Phase I/II trial of dipyridamole, 5-fluorouracil,leukovorin, and mitoxantrone in metastatic breast cancer

Summary Based upon the hypothesis that dipyridamole would potentiate the cytotoxicity of mitoxantrone and the combination of 5-fluorouracil (5-FU) and leukovorin, we performed a phase I/II trial of the combination of dipyridamole, 5-FU, leukovorin, and mitoxantrone in patients with metastatic breast cancer. The dose of dipyridamole was fixed at 175 mg/m² by mouth every 6 h (700 mg/m²/day), based upon a previous phase I trial of oral dipyridamole with 5-FU and leukovorin. Dipyridamole therapy began 24 h prior to the first dose of chemotherapy and continued until 24 h after the last dose of chemotherapy for each course of treatment. At the initial dose level, leukovorin 200 mg/m² was given intravenously immediately prior to 5-FU 375 mg/ m² intravenously on days 1–5. Mitoxantrone 6 mg/m² was given as a single dose on day 3. Unacceptable toxicity was observed at this dose level, leading to successive dose decrements rather than dose increments. The maximum tolerated dose was leukovorin 200 mg/m² days 1–2, 5-FU 375 mg/m² days 1–2, mitoxantrone 6 mg/m² on day 2, and dipyridamole 175 mg/m² every 6 h on days 0–3. Two responses were produced in 15 patients. This regimen is not recommended for further investigation in the treatment of breast cancer.     

Results of a randomized study of early stage Hodgkin's disease using ABVD,EBVD, or MBVD

From January 1986 to December 1989, 157 previously untreated patients, with Hodgkin's disease stage I or II without bulky disease, were enrolled in a clinical comparative study. The objectives of the study were to compare the efficacy and safety of using epirubicine or mitoxantrone instead of adriamycin in the combination chemotherapy regimen ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine). The complete response rate was better in the patients treated with the ABVD or EBVD regimens compared to the MBVD arm. Also, differences in overall survival and relapse-free survival were better in the patients who received ABVD or EBVD compared to the MBVD regimen. Hematological, gastrointestinal and cardiac toxicity were similar in the three groups. Dose intensity, delays and complications were also similar in the three groups. The mitoxantrone-containing regimen was found to have less efficacy in comparison to the other regimens tested in the present study in patients with favorable stage I or II Hodgkin's disease. © 1995 Wi1ey-Liss Inc.     

Mitoxantrone combined to vincristine,cyclophosphamide and fluorouracil in advanced breast cancer

Summary In our wide experience of treating advanced breast carcinoma with chemotherapy, the combination of doxorubicin (DOX), vincristine (VCR), cyclophosphamide (CPM) and fluorouracil (FU) gave a complete plus partial response rate of over 60%, with 100% alopecia and frequent cardiac toxicity depending on total dose.After the EORTC Clinical Screening Group phase II trial we have conducted an expected difference method comparative phase II trial using the combination DOX, VCR, CPM, FU and the combination of MTX (10mg/m²), VCR, CPM and FU on a population of 50 breast carcinoma patients similar to those taking part in the first study.The reasons for similarity of action will be presented and discussed.     

Mitoxantrone: Propensity for free radical formation and lipid peroxidation — implications for cardiotoxicity

