Cardiac safety of pegylated liposomal doxorubicin (Doxil/Caelyx) demonstrated by endomyocardial biopsy in patients with advanced malignancies

Although conventional doxorubicin demonstrates broad activity, its clinical use is limited by cardiotoxicity. A more recent analysis suggests conventional doxorubicin-related cardiotoxicity occurs more frequently and at lower cumulative doses than previously reported. Pegylated liposomal doxorubicin, designed to maintain or improve conventional doxorubicin activity while reducing toxicities, has demonstrated improved cardiac safety versus conventional doxorubicin. In this prospective study, we evaluated endomyocardial biopsies to determine the cardiac effects of pegylated liposomal doxorubicin in patients with advanced malignancies receiving doxorubicin-equivalent doses ≥ 550 mg/m² (including pegylated liposomal doxorubicin) or ≥ 400 mg/m² pegylated liposomal doxorubicin alone. Eight patients were enrolled, and 10 biopsy scores were obtained (two patients had two biopsies). Median biopsy score (Billingham scale) was 0.75 (range, 0-1.5) after a median pegylated liposomal doxorubicin dose of 707.5 mg/m² and median total anthracycline exposure of 908.5 mg/m². These results suggest that pegylated liposomal doxorubicin minimizes doxorubicin-related cardiotoxicity, even at doses exceeding the recommended lifetime cumulative conventional dose (450-550 mg/m²).     

Phase I clinical and pharmacological study of oral methoxymorpholinyl doxorubicin (PNU 152243)

Purpose: The methoxymorpholinyl doxorubicin analogue PNU 152243 was brought into clinical studies because of preclinical observations of its non-cross-resistance in mdr tumor cells, dose-limiting neutropenia, lack of cardiotoxicity, and antitumor activity after oral administration. Methods: PNU 152243 was given orally every 4 weeks to 21 adults with a variety of solid tumors at doses ranging from 59 to 940 μg/m². Antiemetic prophylaxis with 5-HT3 antagonists and steroids, given i.v. on day 1 and orally on days 2–8, was required beginning with the dose of 118 μg/m². The plasma pharmacokinetics of PNU 152243 were determined by an HPLC method with fluorescence detection. The in vitro myelotoxic effects on granulocyte macrophage-colony forming cells (GM-CFC) of the plasma from 11 patients, obtained 4 and 6 h after treatment at all dose levels, were also assessed. Results: Neutropenia was the main hematologic toxic effect and the maximum tolerated dose (MTD) for myelotoxicity was 940 μg/m², with neutropenia grade 3–4 in two of three patients. Dose-dependent nausea and vomiting were dose-limiting and the MTD for gastrointestinal toxicity was fixed at 820 μg/m², with grade 4 vomiting in one of two patients. Other frequent toxic effects were diarrhea and fatigue. Peak levels of PNU 152243 were achieved 4 h after dosing. Dose-dependent Cmax and AUCExp, and significant interpatient variability of the main pharmacokinetic parameters were found. Very low levels of the 13-dihydrometabolite PNU 155051 were detected only at the highest doses. The hematotoxicity tests showed a <70% colony growth inhibition with no correlation between the growth inhibition effect and the degree of myelotoxicity in the same patient. Plasma concentrations of PNU 152243 were 1000 times lower than the concentration inhibiting the growth of 70% of colonies. No objective tumor responses were seen. Conclusions: Owing to the occurrence of severe and prolonged nausea and vomiting, the clinical development of oral PNU 152243 was discontinued. The higher-than-expected neutropenia and its lack of relationship with plasma levels of PNU 152243 and its 13-dihydroderivative PNU 155051 might be related to the formation of potent cytotoxic metabolites present in human plasma at undetectable concentrations and with prolonged half-life, as suggested by hematotoxicity tests performed with plasma from patients in GM-CFC assays. Received: 1 February 1999 / Accepted: 9 April 1999     

A phase II study of the effectiveness of docetaxel (Taxotere) in women with advanced breast cancer previously treated with polychemotherapy

