Anthracycline-induced cardiotoxicity: Overview of studies examining the roles of oxidative stress and free cellular iron

The risk of cardiotoxicity is the most serious drawback to the clinical usefulness of anthracycline antineoplastic antibiotics, which include doxorubicin (adriamycin), daunorubicin or epirubicin. Nevertheless, these compounds remain among the most widely used anticancer drugs. The molecular pathogenesis of anthracycline cardiotoxicity remains highly controversial, although the oxidative stress-based hypothesis involving intramyocardial production of reactive oxygen species (ROS) has gained the widest acceptance. Anthracyclines may promote the formation of ROS through redox cycling of their aglycones as well as their anthracycline-iron complexes. This proposed mechanism has become particularly popular in light of the high cardioprotective efficacy of dexrazoxane (ICRF-187). The mechanism of action of this drug has been attributed to its hydrolytic transformation into the iron-chelating metabolite ADR-925, which may act by displacing iron from anthracycline-iron complexes or by chelating free or loosely bound cellular iron, thus preventing site-specific iron-catalyzed ROS damage. However, during the last decade, calls for the critical reassessment of this “ROS and iron” hypothesis have emerged. Numerous antioxidants, although efficient in cellular or acute animal experiments, have failed to alleviate anthracycline cardiotoxicity in clinically relevant chronic animal models or clinical trials. In addition, studies with chelators that are stronger and more selective for iron than ADR-925 have also yielded negative or, at best, mixed outcomes. Hence, several lines of evidence suggest that mechanisms other than the traditionally emphasized “ROS and iron” hypothesis are involved in anthracycline-induced cardiotoxicity and that these alternative mechanisms may be better bases for designing approaches to achieve efficient and safe cardioprotection.     

~(99m)Tc-MIBI心肌灌注断层显像监测蒽环类药物的心脏毒性

目的 :探讨99mTc-MIBI心肌灌注断层显像在蒽环类药物心脏毒性监测中的价值。方法 :2 3例接受蒽环类药物治疗的患者 ,在治疗前进行心电图、心肌酶学检查、核素心室造影测左室射血分数 (LVEF)和99mTc MIBI心肌灌注断层显像并计算相对定量值。并于每一周期治疗后重复上述检查。结果 :蒽环类药物治疗一周期后 ,2 3例患者心肌相对定量值明显下降 (P <0 .0 1)。其中 11例吡喃阿霉素、6例表阿霉素和 6例米托蒽醌治疗的患者 ,心肌相对定量值明显下降 (P <0 .0 5 ) ,心电图和心肌酶学无明显变化 (P >0 .0 5 )。蒽环类药物治疗多周期后的 10例患者心肌相对定量值较治疗前下降 (P <0 .0 5 )。 9例患者的心肌相对定量值 (最大累积剂量为 2 0 0mg/m2 )与一周期后无明显差别 (P >0 .0 5 )。10例患者治疗前及多周期治疗后LVEF均 >6 0 %,且化疗前后无明显差别 (P >0 .0 5 )。结论 :99mTC MIBI心肌灌注断层显像能监测蒽环类药物所致的心肌损害 ,且较左室射血分数敏感 ,比心电图和心肌酶学检查优越 ,有利于指导蒽环类药物的临床应用。     

Ultrastructure of Nuclear Compartment in Cardiomyocytes during Regenerative and Plastic Insufficiency of the Myocardium

We studied ultrastructure of nuclear compartment in cardiomyocytes during regenerative and plastic insufficiency of the myocardium induced by anthracycline antibiotic daunomycin. A peculiarity of ultrastructural organization of cardiomyocyte nuclei under these conditions is almost complete disappearance of the heterochromatin lumps. The earliest changes in nucleoli under conditions of disturbed DNA-dependent RNA synthesis are segregation of the granular and fibrillar nucleolonema components. Deep alterations in the nucleoli manifested by fragmentation and annulation correlate with pronounced changes in cardiomyocytes ultrastructure, intensive lysis of the myofilaments, reduction of the organelles, and enhanced autophagocytosis.     

