Contribution of an unidentified sodium-dependent nucleoside transport system to the uptake and cytotoxicity of anthracycline in mouse M5076 ovarian sarcoma cells

In the present study, we investigated whether an unidentified system for Na(+)-dependent nucleoside transport is expressed by mouse M5076 ovarian sarcoma cells, besides concentrative nucleoside transporter 2 (CNT2(M)), and is involved in the uptake and cytotoxicity of anthracyclines. In a transport assay involving CNT2(M)-transfectants, CNT2(M) was found to transport [(3)H]cytidine in a Na(+)-dependent manner, and 500 microM cytidine completely inhibited the Na(+)-dependent uptake of [(3)H]uridine via the transporter. In contrast, the Na(+)-dependent [(3)H]uridine uptake by M5076 cells decreased with 500 microM cytidine only to 70% of the control level. Furthermore, transfection of CNT2(M)-specific siRNAs into M5076 cells resulted in a reduction in the Na(+)-dependent uptake of [(3)H]uridine by only 23%, although the expression of CNT2(M) mRNA and Na(+)-dependent uptake of [(3)H]cytidine disappeared in the cells. The uptake of pirarubicin (THP), an anthracycline, by M5076 cells requiring extracellular Na(+) was significantly inhibited by 500 microM uridine, but not 500 microM cytidine. The Na(+)-dependent and cytidine-insensitive uptake of [(3)H]uridine and the that of THP by M5076 cells significantly increased on cotreatment with both cholate and taurocholate, and the enhancement of THP uptake by the bile acids was reversed by cotreatment with 500 microM uridine. Furthermore, the cytotoxicity of THP and doxorubicin, which were previously reported to be taken up via the same transporter, toward M5076 cells was enhanced by cotreatment with both the bile acids. Therefore, it was indicated that an unidentified Na(+)-dependent transport system for nucleosides is expressed by M5076 cells, and contributes to the uptake and cytotoxicity of the anthracyclines.     

Toxicological Aspects of a Novel 9-Aminoanthracycline, SM-5887

The toxicological characteristics of SM-5887 were evaluated in mice after a bolus intravenous injection, and compared with those of adriamycin (ADR). The acute toxic signs observed after SM-5887 administration were body weight decrease, ataxia, hair loss, and myelosuppression. They were qualitatively comparable to those induced by ADR. The 50% lethal dose values determined by 14-day observation after drug administration were in the range of 32 to 50 mg/kg for SM-5887 and 16 to more than 20 mg/kg for ADR in four strains of mice. The maximum tolerated doses (MTD) were estimated to be 25 mg/kg for SM-5887 and 12.5 mg/kg for ADR (no death or body weight loss of more than 3 g occurred). When 14-day survivors were further observed until 90 days after drug administration, ADR frequently and dose-independently showed delayed-type lethal toxicity at doses of more than 10 mg/kg, whereas SM-5887 did not. The myelosuppression of SM-5887 was more severe even at a half of the MTD than that of ADR at the MTD, but its recovery was more rapid than that after ADR, In addition, when the drugs were injected into the subplantar region of mouse hind paws, ADR induced a severe inflammatory reaction, whereas SM-5887 yielded only a slight one. The data suggest that toxic effects of SM-5887 are more reversible and more controllable than those of ADR.     

A longitudinal study of cardiac function in children with cancer over 40 months

A previous study demonstrated impaired systolic function in 29% of patients treated with an thracycline as part of their therapy for malignant disease. A follow-up echocardiographic study was performed to determine whether there had been further deterioration of cardiac function. At least 40 months after the first study, those patients in whom abnormal systolic function had been detected and who had not received further anthracycline were studied by echocardiography using the same protocol as the initial study (group A). A second group of pediatric oncology patients who had not been given anthracycline but who had previously had cardiac assessment was selected as a control group (group N). The age and sex distributions of the two groups were comparable. Group A comprised 29 patients assessed on 2 occasions at mean times of 46 months and 89 months from the last dose of anthracycline. The mean dose of anthracycline received was 233 mg/m² (range 20-400). Nine of 16 patients and 4 of 5 patients who had abnormal ejection fraction (EF) and fractional shortening (FS) at first assessment had normal EF and FS at the second assessment. There were no significant changes in EF, FS, and left ventricular wall stress (LVWS) between the two examinations. In group N, 20 patients were assessed after a mean interval of 43 months. There were no significant changes in EF, FS, or LVWS between the two examinations. At the first but not the second examination there were significant differences in the left ventricular internal diameters, EF, FS, and LVWS between group A and group N. Mildly abnormal cardiac indices detected in children after cessation of treatment with anthracycline did not deteriorate in 3 to 4 years follow-up. A longer cardiac follow-up study is indicated to assess the late outcome.     

右丙亚胺联合环磷腺苷降低蒽环类药物心脏毒性的临床研究

目的：探讨右丙亚胺联合环磷腺苷治疗对血液系统肿瘤患者蒽环类药物多疗程化疗所致心脏不良反应的影响。方法：80例血液系统肿瘤患者随机分为对照组、环磷腺苷组、右丙亚胺组和联合用药组,每组20例。对照组仅予蒽环类药物单纯化疗;环磷腺苷组每次化疗开始予环磷腺苷注射液20ml·d-1,疗程1周;右丙亚胺组化疗前30min予右丙亚胺（与多柔比星剂量比为10：1）快速静滴;联合用药组化疗前30min予右丙亚胺（与多柔比星剂量比为10：1）快速静滴,同时在每次化疗开始予环磷腺苷20ml·d-1疗程1周。4组患者均按要求完成4个化疗周期,观察化疗前后4组患者的心电图改变及超声心动图（左室射血分数LVEF）、B型脑钠肽（BNP）水平变化。结果：右丙亚胺组、联合用药组心电图异常比例明显低于对照组和环磷腺苷组（P〈0．0083）;4组治疗前后LVEF与BNP水平差值比较,各给药组均明显低于对照组,且联合用药组明显低于环磷腺苷组和右丙亚胺组（P〈0．05）。结论：血液系统肿瘤患者接受蒽环类药物多疗程化疗同时配伍使用环磷腺苷及右丙亚胺,可降低蒽环类药物所致心脏毒性,且两药联用疗效最佳,而右丙亚胺单用对心肌细胞保护作用好于环磷腺苷单用。     

