乳腺癌化疗相关心脏毒性的防治研究进展

目前,心血管疾病和肿瘤的全球发病率居高不下,有数据显示,截止到2018年,全世界癌症新发总人数约为1810万例,其中,乳腺癌新发例数约为210万,占女性恶性肿瘤发病率和死亡率的首位[1]。近些年,随着我国医疗卫生服务质量和水平的不断提升,包括乳腺癌在内的癌症患者的五年生存率也相应地得到提高,乳腺癌患者整体生存时间整体延长。乳腺癌的治疗方法包括化疗、放疗、靶向治疗以及手术治疗,其中,化疗是主要的治疗手段。值得注意的是,蒽环类等化疗药物的广泛应用,虽有效提高了乳腺癌患者的远期生存率,但同时也不可避免地带来了心律失常、心力衰竭、心肌病等一系列心血管毒性反应,不仅在一定程度上限制了这些药物的临床应用,也对乳腺癌幸存患者的远期预后以及生活质量造成了严重不良影响。因此,乳腺癌化疗相关的心脏毒性有必要引起心血管及肿瘤科医师的警惕和重视,本文现就乳腺癌化疗相关心脏毒性的防治研究进展做一综述。     

超声心动图评价蒽环类药物对右室功能的影响

摘要：目的：应用超声心动图技术评价蒽环类药物（ATC）对右室功能的影响。方法：41例（LVEF≥55%）采用多柔比星脂质体为主的PAD方案化疗的多发性骨髓瘤患者,分别于化疗2、4、6周期后行经胸二维超声心动图检查,获得常规、组织多普勒及二维应变参数,20例健康者作为对照。结果：RVGLS在化疗各周期均低于对照组且随化疗周期延长不断减低,病例组在各周期E/Em均高于对照组,TAPSE在化疗6周期后明显减低;RVGLS与药物累积剂量呈显著负相关(r =-0.799,P =0.000）,E/Em在ROC曲线下的面积为0.995（P =0.000）,以5.22为截断值,敏感性为 93.7%,特异性为100%。结论：超声心动图可用于临床评估ATC化疗患者右室功能,RVGLS、E/Em、TAPSE可更好的早期评价右室功能变化。     

乳腺癌组织中ERCC1、Ki67、PCNA表达与蒽环类化疗药物敏感性的关系

目的:对乳腺癌组织中,核苷酸切除修复交叉互补基因1(Excision repair cross comp-lementing,ERCC1)、Ki67蛋白、增殖细胞核抗原(Proliferating cell nuclear antigen,PCNA)表达与蒽环类化疗药物敏感性的关系进行探讨。方法:通过免疫组化法对93例乳腺癌组织的ERCC1、Ki67和PCNA表达进行检测;观察患者化疗疗效,对ERCC1、Ki67和PCNA表达水平不同患者使用蒽环类药物化疗的效果差异进行比较。结果:ERCC1的阳性率为65.59%,Ki67的阳性率为69.89%,PCNA的阳性率为64.52%。ERCC1阳性组总有效率为50.82%,ERCC1阴性组总有效率为84.38%;Ki67阳性组中,Ki67表达强度为25%~50%患者有效率为73.68%(14/19),50%~75%患者有效率为85.71%(24/28),75%患者有效率为88.89%(16/18),Ki67阴性组总有效率为60.71%;PCNA阳性组中,PCNA表达强度为25%-50%患者有效率为52.94%(9/17),50%~75%患者有效率为62.07%(18/29),75%患者有效率为71.43%(10/14),PCNA阴性组总有效率为81.82%,以上差异均有统计学意义(P0.01,P0.05,P0.05)。结论:乳腺癌患者ERCC1、Ki67和PCNA的表达情况与蒽环类化疗药物的敏感性均有相关关系,而在临床上对多因子的联合检测将更有助于化疗药物的选择以及化疗方案的制定。     

卡培他滨对难治转移性乳腺癌的疗效与安全性的评价

目的研究卡培他滨在蒽环和紫杉类化疗失败的晚期乳腺癌的疗效和安全性,及其与激素受体和Her2状态与疗效关系。方法 61例晚期乳腺癌病人接受卡培他滨治疗,直到出现肿瘤进展或不能耐受毒性,分析其疗效及毒副反应。结果 CR、PR、SD和PD分别是1.7%、29.5%、39.3%和29.5%;ORR31.2%,临床获益率70.5%;平均缓解持续时间7.3个月,TTP6.0个月。ORR、临床获益率与TTP不受激素受体、Her2状态影响。大部分治疗相关性毒副反应是轻中度,可耐受。结论卡培他滨可能成为难治性转移性乳腺癌的治疗首选药物。     

