Mitoxantrone, 5-fluorouracil and high-dose leucovorin (NFL) in the treatment of metastatic breast cancer: randomized comparison to cyclophosphamide,methotrexate and 5-fluorouracil (CMF) and attempts to improve efficacy by adding paclitaxel

The combination of mitoxantrone (12 mg/m² i.v., day 1) 5-fluorouracil (350 mg/m² i.v. days 1–3) and leucovorin (300 mg i.v. days 1–3) is an active and well-tolerated regimen for metastatic breast cancer. We compared this regimen to a standard CMF regimen (cyclophosphamide 600 mg/m² i.v. day 1; methotrexate 40 mg/m² day 1; 5FU 600 mg/m² i.v. day I) in a randomized, phase II study. One hundred and twenty-eight women receiving first-line chemotherapy for metastatic breast cancer were treated. NFL produced lugher response rates (45% vs. 26%) and longer remissions (9 months vs. 6 months) than did CMF; overall survival was not different (19 months vs. 16 months). Both regimens were well tolerated. In an attempt to improve efficacy, we added paclitaxel(l35 mg/m² i.v. 1-h infusion) to the NFL regimen. Although this regimen was active (51 % response rate in first-second-line treatment], myelosuppression was greater than expected. These results confirm the utility of NFL as an active, well-tolerated regimen for the palliative treatment of metastatic breast cancer.     

米托蒽醌聚乳酸缓释毫微粒针剂的制备

在单因素实验的基础上用均匀设计优化了米托蒽醌聚乳酸缓释微粒的制备方法。空白和载药微粒的平均粒径分别为１２９．９６和１３３．１５ｎｍ;包封率为９９．２３％;载药量为１３．５６％;制备收率为９９．３％。以乳和支架剂制得的冻干针剂外型美观、理化性质稳定,再分散后平均粒径为１５２．０２ｎｍ。用动态透析系统考察了不同分子量聚乳酸毫微粒冻干针剂的体外释药特性,结果显示高分子量聚乳酸微粒的释药速度明显慢于低分子     

Chemotherapy using 5-fluorouracil,mitoxantrone, and cisplatin for patients with advanced hepatocellular carcinoma: an analysis of 63 cases

Background We evaluated the anti-tumor efficacy and toxicity of 5-fluorouracil (5-FU), mitoxantrone, and cisplatin (FMP) in patients with advanced hepatocellular carcinoma (HCC), and conducted an analysis of the prognostic factors for response to such therapy and patient survival.Methods Sixty-three patients suffering from unresectable and non-embolizable HCC and who had objectively measurable tumors, adequate liver and renal function, and adequate bone-marrow reserve were enrolled in this study. The therapeutic regimen consisted of cisplatin 80mg/m² and mitoxantrone 6mg/m² intravenously on day 1, and 5-FU 450mg/m² per day continuous infusion for a period of 5 days. Univariate and multivariate analyses of patient and disease characteristics were used to identify factors predicting patient response and survival.Results The objective response was 23.8% (95% confidence interval [CI], 13.0–34.6%). The median survival for all 63 patients was 4.9 months (95% CI, 3.2–6.6 months). The median time to progression was 2.5 months (95% CI, 1.7–3.3 months). Multivariate analysis identified only performance status (P = 0.050) and liver tumor size (P = 0.012) as being significantly related to patient objective response. Independent variables associated with a better patient survival included: the absence of ascites (P = 0.003), a lower total bilirubin level (P = 0.026), and the patient being a positive chemotherapy responder (P = 0.009).Conclusions The response rate to an FMP regimen was still unsatisfactory, although a specific subgroup of patients (good performance status, smaller liver tumor mass, good liver reserve, and distant metastasis) may benefit from this regimen.     

