维拉帕米逆转肺癌细胞株多药耐药性的研究

体外实验研究钙通道阻滞剂维拉帕米对多药耐药性肺癌细胞株SPC—A1／ADM耐药性的逆转作用。结果显示，无细胞毒作用剂量的维拉帕米可逆转SPC－A1／ADM细胞对长春新碱、阿霉素的耐药性，而对顺铂的耐药性无明显影响，该逆转作用有药物浓度依赖性。表明维拉帕米可望作为一种化学增敏剂应用于肺癌的治疗。     

阿霉素、顺铂为主的联合化疗治疗卵巢恶性肿瘤

1988年11月至1993年2月共收治卵巢恶性肿瘤19例，其中复发性卵巢癌9例，卵巢转移癌10例。采用以阿霉素、顺铂为主的联合化疗方案，15例有腹水者经上述治疗后，显效4例，有效9例，客观有效率为86.7％；9例复发性卵巢癌化疗后完全缓解6例、部分缓解1例，有效率为77.8％。其中3例再次手术后辅以化疗，生存时间延长，1例已存活4年余。全组未发生严重地毒副作用。治疗结果显示，以阿霉素、顺铂为主的联合化疗方案对复发性和卵巢转移癌不失为一有效的治疗方法。     

金丝桃甙对心肌脂质过氧化的影响

用ＴＢＡ法测定丙二醛（ＭＤＡ）含量，观察金丝桃甙（Ｈｙｐ）对阿霉素以及缺氧／再灌注所致心肌脂质过氧化的影响。结果表明：Ｈｙｇ１００ｍｇ·ｋｇ－１和ＥＧＴＡ４００μｍｏｌ·ｋｇ－１ｉｐ可明显抑制阿霉素所致小鼠心肌ＭＤＡ含量的升高，ＨＰＰ可增强ＥＧＴＡ的作用，Ａ２３１８７拮抗Ｈｙｐ的作用。ＨｙＰ１０、１００μｍｏｌ·Ｌ－１可显著减少缺氧；再灌注离体大鼠心脏ＭＤＡ的产生。提示Ｈｙｐ具有抗心肌脂质过氧化的作用，此作用可能与其阻滞钙内流有关。     

Etoposide (VP-16) is a potent inducer of micronuclei in male rat meiosis: Spermatid micronucleus test and DNA flow cytometry after etoposide treatment

The genotoxic and cytotoxic effects of etoposide (VP-16), a topoisomerase II inhibitor, on male rat spermatogenic cells were studied by analysing induction of micronuclei during meiosis. Micronuclei (MN) were scored in early spermatids offer different time intervals corresponding to exposure of different stages of meiotic prophase. Etoposide had a strong effect on diplotene-diakinesis I cells harvested 1 day after exposure, and a significant effect also on late pachytene cells harvested 3 days after exposure. The effect at 18 days corresponding to exposure of preleptotene stage of meiosis (S-phase) was weaker but also statistically significant. Adriamycin was used as a positive control in this study. The results indicate a different mechanism of action of etoposide compared with adriamycin and other chemicals studied previously with the spermatid micronucleus test. DMA flow cytometry was carried out to assess cytotoxic damage at the same time intervals (1, 3, and 18 days after treatment) at stages I and VII of the seminiferous epithelial cycle allowing a study of cytotoxicity to different spermatogenic cell stages. Damage of differentiating sper-matogonia was observed by a decrease in the cell numbers of the 2C peak 1 and 3 days after treatment and by a reduction of the number of 4C cells (primary spermatocytes) 18 d after etoposide treatment. Adriamycin also killed differentiating spermatogonia. Since the cell population which showed a high induction of MN by etoposide was not reduced in number, the genotoxic effect is remarkable. We conclude that etoposide is a potent inducer of genotoxicity and patients treated with this agent during cancer chemotherapy are at a risk of genetic damage. © 1994 Wiley-Liss, Inc.     