Purpose: The aim was to study the effectiveness of docetaxel (Taxotere) in patients with advanced breast cancer treated previously with polychemotherapy. Patients and methods: Forty-nine patients received docetaxel (100 mg/m²; 1-h i.v. infusion) and corticosteroid premedication. Forty-one patients who had received previous anthracycline treatment were divided into anthracycline-refractory and anthracycline-resistant (early and late) groups. Results: Of 45 evaluable patients, 66.7% had a partial response (PR) and 2.2% a complete response (CR), giving an overall response rate (ORR) of 68.9%. The ORR in anthracycline-refractory patients was 60% versus 82.6% in anthracycline-resistant patients; the difference was not significant. The ORR in early-resistance patients was 62.5% versus 93.4% in late-resistance patients (0.05 < P < 0.1). The median response duration and overall survival was 8 months (range, 4–23+ months) and 11.5 months (range, 4–31+ months), respectively, in 39 patients treated previously for metastatic disease. For 295 courses, grade 3/4 neutropenia developed in 28.6% of patients (12.5% of courses) and was febrile in 26.5% of patients (6.1% of courses), including one septic death. Hypersensitivity reactions (HSR) developed in 16.3% of patients, and fluid retention developed in 34.7% of patients (11.9% of courses). Conclusions: Docetaxel is an active second-line drug in advanced breast cancer. The time of relapse after cessation of anthracycline treatment may be a significant prognostic factor. Received: 4 November 1998 / Accepted: 5 February 1999     

Contribution of the Nucleoside Transport System to Doxorubicin Transport in HL60 Cells but Not in Mononuclear Cells

Previously, we reported that pirarubicin (THP), an anthracycline, was transported, at least in part, via a nucleoside transport system in human leukemic HL60 cells, but not in mononuclear cells (MNCs). In this study, the contribution of the nucleoside transport system to the transport of other anthracyclines, doxorubicin (DOX), daunorubicin (DNR) and idarubicin (IDA), in HL60 cells and MNCs was investigated. The experiments were performed after both types of cells had been pretreated with a metabolic inhibitor, 2,4-dinitrophenol, to deplete cellular ATP. The DOX uptake by HL60 cells was partially inhibited by inhibitors of equilibrative nucleoside transporters. In HL60 cells, moreover, the uptake of DOX depended on an inwardly directed Na⁺-gradient, and was inhibited by concentrative nucleoside transporters, but there was no change in the DNR or IDA uptake under any of these conditions. On the other hand, the uptake of the three drugs by MNCs was not affected by any inhibitors of the nucleoside transporters, and there was no dependence of the uptake on an Na⁺-gradient. These results suggested that DOX, but not DNR or IDA, was partially transported in HL60 cells via the nucleoside transport system, whereas in MNCs the system did not contribute to the uptake of any of these three drugs. Thus, nucleoside transport systems contributing to the transport of anthracyclines may be different among different derivatives and cell types.     

In vivo Efficacy and Tumor-selective Metabolism of Amrubicin to Its Active Metabolite

The tissue distribution of a novel antitumor anthracycline antibiotic, amrubicin, was studied using seven human tumor xenografts implanted into nude mice, in order to identify the principal factors determining its therapeutic efficacy. We found a good correlation between the level of the metabolite amrubicinol in the tumor and the in vivo efficacy. High metabolic activity of amrubicin to amrubicinol was detected in tumor tissue homogenates, especially in cell lines highly sensitive to amrubicin in vivo . In contrast to amrubicin, the administration of amrubicinol showed less tumor-selective toxicity in these human tumor xenograft models. These data indicate that the tumor-selective metabolism of amrubicin to amrubicinol resulted in a tumor-selective disposition of amrubicinol, leading to good efficacy in in vivo experimental therapeutic models.     

蒽环类药物心肌损害的体外实验

目的研究蒽环类化疗药物对心肌细胞的损害作用。方法体外传代培养H9c2乳鼠心肌细胞株,细胞传代第3天加入蒽环类药物柔红霉素(DNR)共培养,测定细胞上清液乳酸脱氢酶(LDH)浓度,以反映心肌细胞膜损害程度;采用四甲基偶氮唑盐微量酶反应比色(MTT)法检测心肌细胞生长抑制率,流式细胞仪检测心肌细胞凋亡率。结果①DNR1组、DNR2组、DNR3组的H9c2细胞生长抑制率分别为(24.93±1.52)%、(17.15±2.03)%和(13.48±2.26)%,3组间差异有统计学意义(P<0.01)。②DNR1、DNR2、DNR3组H9c2细胞上清液的LDH浓度分别为(77.00±6.24)、(64.3±10.50)和(5 7.67±7.24)U,均显著高于空白对照组的(37.00±6.56)U(P值均<0.01)。③DNR1、DNR2、DNR3组的H9c2细胞凋亡率分别为(15.47±2.46)%、(9.82±2.08)%和(9.43±1.63)%,均显著高于空白对照组的(4.49±2.96)%(P值均<0.05)。结论DNR能抑制心肌细胞生长,促进凋亡,同时具有对心肌细胞膜的损害作用。     