Primary chemotherapy in operable breast carcinoma comparing CMF (cyclophosphamide, methotrexate, 5-fluorouracil) with an anthracycline-containing regimen: short-term responses translated into long-term outcomes.

BACKGROUND: The role of anthracyclines has been extensively studied in adjuvant chemotherapy, but much less in the primary chemotherapy of early breast carcinoma. This study, comparing CMF (cyclophosphamide, methotrexate, 5-fluorouracil) with the rotational anthracycline-containing regimen CMFEV (CMF plus epirubicin and vincristine) administered as primary chemotherapy, demonstrated a significant increase in clinical complete response in premenopausal women. We report the long-term results. PATIENTS AND METHODS: Two hundred and eleven patients with stage I or II palpable breast carcinoma and a tumour diameter of >2.5 cm were randomised to receive CMF or CMFEV for four cycles before surgery. After surgery, the patients in both arms received adjuvant CMF for three cycles. RESULTS: In the study population as a whole, there was a non-significant 20% reduction in mortality and relapse rates in the CMFEV arm. However, the effect of the experimental regimen was only found in premenopausal patients, especially in terms of relapse-free survival (P=0.07) and locoregional relapse-free survival (P=0.0009), thus mirroring the effect on response rates. After 10 years, the proportions of premenopausal patients free from locoregional relapse as a first event in the CMF and CMFEV groups were 68% and 97%, respectively. No relevant differences were found in postmenopausal patients. CONCLUSION: The overall results of this study showed that the greater activity of the experimental anthracycline-containing combination over CMF as primary chemotherapy in premenopausal patients translated into long-term effects in the same subgroup.     

The role of pixantrone in the treatment of non-Hodgkin’s lymphoma

Pixantrone is an anthraquinone-based inhibitor of topoisomerase II. It is similar to both the anthracycline doxorubicin and the anthracenedione mitoxantrone, but lacks the 5,8-dihydroxy substitution pattern of mitoxantrone, and has a tricyclic system unlike the tetracyclic structure seen with anthracyclines. Anthracyclines are the most active drugs in lymphoma therapy, but their use is limited by their cumulative and irreversible cardiotoxicity. Pixantrone was developed to improve the toxicity profile of the current anthracyclines and anthracenediones while maintaining their activity. Interestingly, pixantrone showed no measurable cardiotoxicity compared with its parent compound mitoxantrone or other anthracyclines at equi-effective doses in several animal models. Together with its superior cytotoxic activity in leukaemia and lymphoma models, these features render the drug a promising candidate for clinical development in indolent and aggressive non-Hodgkin’s lymphoma. In this review, the latest results of the use of pixantrone in indolen-t and aggressive non-Hodgkin’s lymphomas are summarised.     

Early detection of cardiotoxicity by 3D speckle tracking imaging of area strain in breast cancer patients receiving chemotherapy

Eighty‐three breast cancer patients who underwent six cycles of EC chemotherapy regimen (epirubicin + cyclophosphamide) without symptoms and signs of heart disease were enrolled in the study. Three‐dimensional speckle tracking imaging technique (3D‐STI) was used to measure left ventricular global area strain (GAS), overall annular strain (GCS), overall longitudinal strain (GLS), and overall radial strain (GRS). Meanwhile, serum troponin T (Hs‐cTnT) was measured. The clinical value of each index on cardiotoxicity after chemotherapy was analyzed using the receiver operating characteristic (ROC) curve. Hs‐cTnT increased from the early stage to the end during chemotherapy, but it was still in the normal range. During the mid‐chemotherapy and the end‐chemotherapy, GAS, GLS, GCS, and E/A significantly reduced, while the changes in LVESV, LVEDV, LVEF, and GRS were not significant after chemotherapy. Pearson correlation analysis showed a significant negative correlation between GAS and anthracycline doses (r = ?.772, P < .01); GAS and Hs‐cTnT were significantly negatively correlated (P < .05). The area under the curve (AUC) of GAS, GLS, GCS, and GRS are 0.815, 0.683, 0.645, and 0.585, respectively. A GAS of ?31.5% was used as the cutoff value for diagnosing left ventricular systolic dysfunction after receiving chemotherapy. The sensitivity of the previous parameters was 81.9%, and the specificity was 80.3%. Interobserver consistency analysis showed that 3D‐STI strain parameter measurement has good repeatability. GAS has greater value in predicting early myocardial damage after anthracycline chemotherapy.     

