic doxorubicin resistance as compared to the other lines, originating from a rat glioblastoma and from simian-virus-40-transformed mouse hepatocytes. This intrinsic resistance, as well as the doxorubicin resistance exhibited by the vincristine-selected glioblastoma variant, could be entirely attributed to decreased drug accumulation due to drug efflux. In contrast, the doxorubicin-selected variants of the three lines exhibited an intracellular tolerance to this drug. Despite a reduction in drug accumulation when exposed to the same amount of doxorubicin, they accumulated 6–12 times more doxorubicin than wild lines when submitted to equitoxic exposures. Verapamil could restore, in these lines the doxorubicin accumulation observed in sensitive lines but could not restore doxorubicin cytotoxicity. Quantitative evaluation of P-glycoprotein expression by Western blotting with the C219 antibody indicated that the wild hepatoma line overexpressed P-glycoprotein by a factor of 5 in comparison with the other wild lines, and that the vincristine-selected glioblastoma variant overexpressed this protein almost as much as the doxorubicin-selected variants. These observations favor the existence of P-glycoprotein-independent mechanisms of doxorubicin resistance, which are added to the classical multidrug-resistant phenotype in doxorubicin-selected highly resistant variant cell lines.     

Anthracycline antitumour agents

A review of physicochemical and analytical properties of anthracycline antitumour agents is presented. The following subjects are discussed: protolytic equilibria, partition and partition coefficients, self-association, adsorptive properties, metal complexation, spectroscopy and chromatography. Furthermore, the stability of anthracyclines in solutions, in pharmaceutical preparations and in biological media is discussed.     

Adjuvant chemotherapy in 2005: standards and beyond

The 2003 St. Gallen consensus panel divided the many available adjuvant chemotherapy (CT) regimens into those with "standard efficacy" (ACx4, CMFx6) and those with "superior efficacy" (FA(E)Cx6, CA(E)Fx6, A(E)-->CMF, TACx6, ACx4--> paclitaxel (P)x4 or docetaxel (D)x4) but also greater complexity, toxicity and cost. This paper will summarize the latest information on long-term side effects of the "superior" regimens and 5-year benefits reported in taxane trials, including those of a "new" sequential regimen, FECx3--> docetaxelx3. Rapidly expanding evidence of marked heterogeneity in the magnitude of CT benefits according to the tumour oestrogen receptor (ER) status, a claim made for many years by IBCSG investigators, will be reviewed; it will lead to the conclusion that a revolution needs to take place in the way oncologists think about the CT added value and design adjuvant clinical trials. The conclusions proposed to the 2005 St. Gallen consensus panel are that: adequately dosed anthracycline-based CT regimens remain an acceptable standard for many women; a lower threshold for using taxanes in sequence or combination with anthracyclines (A) is justified in the presence of an ER-negative or low-ER tumour status, other aggressive biologic features (such as HER-2 overexpression), fear about A-induced cardiotoxicity; no recommendation can yet be made as far as the optimal taxane-A regimen, the best taxane or the best taxane schedule.     

Prevention of chronic anthracycline cardiotoxicity in the adult Fischer 344 rat by dexrazoxane and effects on iron metabolism

Purpose: Anthracyclines, such as doxorubicin and daunorubicin, continue to be widely used in the treatment of cancer, although they share the adverse effect of chronic, cumulative dose-related cardiotoxicity. The only approved treatment in prevention of anthracycline cardiotoxicity is dexrazoxane, a putative iron chelator. Previous in vitro studies have shown that disorders of iron metabolism, including altered IRP1–IRE binding, may be an important mechanism of anthracycline cardiotoxicity. Methods: This study examined the role of IRP1–IRE binding ex vivo in a chronic model of daunorubicin cardiotoxicity in the Fischer 344 rat and whether dexrazoxane could prevent any daunorubicin-induced changes in IRP1 binding. Young adult (5–6 months) Fischer 344 rats received daunorubicin (2.5 mg/kg iv once per week for 6 weeks) with and without pretreatment with dexrazoxane (50 mg/kg ip). Other groups received saline (controls) or dexrazoxane alone. Rats were killed either 4 h or 2 weeks after the last dose of daunorubicin to assess IRP1–IRE binding. Results: Contractility (dF/dt) of atrial tissue, obtained from rats 2 weeks after the last dose of daunorubicin, was significantly reduced in daunorubicin-treated compared to control rats. Dexrazoxane pretreatment protected against the daunorubicin-induced decrease in atrial dF/dt. However, left ventricular IRP1/IRE binding was not affected by daunorubicin treatment either 4 h or 2 weeks after the last dose of daunorubicin. Conclusions: IRP1 binding may not be altered in the rat model of chronic anthracycline cardiotoxicity.The authors state there are no conflicts of interest regarding the work in this paper.     

Anthracycline-induced cardiotoxicity: comparison of recommendations for monitoring cardiac function during therapy in paediatric oncology trials

The use of anthracyclines is limited by a dose-dependent cardiotoxicity (A-CT). The aim of this study was to gain insight in the currently available guidelines for monitoring cardiotoxicity during anthracycline therapy in children and in the monitoring recommendations currently used in European paediatric oncology trials. An extensive literature search to identify guidelines was performed and one guideline was identified. Twelve protocols including anthracycline therapy were evaluated.With regard to the minimally required diagnostic tests, parameters and definitions of A-CT most protocols roughly followed the guideline. However, both monitoring schedules and recommendations to prevent further cardiac damage in case A-CT was diagnosed varied widely between protocols and only a minority of the protocols followed the recommendations of the guideline.In conclusion, despite an existing guideline, there is a wide variation in the recommendations for monitoring cardiac function during anthracycline therapy in the currently used European paediatric oncology protocols. A possible explanation could be the lack of rigorous evidence on the most optimal way to monitor cardiac function in children treated with anthracyclines. There is a strong need for evidence from clinical research which can support recommendations for monitoring cardiac function during anthracycline therapy for childhood cancer. In the meantime, it is important to uniformise the used cardiac monitoring schedules.     

不同化疗方案对蒽环和紫杉类药物治疗后复发的三阴性乳腺癌患者的疗效及安全性研究

目的：探讨两种不同的化疗方案对蒽环和紫杉类药物治疗后复发的三阴性乳腺癌（TNBC）患者的效果。方法：选取河北中石油中心医院收治的60例蒽环和紫杉类药物治疗后复发的TNBC患者,采用前瞻性研究方式,应用随机数字表将其分为GP组（吉西他滨联合顺铂）和NP组（长春瑞滨联合顺铂）各30例。比较两组的疗效、预后及血清miR-21、miR-200a、miR-200b水平。结果：治疗后,两组患者的血清miR-21、miR-200a水平较本组治疗前均显著降低（P<0.05）,两组患者的血清miR-200b水平较本组治疗前均显著升高（P<0.05）;NP组患者在化疗过程中的白细胞降低、血红蛋白降低程度较GP组更严重,差异有统计学意义（P<0.05）;GP组患者的肿瘤无进展生存中位时间为34.0个月,长于NP组的28.0个月（P<0.05）。结论：吉西他滨联合顺铂与长春瑞滨联合顺铂方案治疗对蒽环和紫杉类药物耐药复发的TNBC患者效果差异不大,但吉西他滨联合顺铂方案的毒副反应较少,可有效延长患者的肿瘤无进展生存时间。