Summary Results of comparative studies on stimulation of the rates of cofactor consumption, superoxide generation and hydrogen peroxide production by mitoxantrone (Novantrone®; dihydroxyanthracenedione; MXN), ametantrone (AM), doxorubicin (DOX) and daunorubicin (DNR) in the presence of NADPH-cytochrome P-450 reductase, NADH dehydrogenase, or rabbit hepatic microsomes have been reported. MXN and AM were substantially less effective in stimulating the rate of cofactor oxidation, superoxide formation or hydrogen peroxide production relative to the anthracyclines. In the presence of P-450 reductase, the rate of NADPH oxidation or superoxide generation produced by 100 M MXN or AM was only 15% and 2% respectively of that produced by 100 M anthracycline.The effects of MXN and AM on lipid peroxidation in hepatic microsomes, cardiac sarcosomes and cardiac mitochondria were determined and compared with those produced by ADM. MXN and AM at 50 M inhibited the basal rate of NADPH-dependent rabbit liver microsomal lipid peroxidation by 50%; in contrast, DOX enhanced the rate of hepatic microsomal lipid peroxidation by 2-and 2.5-fold at 100 and 200 M, respectively. Rabbit cardiac sarcosomal NADPH-dependent lipid peroxidation was inhibited completely at 100 M anthracenedione. NADH-dependent lipid peroxidation in cardiac mitochondria was diminished by 50 M MXN and AM, whereas 50 M DOX produced a 2-fold stimulation in lipid peroxidation. The anthracenediones also effectively inhibited DOX-stimulated lipid peroxidation with 50% inhibition occurring at 4 M (MXN) and 6 M (AM). Moreover, both MXN and AM potently inhibited iron (100 M)-stimulated lipid peroxidation in rabbit hepatic microsomes with 80% inhibition produced by 15 M anthracenedione.These results are consistent with the diminished cardiotoxicity of mitoxantrone and ametantrone relative to DOX or DNR and may require a reassessment of the role of lipid peroxidation in the mechanism(s) of quinone antineoplastic agent-mediated cardiotoxicity.     

Quantitation of differential sensitivity of normal marrow myeloid progenitor cells to anthracene derivatives

The effect of 3 anthracene derivatives, mitoxantrone, ametantrone, bisantrene, on 4 normal human bone marrows, was studied using the myeloid stem cell assay developed by Pike and Robinson, in order to define to what extent this test could be used to predict the relative clinical hematologic toxicity of new anticancer agents. For the 3 drugs, an exponential relationship between colony survival and drug concentration was found, but was much steeper for mitoxantrone (slope = -195.2 ± 8.8/g/ml) than for ametantrone (slope = 5.1 ± 1.0/g/ml, p0.001) and bisantrene (slope = 7.1 ± 0.3/g/ml, p0.001). The difference of slope between ametantrone and bisantrene was of borderline significance (p0.05). The ratios of concentrations inducing a 50% growth inhibition for mitoxantrone versus bisantrene and for ametantrone versus bisantrene were close to the corresponding ratios of concentrations inducing a 90% growth inhibition. The relative in vitro toxicities reproduce very well the relative myelosuppression observed in clinical trials with mitoxantrone versus bisantrene but the results were less satisfactory for the comparison of these 2 agents with ametantrone. In addition, our data suggest that, for these 3 compounds, intrinsic myeloid progenitor sensitivity is a major determinant of leukopenia.     

Heterogeneity ofin vitro chemosensitivity in perioperative breast cancer cells to mitoxantroneversus doxorubicin evaluated by a microplate ATP bioluminescence assay

Summary Apart from clinical trials, mitoxantrone (MX) is rarely used in breast cancer (BC) due to the anticipated anthracycline cross-resistance. We have examined this drug versus doxorubicin (DOX) using data obtained fromin vitro microplate ATP tumor chemosensitivity assays (ATP-TCA) of BC cells which were derived from 55 chemotherapy-naive patients at time of primary surgery. Both drugs were tested at 6 different concentrations ranging from 6.25% to 200% peak plasma concentrationin vivo (PPC). Differences between DOX and MX observed for mean IC₅₀, IC₉₀, and a sensitivity index (SI) were not statistically significant.In vitro response rates were 44% for DOX and 52% for MX. 34 of 52 eligible assays (65%) showed comparable activity of both drugs whereas a lack of cross-resistance was observed in the remaining 18 (35%) tumors as indicated by differences for SI. Cumulative concentration-response plots of tumors respondingin vitro with a 50 percent or 90 percent tumor cell inhibition showed a strong dose-dependence for both DOX and MX at concentrations which normally can be achieved within clinical tumors (i.e. 6.25%-50% PPC). At higher concentrations, however, cytotoxicity of DOX and MX could not be improved by furtherin vitro dose escalation. Moreover, a substantial proportion of BC specimens (DOX: 48.1%; MX: 40.4%) did not experience a 90 tumor cell inhibition at 200% PPC. In conclusion,in vitro results obtained by ATP-TCA indicate that there is no cross-resistance between MX and DOX in a substantial proportion of BC patients. This may be clinically useful and suggests that combinations including MX should be tested in patients clinically resistant to DOX containing regimens. Since both drugs produced sigmoidal concentration-response curves, dose escalation beyond a certain point may not produce increased sensitivity.     