Pyridoxal Isonicotinoyl Hydrazone (PIH) and its Analogs as Protectants Against Anthracycline-Induced Cardiotoxicity

The risk of cardiotoxicity is the main drawback of anthracycline antibiotics. However, these drugs remain among the most effective and frequently used anti cancer drugs. In this study we aimed to assess the cardioprotective effects of aroylhydrazone iron (FE) chelators: pyridoxal isonicotinoyl hydrazone (PIH) and its two analogs: salicyladehyde isonicotinoyl hydrazone (SIH) and pyridoxal o-chlorbenzoyl hydrazone (o-108). In rabbits, chronic treatment with daunorubicin (DAU) (3 mg/kg weekly for 10 weeks) induced mortality (33%) as well as left ventricular (LV) dysfunction. Co-administrations of PIH (25 mg/kg, i.p.), SIH hydrochloride [1 mg/kg, iv] as well as o-108 (10 mg/kg, i.p.), fully prevented premature deaths and most of the DAU-induced functional impairments were significantly suppressed. However, when 2- to 2.5-fold higher doses of the chelators were used, they led to rather paradoxical and mostly negative results regarding both cardioprotection and overall mortality.     

Cardioprotective effects of rosuvastatin and carvedilol on delayed cardiotoxicity of doxorubicin in rats

Context: Doxorubicin is widely used anti-neoplastic drug but has serious cardiotoxicity. Long-term cardioprotective effects of statin and carvedilol against delayed cardiotoxicity of doxorubicin was not well elucidated.

Objective: To evaluate long-term cardioprotective effects of co-administered rosuvastatin and carvedilol against chronic doxorubicin-induced cardiomyopathy (DIC) in rats.

Methods: Sixty-one rats were assigned to six groups: group I, control; group II, doxorubicin only (1.25 mg/kg, bi-daily, I.P.); group III, doxorubicin + rosuvastatin (2 mg/kg/day, P.O.); group IV, doxorubicin + rosuvastatin(10 mg/kg/day, P.O.); group V, doxorubicin + carvedilol (5 mg/kg/day, P.O.); group VI, doxorubicin + carvedilol (10 mg/kg/day, P.O.). Drugs were administered for 4 weeks (by week 4) and rats were observed without drugs for 4 weeks (by week 8).

Results: After 4 weeks discontinuation of drugs (week 8), group III showed higher +dP/dt (p = 0.058), lower ?dP/dt (p = 0.009), lower left ventricular (LV) tissue malondialdehyde (MDA; p = 0.022), and less LV fibrosis (p = 0.011) than group II. Group IV showed similar results to group III. However, in group V and VI, carvedilol failed to reduce LV dysfunction, elevation of troponin or myocardial fibrosis, although group V showed lower LV tissue MDA (p = 0.004) than group II.

Discussion and conclusions: Myocardial injury and LV systolic/diastolic dysfunction at week 8 was alleviated by co-administered rosuvastatin, but not by carvedilol. It is unclear whether the cardioprotective effect of rosuvastatin is attributed to a suppression of oxidative stress induced by doxorubicin, because carvedilol did not exhibit a cardioprotective effect despite its antioxidant effects.     

A murine experimental anthracycline extravasation model: Pathology and study of the involvement of topoisomerase II alpha and iron in the mechanism of tissue damage

The bisdioxopiperazine topoisomerase II catalytic inhibitor dexrazoxane has successfully been introduced into the clinic as an antidote to accidental anthracycline extravasation based on our preclinical mouse studies. The histology of this mouse extravasation model was investigated and found to be similar to findings in humans: massive necrosis in the subcutis, dermis and epidermis followed by sequestration and healing with granulation tissue, and a graft-versus-host-like reaction with hyperkeratotic and acanthotic keratinocytes, occasional apoptoses, epidermal invasion by lymphocytes and healing with dense dermal connective tissue. The extension of this fibrosis was quantified, and dexrazoxane intervention resulted in a statistically significant decrease in fibrosis extension, as also observed in the clinic. Several mechanisms have been proposed in anthracycline extravasation cytotoxicity, and we tested two major hypotheses: (1) interaction with topoisomerase II alpha and (2) the formation of tissue damaging reactive oxygen species following redox cycling of an anthracycline Fe²⁺ complex. Dexrazoxane could minimise skin damage via both mechanisms, as it stops the catalytic activity of topoisomerase II alpha and thereby prevents access of anthracycline to the enzyme and thus cytotoxicity, and also acts as a strong iron chelator following opening of its two bisdioxopiperazine rings. Using the model of extravasation in a dexrazoxane-resistant transgenic mouse with a heterozygous mutation in the topoisomerase II alpha gene (Top2a^Y165S/+), we found that dexrazoxane provided a protection against anthracycline-induced skin wounds that was indistinguishable from that found in wildtype mice. Thus, interaction with topoisomerase II alpha is not central in the pathogenesis of anthracycline-induced skin damage. In contrast to dexrazoxane, the iron-chelating bisdioxopiperazine ICRF-161 do not inhibit the catalytic cycle of topoisomerase II alpha. This compound was used to isolate and test the importance of iron in the wound pathogenesis. ICRF-161 was found ineffective in the treatment of anthracycline-induced skin damage, suggesting that iron does not play a dominant role in the genesis of wounds.     