MA方案联合小剂量反应停治疗难治复发性急性髓细胞性白血病15例

[目的]探讨难治复发性急性髓细胞性白血病有效治疗方法。[方法]应用MA方案联合小剂量反应停治疗难治复发急性髓细胞白血病共15例。[结果]1个疗程有效率60%,未缓解并死于感染2例(13.3%),2个疗程总33.3%,总有效率80%。[结论]应用MA方案联合小剂量反应停治疗难治复发急性髓细胞白血病临床有效。     

Mitoxantrone-Mediated Apoptotic B 16-F1 Cells Induce Specific Anti-tumor Immune Response

In the process of cell apoptosis induced by specific reagents, calreticulin (CRT) in endoplasmic reticulum is transferred and coated onto the cell membrane. As a sort of specific ligand, the CRT on the surface of apoptotic cells could mediate recognition and clearance of apoptotic cells by phagocytes. In this research we discovered that mitoxantrone could induce apoptosis of mouse melonoma B16-F1 tumor cells, accompanied by the membrane translocation and coating of CRT. When mitoxantrone-treated B16-F1 cells were used as antigen to inoculate mice, the mice acquired an ability to suppress proliferation of homologous tumor cells. Splenocytes from these mice showed an increased cytolytic effect on homologous B16-F1 cells but no such effect on non-homologous H22 tumor cells. All these results suggested that mitoxantrone-treated apoptotic B16-F1 cells could be used as a sort of cell vaccine to initiate effective anti-tumor immunoresponse in mice.     

Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters

Nilotinib, a BCR-Abl tyrosine kinase inhibitor (TKI), was developed to surmount resistance or intolerance to imatinib in patients with Philadelphia positive chronic myelogenous leukemia. Recently, it was shown that several human multidrug resistance (MDR) ATP-binding cassette (ABC) proteins could be modulated by specific TKIs. MDR can produce cancer chemotherapy failure, typically due to overexpression of ABC transporters, which are involved in the extrusion of therapeutic drugs. Here, we report for the first time that nilotinib potentiates the cytotoxicity of widely used therapeutic substrates of ABCG2, such as mitoxantrone, doxorubicin, and ABCB1 substrates including colchicine, vincristine, and paclitaxel. Nilotinib also significantly enhances the accumulation of paclitaxel in cell lines overexpressing ABCB1. Similarly, nilotinib significantly increases the intracellular accumulation of mitoxantrone in cells transfected with ABCG2. Furthermore, nilotinib produces a concentration-dependent inhibition of the ABCG2-mediated transport of methotrexate (MTX), as well as E₂17βG a physiological substrate of ABCG2. Uptake studies in membrane vesicles overexpressing ABCG2 have indicated that nilotinib inhibits ABCG2 similar to other established TKIs as well as fumitremorgin C. Nilotinib is a potent competitive inhibitor of MTX transport by ABCG2 with a K_i value of 0.69 ± 0.083 μM as demonstrated by kinetic analysis of nilotinib. Overall, our results indicate that nilotinib could reverse ABCB1- and ABCG2-mediated MDR by blocking the efflux function of these transporters. These findings may be used to guide the design of present and future clinical trials with nilotinib, elucidating potential pharmacokinetic interactions. Also, these findings may be useful in clinical practice for cancer combination therapy with nilotinib.     

A phase II study of high-dose calcitriol combined with mitoxantrone and prednisone for androgen-independent prostate cancer

OBJECTIVE

To evaluate the preliminary efficacy, safety, and impact on quality of life (QoL) of high‐dose calcitriol (DN‐101) combined with mitoxantrone and glucocorticoids in androgen‐independent prostate cancer (AIPC).

PATIENTS AND METHODS

Nineteen patients with metastatic AIPC and no previous chemotherapy received DN‐101 180 µg orally on day 1 and mitoxantrone 12 mg/m² intravenously on day 2 every 21 days with continuous daily prednisone 10 mg orally for a maximum of 12 cycles. A confirmed decline in prostate‐specific antigen (PSA) levels by half was the primary endpoint. QoL was evaluated using the European Organization for Research and Treatment of Cancer QLQ‐C30 questionnaire, and pain and analgesic use were evaluated.

RESULTS

Five of 19 patients (26%; 95% confidence interval, CI, 9–51) achieved a ≥50% decline in PSA level. The median (95% CI) time to PSA progression was 16 (6–26) weeks. The overall median (95% CI) survival was 16 (6–26) months; 47 (21–73)% of patients achieved an analgesic response. Toxicity was similar to that expected with mitoxantrone and prednisone alone. The QoL analysis suggested a decrease in physical functioning and increase in fatigue, insomnia, and diarrhoea.