MA方案治疗成人急性非淋巴细胞白血病的疗效分析

[目的]评价米托蒽醌、阿糖胞苷(MA)方案作诱导治疗成人急性非淋巴细胞白血病(ANLL)初治患者的疗效。[方法]对诊断明确者分为M1、M2型及M4、M5型，各型内部随机分为MA组和柔红霉素、阿糖胞苷(DA)组，1、2个疗程后，分别评价疗效。[结果]M1、M2型中，MA、DA组1个疗程后CR分别为70．0％、63.6％，2个疗程总CR分别为75．0％、68．2％，总有效率分别为85.0％、81．8％，两组间均无显著性差异。M4、M5型中，MA、DA组1个疗程CR分别为68．8％、33．3％，两者有显著差异，而2个疗程总CR分别为68．8％、46。7％，总有效率分别为81．3％、60．0%，两组问无显著性差异。MA组骨髓抑制作用强于传统DA组。[结论]MA方案可作为成人ANLL（M4、M5)首选诱导治疗方案。     

pH梯度法制备抗癌复方硫酸长春新碱脂质体

目的：制备同时包结硫酸长春新碱(VCR)、盐酸米托蒽醌(MTO)的复方脂质体并考察其制剂学性质。方法：采用pH梯度法合并逆相蒸发制备同时包结VCR、MTO的复方脂质体；用Sephadex G-50葡聚糖凝胶柱分离,HPLC同时测定VCR和MTO的包封率；以激光散射粒径分析仪测定复方脂质体的平均粒径及Z-电位；透射电镜观测形态；体外释放实验考察复方脂质体的释药特性。结果：所制备复方脂质体VCR的包封率为95.77%,MTO的包封率达99.53%；平均粒径为72.22 nm,Z-电位为-30.97 mV；外观圆整而均匀；体外释放结果复方脂质体中VCR的T_1/2为6.82 h,对照溶液中VCR的T_1/2为1.70 h,MTO在288 h仅释放了0.05%,对照溶液中MTO在12 h释放完全。结论：采用pH梯度法结合逆相法可制得同时包结VCR和MTO的复方脂质体,且包封率高、粒径小,体外释放证实复方脂质体具有缓释特性。     

Mitoxantrone in the treatment of advanced non-squamous carcinoma of the cervix (A phase II trial of the gynecologic oncology group)

Twenty-five evaluable patients with advanced non-squamous carcinoma of the uterine cervix were treated with mitoxantrone 12 mg/m² every three weeks. All patients had good performance status and measurable disease and only 11 had received prior chemotherapy. One complete and one partial response were noted among 15 patients with no prior chemotherapy while no responses were seen in 11 previously treated patients. The major toxicity was myelosuppression; other toxicity was mild. The median progression-free interval was 2.1 months and median survival 4.3 months. Mitoxantrone displays minimal activity in patients with advanced non-squamous carcinoma of the cervix.     

盐酸米托蒽醌有关物质测定的3种标准方法比较

目的比较研究测定盐酸米托蒽醌有关物质的3种标准测定方法。方法这3种方法分别收载于美国药典（USP24-32）、中国药典（2000,2005年版二部）和国家药品标准犤WS1-（X-038）-2002Z和WS1-（X-040）-2002Z犦中。美国药典和国家药品标准方法采用高效液相色谱法,色谱柱分别为μBondapak^TMPhenyl（300mm×3.9mm,10μm,125A）和PromosilC18（250mm×4.6mm,5μm,100A）,流动相为水-乙腈-庚烷磺酸钠溶液。结果国家药品标准中的高效液相色谱（HPLC）法测定盐酸米托蒽醌有关物质优于美国药典和中国药典方法。结论建议测定盐酸米托蒽醌有关物质时推广使用国家药品标准中的高效液相色谱法。