Treatment of anthracycline extravasation in mice with dexrazoxane with or without DMSO and hydrocortisone

Dexrazoxane has been reported to be protective against anthracycline induced subcutaneous ulceration in mice. It is currently under clinical investigation as an acute antidote in accidental anthracycline extravasation, for which indication topical dimethylsulfoxide (DMSO) and intralesional hydrocortisone are used empirically. We studied the effect in 72 mice of monotherapy with and combined therapy of intraperitoneal dexrazoxane, topical DMSO, and intralesional hydrocortisone as acute antidotes against ulceration after subcutaneous daunorubicin. Dexrazoxane completely prevented wounds from occurring, while neither DMSO nor hydrocortisone had any preventive effect. The addition of topical DMSO actually reduced the efficacy of dexrazoxane. In conclusion, the present study does not support the concomitant use of topical DMSO + systemic dexrazoxane or intralesional hydrocortisone + systemic dexrazoxane. Monotherapy with systemic dexrazoxane seems preferable and is highly efficacious in preventing ulceration.     

蒽环类化疗药物外渗漏的治疗进展

蒽环类化疗药物是一种常用的抗肿瘤药物，在静脉给药过程中如果发生外渗可导致严重化疗并发症，本文阐述了蒽环类化疗药物外渗的机制、原因、临床表现及诊疗，重点介绍蒽环类化疗药物外渗漏的相关治疗的研究进展，包括针对蒽环类药物外渗漏解毒剂的介绍，并讨论了治疗过程中存在的一些争议性的问题。     

Phase II study of dose-dense doxorubicin and docetaxel as neoadjuvant chemotherapy with G-CSF support in patients with large or locally advanced breast cancer

Introduction  To evaluate the efficacy and safety profile of the concomitant dose-dense administration of doxorubicin and docetaxel as primary chemotherapy for patients with large or locally advanced breast cancer. Materials and methods  Forty-seven patients were included and received 50 mg/m² of doxorubicin and 75 mg/m² of docetaxel every two weeks for four cycles. Primary prophylaxis with granulocyte colony stimulating factor was administered. Results  Patients included had mainly stage III disease (66%). Efficacy and toxicity analyses were carried out on an intention-to-treat basis. After study treatment, the rate of clinical responses was 85% (95% CI: 75–95) with 6% judged as clinical complete responses. Surgery was performed on 94% patients for whom the breast was conserved in 27%. Only one patient obtained a pathological complete response (with no evidence of invasive or non-invasive tumour in the breast and the lymph nodes). In three additional patients, malignant cells were detected only in one lymph node. The single severe haematological toxicity was neutropenia, occurring in one patient (2%) and two cycles (1%), being grade 3 in one and grade 4 in the other. Severe non-haematological toxicities were grade 3, and the most common was asthenia (8% of patients), followed by cutaneous toxicity, arthromyalgia and stomatitis, which occurred in fewer than 4% of patients in each case. Conclusions  The concomitant dose-dense administration of doxorubicin and docetaxel as neoadjuvant chemotherapy with granulocyte colony stimulating factor support is a feasible and effective schedule with a safe toxicity profile for women with large or locally advanced breast cancer.     

Anthracycline cardiomyopathy

Summary Life-threatening irreversible cardiomyopathy is a major complication of anthracycline therapy, particularly in the pediatric population. The pediatric cardiologist, in concert with the primary oncologist, should therefore play a major role in the care of patients receiving these agents and in clinical trials involving their use. Many risk factors and their relationships to drug pharmacokinetics, mechanisms of action, and toxicity have been identified. These data provide a rational basis for present-day recommendations regarding anthracycline administration and dosage scheduling. They furthermore provide potential avenues for clinical investigation aimed at improving the therapeutic index of these agents: -tocopherol, cytochrome Q₁₀, and other free radical scavengers may decrease the deleterious effects of free radical generation on the myocardium without apparent interference with tumoricidal effect. The cardiac glycosides may decrease cardiac toxicity by specific myocardial exclusion. Anthracycline analogs have been designed to specifically inhibit myocardial binding and/or free radical generation. Clinical trials involving these agents are difficult to interpret because of variability in front end risk factors and dosage schedules in the study population. Furthermore, the relatively low (5 to 10%) incidence of affected patients implies the need for large numbers to demonstrate a statistically significant benefit. Pediatric protocols addressing these issues are urgently needed. Guidelines for present-day management and future studies are outlined.Supported in part by Hematology Research Training Grant 2T32-HL07145-06A1 and USPH Grant CA 07306. This paper was part of the Ray C. Anderson Symposium