Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitoxantrone is a dihydroxyanthracenedione derivative which as intravenous mono- and combination therapy has demonstrated therapeutic efficacy similar to that of standard induction and salvage treatment regimens in advanced breast cancer, non-Hodgkin's lymphoma, acute nonlymphoblastic leukaemia and chronic myelogenous leukaemia in blast crisis; it appears to be an effective alternative to the anthracycline component of standard treatment regimens in these indications. Mitoxantrone is also effective as a component of predominantly palliative treatment regimens for hepatic and advanced ovarian carcinoma. Limited studies suggest useful therapeutic activity in multiple myeloma and acute lymphoblastic leukaemia. Regional therapy of malignant effusions, hepatic and ovarian carcinomas has also been very effective, with a reduction in systemic adverse effects. Mitoxantrone inhibits DNA synthesis by intercalating DNA, inducing DNA strand breaks, and causing DNA aggregation and compaction, and delays cell cycle progression, particularly in late S phase. In vitro antitumour activity is concentration- and exposure time-proportional, and synergy with other antineoplastic drugs has been demonstrated in murine tumour models. Leucopenia may be dose-limiting in patients with solid tumours, whereas stomatitis may be dose-limiting in patients with leukaemia. Other adverse effects are usually of mild or moderate severity although cardiac effects, particularly congestive heart failure, may be of concern, especially in patients with a history of anthracycline therapy, mediastinal irradiation or cardiovascular disease. Mitoxantrone displays an improved tolerability profile compared with doxorubicin and other anthracyclines, although myelosuppression may occur more frequently. Thus, mitoxantrone is an effective and better tolerated alternative to the anthracyclines in most haematological malignancies, in breast cancer and in advanced hepatic or ovarian carcinoma. Further studies may consolidate its role in the treatment of these and other malignancies.
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PMID:Mitoxantrone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer. 171 46

Mitoxantrone (DHAD), an anthracenedione with antineoplastic properties similar to doxorubicin, was tested for therapeutic efficacy and for immunomodulating action on lymphocyte subsets in 16 metastatic breast cancer patients, 12 of whom had been previously treated with chemotherapy. DHAD was given intravenously at a dose of 14 mg/m2 every 21 days. To evaluate total T lymphocytes (CD3), T helper (CD4), and T suppressor/cytotoxic cells (CD8) and the CD4/CD8 ratio, venous blood samples were drawn before and after the first DHAD cycle. Moreover, in 8/16 patients, B lymphocytes (CD20), T suppressor cells (CD8+/CD57+), T cytotoxic cells (CD8+/CD57-), NK (CD16) and IL-2 receptor-expressing cells (CD25) were also measured at the same time. An objective tumor response was achieved in 5/16 (31%) patients and the response rate was significantly higher in patients pretreated with hormone therapy alone than in those pretreated with chemotherapy. No relation was found between clinical response and changes in the CD4/CD8 ratio. Neither the mean number nor the percentage of CD3, CDA and CD8 cells observed after DHAD were significantly different with respect to those seen before. In contrast, the mean number of T suppressor cells, B lymphocytes and CD25-positive cells was significantly lower after than before DHAD administration, whereas no difference was seen in NK cells. These results confirm in humans the immunomodulating properties of DHAD previously described in experimental conditions. However, the DHAD-induced changes in lymphocyte subsets do not seem to be related to the clinical response in breast cancer.
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PMID:Mitoxantrone as a single agent in pretreated metastatic breast cancer: effects on T lymphocyte subsets and their relation to clinical response. 186 50

Mitoxantrone, an anthracenedione derivative, has been used for preclinical and clinical studies from the end of the 1970s. Several working mechanisms are suggested such as intercalation and electrostatic interactions with DNA with or without involvement of topoisomerase II, immunosuppressive effects and inhibition of prostacyclin synthesis. Efficacy of mitoxantrone alone or in combination with other chemotherapeutic drugs has been especially demonstrated in patients with breast cancer, leukemia and lymphoma. Locoregional (but not intrathecal) therapy with this drug is possible because it is not a vesicant. It has an improved tolerability profile compared with doxorubicin. Dose-limiting toxicity is myelotoxicity and mucositis. Therefore this drug has recently also been used in high doses with bone marrow support and in combination with hematopoietic growth factors. Cardiotoxicity is less frequent than after doxorubicin and daunorubicin. However, cardiac function tests are warranted after cumulative doses greater than 160 mg/m2 or earlier if additional risk factors, namely previous mediastinal irradiation, anthracycline therapy or cardiovascular disease, are present.
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PMID:Mitoxantrone: bluebeard for malignancies. 215 49