新型蒽环类衍生物HYY-014大鼠体内药代动力学和组织分布的研究

目的：研究新型蒽环类衍生物HYY-014在大鼠体内的药代动力学和组织分布特征,为临床研究提供实验依据。方法大鼠单次尾静脉注射1．5 mg/kg的HYY-014后,采用LC-MS/MS法测定各时间点血浆和组织中HYY-014及其代谢物HYY-M3的浓度,药代动力学参数经DAS 3．0统计软件计算获得。结果采用统计矩方法处理药物浓度时间数据, HYY-014药代动力学参数 Cmax、T1/2、Vd、CL、AUC0-t、MRT0-t分别为(1628．6±618．6)μg/L、(24．4±3．6) h、(23．4±5．2) L/kg、(0．66±0．08) L/kg/h、(2219．5±276．9)μg/L ·h、(15．1±2．4) h;HYY-M3药代动力学参数Cmax、AUC0-t分别为(2．2±0．6)μg/L、(103．1±13．7)μg/L·h。静脉注射该药后,很快向机体的各组织广泛分布,且具有明显的靶向性,主要分布在脾、肾、肺、心脏、肝等组织,脑组织中浓度极低。结论静脉注射HYY-014组织分布广泛,具有明显的靶向性,肺、肝组织中的药物浓度均较高,不能通过血脑屏障。     

Phase II study of liposome-encapsulated doxorubicin plus cyclophosphamide,followed by sequential trastuzumab plus docetaxel as primary systemic therapy for breast cancer patients with HER2 overexpression or amplification

Purpose of the studyTrastuzumab combined with sequential chemotherapy with taxanes and anthracyclines as primary systemic therapy achieved high rates of pathologic complete response (pCR). Non-pegylated liposome-encapsulated doxorubicin (NPLD) has shown equal efficacy but minor cardiotoxicity compared to doxorubicin. This phase II study aimed to evaluate the activity and safety of trastuzumab with sequential chemotherapy for early or locally advanced HER2 positive BC.MethodsPreoperative treatment included NPLD (60 mg/mq iv) plus cyclophosphamide (600 mg/mq iv) every 3 weeks for 4 cycles followed by docetaxel (35 mg/mq iv) plus trastuzumab (4 mg/mq loading dose iv, then 2 mg/mq iv) weekly for 16 weeks. Primary endpoint was pCR defined as the absence of residual invasive cancer both in the breast and regional nodes. Clinical staging was exploratory evaluated by CT-PET.Results43 pts were treated from december 2005 to September 2011, 39 of them were evaluable for the purpose of study. Median age was 53 years (range: 31–78), the majority of pts had tumour stage cT2 (63%), tumour grade 3 (86%), clinical nodes involvement N+ (77%), ER positive (56%) and Ki-67 ≥20% (77%). pCR was reported in 19 (49%) of 39 pts. There was an association between Ki-67 ≥20% at baseline and pCR (p = 0.018). No cardiac toxicity or discontinuation of trastuzumab was reported. CT-PET modified the clinical stage for 10 patients showing new loco-regional lymph nodes.ConclusionsThis study confirms that integrating anti-HER2 therapy in primary treatment for HER2 positive breast cancer is active. NPLD is a safe option to minimize cardiotoxicity.