Stabilization of mitochondrial membrane potential prevents doxorubicin-induced cardiotoxicity in isolated rat heart

The present study was undertaken to examine the effects of doxorubicin on left ventricular function and cellular energy state in intact isolated hearts, and, to test whether inhibition of mitochondrial membrane potential dissipation would prevent doxorubicin-induced mitochondrial and myocardial dysfunction. Myocardial contractile performance and mitochondrial respiration were evaluated by left ventricular tension and its first derivatives and cardiac fiber respirometry, respectively. NADH levels, mitochondrial membrane potential and glucose uptake were monitored non-invasively via epicardial imaging of the left ventricular wall of Langendorff-perfused rat hearts.Heart performance was reduced in a time-dependent manner in isolated rat hearts perfused with Krebs-Henseleit solution containing 1 μM doxorubicin. Compared with controls, doxorubicin induced acute myocardial dysfunction (dF/dt_max of 105 ± 8 mN/s in control hearts vs. 49 ± 7 mN/s in doxorubicin-treated hearts; ?p < 0.05). In cardiac fibers prepared from perfused hearts, doxorubicin induced depression of mitochondrial respiration (respiratory control ratio of 4.0 ± 0.2 in control hearts vs. 2.2 ± 0.2 in doxorubicin-treated hearts; ?p < 0.05) and cytochrome c oxidase kinetic activity (24 ± 1 μM cytochrome c/min/mg in control hearts vs. 14 ± 3 μM cytochrome c/min/mg in doxorubicin-treated hearts; ?p < 0.05). Acute cardiotoxicity induced by doxorubicin was accompanied by NADH redox state, mitochondrial membrane potential, and glucose uptake reduction. Inhibition of mitochondrial permeability transition pore opening by cyclosporine A largely prevented mitochondrial membrane potential dissipation, cardiac energy state and dysfunction. These results suggest that in intact hearts an impairment of mitochondrial metabolism is involved in the development of doxorubicin cardiotoxicity.     

乳腺癌晚期的化疗药物研究

目的探讨乳腺癌晚期患者的化疗治疗方案。方法对乳腺癌晚期的常用化疗药物进行研究。结果目前乳腺癌晚期患者进行全面的医治效果不佳,应用诺维本、蒽环类、紫杉类以及吉西他滨药物治疗乳腺癌疗效较高。结论诺维本、蒽环类、紫杉类以及吉西他滨药物治疗乳腺癌晚期患者安全可靠,单用、并用均可。     

Clinical experience with anthracycline antibiotics–HPMA copolymer–human immunoglobulin conjugates

This paper reviews an early clinical experience with anthracycline (epirubicin; Epi or doxorubicin; Dox) containing an N-(2-hydroyxypropyl)methacrylamide copolymer carrier targeted with autologous or commercial human immunoglobulin in six patients aged 28–55 suffering from therapy-resistant metastatic cancer. More than 100 biochemical, hematological and immunological parameters, including nine tumor markers, were tested in blood samples taken 24 h after the first and up to 10 months after the last application. The intravenous application proceeded without serious adverse or side effects and did not require hospitalization. Cardiotoxicity was not observed. Four of six monitored patients attained stabilization of disease (liver ultrasound scan and bone computer tomography) with a very good quality of life lasting from seven up to 18 months. Positive response to the treatment was, among others, evaluated as decreased CA 15-3 and CEA tumor markers. In three of five tested patients the serum level of C-reactive protein was temporarily increased 72 h after the treatment. A stable or elevated number of peripheral blood reticulocytes together with activation of natural killer (NK) cells and lymphokine-activated killer (LAK) cells supports the data previously obtained in experimental animals pointing to a dual role, i.e. the cytotoxic and immunomobilizing character of doxorubicin–HPMA conjugates.