Mitoxantrone, a cytotoxic anthracenedione derivative, has given clinical evidence of beneficial activity in breast cancer, lymphoma and leukaemia. Several different mechanisms of action have been suggested to account for this. In addition to intercalation, biological effects such as electrostatic interactions with DNA, DNA-protein cross-links, immunosuppressive activities, inhibition of topoisomerase II, prostaglandin biosynthesis and calcium release have been described. Various methods of drug monitoring in biological fluids and tissues are available: the highest sensitivity has been achieved with high performance liquid chromatography with electrochemical detection, radioimmunoassay and enzyme linked immunosorbent assay. Early pharmacokinetic studies of mitoxantrone in experimental animals using radioactive material showed an extensive tissue distribution and a long terminal plasma half-life. The best fit for the plasma concentration-time curve in humans is achieved in a 3-compartment model. All studies reported a short absorption half-life of between 4.1 and 10.7 minutes, with the distribution phase being between 0.3 and 3.1 hours. In contrast, the values of the terminal half-life are quite variable, ranging from 8.9 hours to 9 days. Differences might be attributed to assay sensitivity, number and weighting of data points beyond 24 hours and coadministration drugs. Many studies showed a very large volume of distribution with sequestration of mitoxantrone in a deep tissue compartment. In autopsy studies, relatively high tissue concentrations have been measured in liver, bone marrow, heart, lung, spleen and kidney. Bile is the major route for the elimination of mitoxantrone, with lesser amounts excreted in the urine. Several metabolites have been separated, 2 of which were identified as the monocarboxylic and dicarboxylic acid derivatives. Mitoxantrone is usually administered by rapid intravenous infusion at 3-weekly intervals; other regimens include continuous infusion, daily repeated doses or weekly administration. In peritoneal carcinosis, the pharmacological advantage of intraperitoneal administration is clear. The optimal regimen for different disease categories with respect to efficacy and side-effects remains to be determined in future clinical trials.
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PMID:Pharmacokinetics and metabolism of mitoxantrone. A review. 218 7

Mitoxantrone was given to 19 patients with liver metastases from breast cancer and biochemical evidence of liver dysfunction. In all, 2 patients received the drug at a dose of 10 mg/m2 on days 1 and 2 of the first course of treatment; 1 patient was given 9 mg/m2 and 17 received 8 mg/m2. Subsequent courses were given at a dose of 10 mg/m2. Three patients (16%) showed a partial response, with time to progression of between 3 and 7 months. Toxicity was considerable, with myelosuppression being the major problem.
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PMID:Phase II study of mitoxantrone for liver metastases from breast cancer. 259 Oct 4

Mitoxantrone, an anthracenedione derivative structurally similar to anthracycline, was tested in 25 Phase II patients with advanced breast cancer, previously treated with different cycles of 5-fluorouracil. Cardiac toxicity was evaluated by means of electrocardiography, echocardiography and radionuclide left-ventricular ejection fraction. Ten patients received a cumulative dose less than 70 mg/m2 (median 33.6, range 28-63) and 15 a dose equal to or more than 70 mg/m2 (median 81, range 70-84). ECG abnormalities in the form of dysrhythmias and ST-T changes were observed in 41% of the patients. Echocardiographic myocardial function parameters recorded in 10 of the 15 patients who received more than 70 mg/m2 demonstrated a trend to deterioration, whereas the nuclear angiographic ejection fraction recorded in all 15 patients who had more than 70 mg/m2 had significantly decreased. No patients developed congestive heart failure but almost one-quarter of them had a fall in myocardial function parameters of more than 15% compared to pretreatment values. These data indicate that mitoxantrone has a significant toxic effect on myocardial cells also at cumulative doses of less than 85 mg/m2 which is generally considered beyond the limit of safety for patients without risk factors.
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PMID:Evaluation of ventricular function by echocardiography and radionuclide angiography in patients treated with mitoxantrone. 263 18

Mitoxantrone, an anthracenedione, has been shown to be as effective as doxorubicin, but with less local or systemic toxicity, when used for the treatment of advanced breast cancer. As the high molecular weight and hydrophilic property of this drug let us predict a slow intracavity resorption, we tested its use in the treatment of malignant effusions refractory to systemic chemotherapy. 18 women, 43 to 83 years old, with cytologically demonstrated metastatic pleural effusions, and with prominent clinical symptoms, were included in the study. All these patients were refractory to hormonotherapy and combination chemotherapy (previous regimens included anthracyclines in 17 patients but none had received systemic mitoxantrone). No previous local treatment had been attempted. During the study period, no other treatment has been given. Mitoxantrone (6 mg/m2) has been administrated after effusion aspiration. A complete response was seen in 8 patients, a partial response in 5, and no change in the 5 others but one had received only one injection on account of a transitory shock immediately after. No others side effects were reported (fever, local pain, alopecia, vomiting). No patient had evidence of myelosuppression. These results suggest that intracavity injection of mitoxantrone is feasible and generally safe in most patients. Some efficiency has been seen in previously heavily treated patients refractory to systemic chemotherapy. Local administration of mitoxantrone deserves further investigation.
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PMID:[Efficacy and toxicity of intrapleural mitoxantrone: apropos of 18 cases of pleural metastases of breast cancer]. 266 79