CONCLUSIONS

DN‐101 given every 3 weeks does not add significant activity to mitoxantrone and prednisone in AIPC, as measured by the PSA decline. The high rate of analgesic response is encouraging. The addition of DN‐101 does not appear to increase the toxicity of mitoxantrone.     

Glatiramer acetate after mitoxantrone induction improves MRI markers of lesion volume and permanent tissue injury in MS

BACKGROUND : Glatiramer acetate (GA) therapy following brief, low-dose induction with mitoxantrone was safe and more effective than GA alone in suppressing inflammatory disease activity, as determined by a significant reduction in gadolinium (Gd)- enhancing MRI lesions, in a 15- month, randomized, single-blind study of relapsing-remitting multiple sclerosis (RRMS) patients. OBJECTIVE : To determine whether effects on MRI markers of disease burden and tissue damage support and extend data on the benefits of mitoxantrone induction therapy before initiation of long-term GA therapy. DESIGN/METHODS : 40 RRMS patients, aged 18 to 55 years, with 1-15 Gd-enhancing lesions on screening MRI and EDSS score 0-6.5 were randomized to receive GA (20 mg/d SC), starting 2 weeks after the last of 3 monthly mitoxantrone infusions (36 mg/m2 total; n = 21), or to GA alone (20 mg/d SC; n = 19), for a total of 15 months. MRIs were obtained at baseline and months 6, 9, 12, and 15. RESULTS : At baseline, mean (+/- SD) age was 37.2 +/- 9.7 years; disease duration, 3.5 +/- 4.8 years; EDSS score, 2.3 +/- 1.1; and number of Gd-enhancing lesions, 3.75 +/- 3.95. Reductions in Gd-enhancing lesions (RR = 0.30, 95 % CI, 0.11-0.86, p = 0.0147) and relapse activity favoring mitoxantrone- GA were accompanied by significant differences in changes in T2w lesion volume (p = 0.0139), T1w hypointense lesion volume (p = 0.0303), and proportion of Gdenhancing lesions that evolved into black holes (p = 0.0023) compared with GA alone. CONCLUSIONS : Longterm continuous GA after brief, low-dose mitoxantrone induction is safe and more effective than GA alone. A trend toward decreased clinical disease activity was accompanied by major effects on MRI measures of disease burden and severe tissue injury.     

Silibinin synergizes with mitoxantrone to inhibit cell growth and induce apoptosis in human prostate cancer cells

The purpose of these experiments was to assess the synergistic activity of silibinin with chemotherapy agents in clinical use against prostate cancer. Silybin-phytosome, a commercially available formulation containing silibinin, has recently been studied in a phase I clinical trial. The silibinin doses used in the present study are clinically achievable based on the preliminary phase I data. DU145, PC-3 and LNCaP prostate cancer cells were seeded in 96-well plates in triplicate. Twenty-four hours later, silibinin (10, 20 and 40 microM) and either mitoxantrone or docetaxel were added to the designated wells. Seventy-two hours post-treatment, cell viability was determined with a tetrazolium-based assay. The combination index (CI) for determination of a synergistic effect was calculated, with values of <0.9 indicating synergy and values >1.1 antagonism. Apoptosis was also assessed using a luminescent assay after 72 hr of treatment with media alone, silibinin, mitoxantrone, or silibinin plus mitoxantrone. Silibinin showed a synergistic effect with mitoxantrone, as measured by reduction in cell viability. The CI values ranged from 0.413 to 2.650 for the combination of silibinin and mitoxantrone; in contrast, treatment with docetaxel and silibinin showed little or no synergy, with CI values of 0.898-4.469. In concordance with these findings, the addition of silibinin increased the level of apoptosis compared to mitoxantrone alone, particularly in the PC-3 cells. The combination of silibinin and mitoxantrone exhibits a pattern of synergy in reducing cell viability with increased apoptosis. These data are important in the planning of future clinical applications of silibinin.