DNA fragmentation as a consequence of cell cycle traverse in doxorubicin- and idarubicin-treated human lymphoma cells

Summary We have studied some of the factors involved in the cytotoxic actions of the anticancer anthracycline antibiotics doxorubicin (DOX) and idarubicin (IDA) towards human B-cell lymphoma cells in vitro. IDA was found to accumulate within cells to a greater degree than the related drug DOX for both short (1 h) and long-term (24 h) exposures. Both agents showed a similar capacity for trapping topoisomerase II in intact cells, but cross-linking activity was significantly lower than that induced by the specific poison VP16. IDA was four- to eight fold more potent for the induction of cytostasis and cell cycle arrest and for the instigation of DNA breakdown as a prelude to the full expression of apoptosis. Inhibition of DNA fragmentation at higher drug doses was linked closely with the inhibition of S-phase traverse. The findings suggest that DOX and IDA act in a similar fashion, the latter agent being more effective due to enhanced intracellular accumulation. We conclude that the presence of drug and topoisomerase II-associated DNA damage is not sufficient to induce DNA fragmentation; rather, unregulated commitment to S-phase traverse is an important factor in the activation of programmed cell death. CSG-CR Cooperative Study Group — Cellular Resistance     

乳腺癌蒽环类药物化疗疗效与TOPOⅡα、HER-2的关系

目的探讨乳腺癌TOPOⅡα、HER-2蛋白表达与蒽环类药物新辅助化疗疗效之间的关系。方法通过免疫组化(IHC)方法检测50例乳腺癌患者TOPOⅡα及HER-2蛋白的表达,分析TOPOⅡα和HER-2蛋白表达与临床病理疗效的关系、TOPOⅡα与HER-2表达的相关性及联合表达与临床病理疗效之间的关系。结果 50例乳腺癌患者中,TOPOⅡα蛋白表达17例,阳性率为34%(17/50),TOPOⅡα表达组的临床及病理有效率均优于TOPOⅡα未表达组(P0.05)。TOPOⅡα与HER-2的表达具有相关性(P0.05),HER-2及TOPOⅡα共同表达的病例为12例,但经相关性分析蒽环类药物新辅助化疗效果无明显差异(P0.05)。结论乳腺癌组织中TOPOⅡα蛋白表达与HER-2蛋白表达具有相关性,TOPOⅡα蛋白表达对基于蒽环类药物的新辅助化疗的疗效预测有正相关作用。     

二维斑点追踪成像评价蒽环类抗肿瘤药对乳腺癌患者左房功能的影响

目的探讨二维斑点追踪成像(STI)评价蒽环类抗肿瘤药(ATC)对乳腺癌左房功能的影响。方法 40例乳腺癌患者术后行化疗为化疗组,30例乳腺癌患者术后未化疗为对照组。应用Simpson法在心尖双平面测量左房最小容积(LAVmin)、最大容积(LAVmax)及P容积(LAVp),计算左房总排空分数(LATEF)、被动射血分数(LAPEF)及主动射血分数(LAAEF)。应用STI于心尖四腔心切面测量左房收缩期峰值应变率(SRs)、舒张早期峰值应变率(SRe)、舒张晚期峰值应变率(SRa),并计算其平均峰值(m SRs、m SRe、m SRa)。结果化疗组LATEF、LAPEF、LAAEF、m SRs、m SRe、m SRa较对照组均减低(均P0.05)。两组LATEF与m SRs、LAPEF与m SRe、LAAEF与m SRa均呈正相关(r分别为0.859、0.866、0.882,P0.001)。结论使用ATC乳腺癌患者左房功能发生改变,表现为储备功能、管道功能及泵功能减低。STI与左房容积指标有良好的相关性,能够准确评价左房功能。     

Tei指数监测蒽环类药物对肿瘤患者左心功能的影响

目的探讨心肌做功指数（myocardial performance index，MPI又称Tel index）在评价蒽环类药物（anthracycline，ATC）对肿瘤患者左心功能早期损害方面的临床应用价值。方法测定并比较50例肿瘤患者ATC化疗前和化疗后6个月常规超声心动图参数及Tei指数的变化。结果与化疗前相比，左心室等容舒张时间（IRT）延长（P〈0．05），左心室Tei指数明显升高（P〈0．01）。而左心内径及收缩功能指标（EF、FS）化疗前后无显著性差异，仅14例（28％）患者化疗后出现一项或多项常规左室舒张功能指标异常（E峰减低，A峰升高，E／A〈1）。结论Tei指数能更早、更敏感地评价ATC对肿瘤患者左心功能的损害。     

超声心动图检测蒽环类抗肿瘤药心脏毒性

蒽环类抗肿瘤药可引起心脏毒性已众所周知，但由于其广谱有效的化疗效果使其成为肿瘤化疗中不可或缺的药物之一。因此早期心脏毒性的检测对于及时预防或治疗迟发性心脏损害甚为重要。随着医疗技术的发展，相应检测方法不断发展完善，常规超声心动图结合超声心动图新技术是其中颇有价值的方法之一。