Hemodynamic effects of chronic 4′ epi-adriamycin administration

Summary Adriamycin (ADM) is an effective antineoplastic drug. However, the amount of ADM that can be administered must be limited because of the risk of developing a severe dose-dependent cardiomyopathy. 4Epi-adriamycin (4 ADM) is a new anthracycline analog with similar antineoplastic properties as ADM, but with perhaps less cardiac toxicity. To determine myocardial performance after a chronic treatment with 4ADM, we studied 17 patients (mean age 36.6 years) suffering from lymphomas by means of 24-hour ambulatory ECG, x-ray, M-mode echocardiogram, and rest-exercise gated radionuclide ventriculography (RNV), performed prior to and 2 months after the end of the treatment. Pretreatment and post-treatment shortening fractions, basal pretreatment and post-treatment ejection fractions, and postexercise pretreatment and post-treatment ejection fractions, were tested for correlation with individual 4ADM doses and pretreatment with ADM. No association was noted among them, showing the lack of correlation between doses and impairment of ventricular performance. 4ADM doses ranged from 400 to 1100, 748±174 mg/m²; allnoninvasive studies including RNV doses and RNV (Pearson's correlation coefficient, p=ns). No deterioration of ventricular performance could be demonstrated. Conversely, the basal pretreatment ejection fraction changed from 56.17±7.6% to 61.52±8.3% in posttreatment (p<0.0001). Surprisingly, the postexercise pretreatment ejection fraction also increased from 55.47±7.7% to 63.35±10% in post-treatment (p<0.03). The shortening fraction changed from 35.47±4.8% to 36.47±4.2% after 4ADM treatment (ns). No impairment of cardiac function could be shown in patients previously treated with ADM or radiotherapy. On the basis of these data, treatment with 4ADM did not impair but improved cardiac function     

α‐Actinin‐4 is involved in the process by which dexamethasone protects actin cytoskeleton stabilization from adriamycin‐induced podocyte injury

Aim: Glucocorticoid therapy has been used in childhood nephrotic syndrome since the 1950s, where the characteristic change is effacement of the actin‐rich foot process of glomerular podocytes. Recent studies have shown that glucocorticoids, in addition to their general immunosuppressive and anti‐inflammatory effects, have a direct effect on podocytes, regulate some apoptotic factors, and increase the stability of actin filaments. However, the precise mechanism(s) underlying the protective effects of glucocorticoids on podocytes remain unclear. It is known that adriamycin (ADR) can induce podocyte foot process effacement and trigger massive proteinuria in rodent models. However, few reports have examined the direct role of ADR in podocyte actin rearrangement in vitro. In this study, we investigated how ADR directly induced podocyte actin cytoskeleton rearrangement and further analyzed how dexamethasone prevented such injury. Methods: We used confocal microscopy to assess podocyte actin rearrangement. Western blot analysis and real‐time polymerase chain reaction were performed to measure the protein and mRNA levels of α‐actinin‐4. Results: We demonstrated that there was a time‐dependent ADR‐induced podocyte actin rearrangement with less than 12 h of ADR treatment in cultured podocytes. Dexamethasone could protect podocytes from ADR‐induced injury and also stabilize the expression of α‐actinin‐4. Conclusion: This study showed that dexamethasone had direct effects on podocytes: α‐actinin‐4 may be one of the potential target molecules.     

Acute effect of calcium channel blockers on adriamycin exposed isolated adult cardiocytes

Summary When tested with isolated, calcium-resistant resting rat cardiocytes in an in vitro assay system, adriamycin exerted a dose-dependent cytotoxic effect which could easily be assessed by the ATP depletion of the heart cells and the loss of vitality as monitored by morphological changes (blebbing, spherical contraction). Apart from extremely high non pharmacological concentrations of verapamil and diltiazem, both calcium antagonists left the cardiocytes intact and without loss of internal ATP when given alone to the medium. Coincubation of adriamycin and verapamil or diltiazem did not increase adriamycin toxicity to the cardiocytes; instead a remarkable ATP preservation by verapamil could be demonstrated when both drugs (adriamycin and verapamil) were incubated simultaneously with the heart cells. This acute protective effect was limited in time and could no longer be detected after 9 hours. Diltiazem in coincubation experiments exerted neither a toxic nor an acute protective effect on adriamycin-exposed heart cells.Devoted to my distinguished academic teacher in cardiac physiology Prof. Dr. Ruthard Jacob on the occasion of his 60th birthdaySupported in part by DFG-grants MA 780/1-5     