To determine the safety and efficacy of mitoxantrone use in hyperbilirubinemic breast cancer patients, a prospectively determined dosage schedule was evaluated in a multi-center trial. Pretreatment bilirubin prospectively defined three groups: Controls (with normal bilirubin) and two Study groups (with either moderate or severe bilirubin increase). Bilirubin determined initial mitoxantrone dose as well: bilirubin less than 3.5 mg/dl, 14 mg/m2; and bilirubin greater than or equal to 3.5 mg/dl, 8 mg/m2. Mitoxantrone at 14 mg/m2 was well tolerated in patients with moderate hepatic dysfunction. Patients with severe hepatic dysfunction demonstrated a mixed toxicity picture, with performance status (ECOG level 3) defining a population with limiting myelosuppression and/or early death. The survival of Study patients with severe hepatic dysfunction (median 17 days) was significantly worse than both Control (p less than 0.01) and Study (p less than 0.05) patients with lower bilirubin. Entry performance status (ECOG level 0-2 versus level 3) profoundly influenced survival (median survival 222 days versus 25 days, respectively, p less than 0.0001). Objective responses were seen in patients with both normal and elevated bilirubin. Bilirubin reduction following mitoxantrone commonly occurred, representing at least an indicator of favorable prognosis. Recommendations for mitoxantrone use include: 1. Patients with moderate bilirubinemia tolerate 14 mg/m2 mitoxantrone with reasonable chance for benefit. 2. Patients with severe hepatic dysfunction and poor performance status should not be given mitoxantrone. A definitive recommendation regarding use of reduced 8 mg/m2 mitoxantrone in patients with severe hyperbilirubinemia and favorable performance status requires further study.
Breast Cancer Res Treat 1989 Dec
PMID:Mitoxantrone use in breast cancer patients with elevated bilirubin. 269 28

Mitoxantrone prepared by Shanghai Institute of Pharmaceutical Industry is reported. 154 patients with various advanced cancers confirmed by pathology were treated by mitoxantrone with a dose of 14 mg/M2, i. v., once every 3 or 4 weeks from Feb. 1985 to Feb. 1987. There were 96 males and 58 females. The ages ranged from 16 to 76 years with an mean age of 48 +/- 15. Objective response rates were 21% in breast cancer, 36% in non-Hodgkin's lymphoma, 56% in acute lymphocytic leukemia, 14% in acute nonlymphocytic leukemia, 31% in gastric cancer and 5% in primary hepatic cancer. The side effects were leukopenia and gastro-intestinal disturbances. No marked cardiac toxicity was observed.
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PMID:[Phase II clinical trial on mitoxantrone]. 269 25

Anthracycline antibiotics remain among the most potent anticancer drugs, but their efficacy is limited by the development of a dose-dependent irreversible cardiomyopathy and by the emergence of clones of tumor cells resistant to the effects of the drug. Modifications of the basic anthracycline structure have resulted in molecules that may share the activity of the parent compound, with amelioration of some toxicities, absence of cross-resistance, or activity against tumors insensitive to the parent drug. Epirubicin has a unique metabolic pathway, glucuronidation, that may result in more rapid plasma clearance and reduced toxicity as compared with doxorubicin. Epirubicin has demonstrated comparable activity to doxorubicin in breast cancer, with possibly reduced toxicity. Idarubicin is of interest because of its cytotoxic activity when given orally. Idarubicin has prolonged retention in the plasma and has equal cytotoxic activity to the parent compound. Idarubicin has demonstrated activity against acute leukemia and breast cancer; in the latter tumor category, some doxorubicin-resistant tumors have responded. Esorubicin is of interest because of its nearly absent cardiac toxicity. This agent has some activity against solid tumors and is currently being clinically tested. Aclacinomycin A is an anthracycline in which a trisaccharide is substituted for the aminosugar. Aclacinomycin A and the related compound marcellomycin are of interest as both cytotoxic and differentiating agents. Menogaril is an anthracycline with the aminosugar on the D ring; it does not exhibit cross-resistance with doxorubicin or cardiotoxicity. Mitoxantrone is a compound that is related to the anthracyclines but has a different mechanism of action. This agent has significant activity against acute leukemia and breast cancer and is currently being compared with doxorubicin. Amsacrine is another compound related to the anthracyclines that possesses major activity against acute leukemias. Minor modifications of the anthracycline molecule have had major impact on the biologic activity of these drugs. New anthracycline analogues with up to 100 times the potency of currently available anthracyclines are being developed for clinical testing, and these complex molecules retain a nearly unlimited potential for structural modification.
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PMID:Phase I and II agents in cancer therapy: I. Anthracyclines and related compounds. 294 17


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