1,6-二磷酸果糖对阿霉素所致大鼠心肌损伤的影响

目的研究1，6-二磷酸果糖(FDP)对阿霉素(ADM)导致大鼠心肌损伤的影响。方法采用wistar大鼠36只，随机分为ADM组、ADM FDP组及对照组。实验30d后进行心肌光镜病理形态学观察，测定血清及心肌超氧化物歧化酶(SOD)、肌酸激酶(CK)、乳酸脱氢酶(LDH)的活性及脂质过氧化物(LPO)的含量。结果光镜下ADM FDP组病理损害程度较ADM组轻；各组之间心肌及血清CK、LDH差异无统计学意义；和ADM组比较ADM FDP组血浆、心肌LPO含量显著降低，而SOD活性显著增加。结论FDP对ADM所致大鼠心肌损伤有保护作用。     

原代培养的心肌细胞中毒性心肌炎模型的建立

目的 为阿霉素(ADR)中毒性心肌炎机制的研究及药物治疗提供依据.方法 取0～2日龄sD乳鼠原代心肌细胞培养,观察ADR不同浓度(0.01、0.1、1、10、100μg/ml)及不同作用时间(1μg/ml ADR作用24,48,72h)对心肌细胞存活率及培养上清液乳酸脱氢酶(LDH)、谷草转氨酶(GOT)水平的影响,并检测细胞搏动频率.结果 不同浓度ADR均可降低细胞存活率,但10 ng/ml作用后存活率明显降低,呈浓度依赖性.不同浓度ADR均可升高LDH和GOT释放量,亦呈浓度依赖性;随ADR作用时间延长,心肌细胞存活率降低,LDH和COT升高,呈时间依赖性.结论 ADR对原代培养的心肌细胞可造成氧化损伤,损伤程度与ADR浓度及作用时间呈正比.     

Acute effects of doxorubicin (adriamycin) on left ventricular function in dogs

Although chronic doxorubicin (adriamycin) cardiotoxicity often is attributed to repeated episodes of acute myocardial injury, the acute effects of doxorubicin on in vivo left ventricular performance have not been studied in a carefully controlled setting. Accordingly, we recorded high-fidelity left ventricular pressures and segmental dimensions before and after either intravenous or intracoronary doxorubicin in twelve open-chest dogs. Propranolol was administered to prevent reflex sympathetic stimulation, and heart rate was held constant by atrial pacing. Intravenous doxorubicin (1.5 mg/kg) (n = 6) caused significant decreases in all measured indices of myocardial contractility, in association with a large decrease in left ventricular systolic pressure (125 ± 28 and 81 ± 23 mm Hg before and 5 min after doxorubicin, respectively, P < 0.01). Intracoronary doxorubicin (0.075 to 0.3 mg/kg) (n = 6) caused similar decreases in percent segment shortening (from 19 ± 7 to 16 ± 8, P < 0.05), mean normalized shortening rate (from 0.87 ± 0.34 to 0.71 ± 0.37 segment lengths/sec, P < 0.05), and peak positive left ventricular $\text{dP}\text{dt}$ (by 10 ± 11%, P < 0.07), although left ventricular systolic pressure was only modestly decreased (126 ± 20 and 113 ± 17 mm Hg before and after doxorubicin, respectively, P < 0.01). Intracoronary doxorubicin also slowed the rate of left ventricular relaxation, as evidenced by an increase in the time constant for isovolumic pressure fall from 32.0 ± 9.0 to 36.9 ± 7.5 msec, and significantly altered the relationship between left ventricular pressure and dimension at end-diastole.We conclude that a single dose of doxorubicin can acutely alter both systolic and diastolic left ventricular function in dogs. These effects are nearly immediate in onset, and are independent of potential functional alterations due to drug-induced systemic hypotension.