Disease relevance of Novantron

• Selective alopecia with mitoxantrone [1].
• Intensive single-agent mitoxantrone for metastatic breast cancer [2].
• New DNA topoisomerase II inhibitors less prone to redox reactions, such as mitoxantrone and more recently the anthrapyrazoles, were developed to circumvent this toxicity [3].
• RESULTS: A variety of drug-resistant human cancer cell lines derived by selection with mitoxantrone markedly overexpressed BCRP mRNA; these cell lines included sublines of human breast carcinoma (MCF-7), colon carcinoma (S1 and HT29), gastric carcinoma (EPG85-257), fibrosarcoma (EPF86-079), and myeloma (8226) origins [4].
• Mitoxantrone trial in multiple sclerosis [5].

Psychiatry related information on Novantron

• The most common signs of toxicosis after treatment with mitoxantrone were vomiting, anorexia, diarrhea, lethargy, sepsis secondary to myelosuppression, and seizures [6].
• Patients who proceeded to haematopoietic stem cell transplants (HDTs) received conditioning therapy with BEAM [for the Hodgkin's Lymphoma (HL) and non-Hodgkin's Lymphoma (NHL) groups], or melphalan 100 mg/m2 and mitoxantrone [for the multiple myeloma (MM) patients] [7].
• AIMS: To assess the efficacy of low-dose (5 mg/m2 3 monthly) mitozantrone using patient self-assessment questionnaire (SAQ), expanded disability status score (EDSS), multiple sclerosis functional composite score (MSFC), and the fatigue severity scale (FSS) [8].
• CONCLUSIONS: Intraperitoneal mitoxanthrone appears to be an effective second-line therapy in ovarian cancer; it is well tolerated as far as toxic effects are concerned, allowing cost reduction and improved patient compliance [9].

High impact information on Novantron

• Cisplatin, mitomycin, methotrexate, mitoxantrone, doxorubicin, and bleomycin at concentrations present in the sera of patients during therapy led to an upregulation of both CD95 receptor and CD95 ligand [10].
• Bcrp1, the murine homologue of BCRP, was expressed in the polarized mammalian cell lines LLC-PK1 and MDCK-II, and the direction of Bcrp1-mediated transport of topotecan and mitoxantrone was determined [11].
• Atypical multidrug resistance: breast cancer resistance protein messenger RNA expression in mitoxantrone-selected cell lines [4].
• Introduction of antisense BRCA2 deoxyribonucleotides into cells possessing normal BRCA2 function led to increased sensitivity to mitoxantrone (two-sided P = .008) [12].
• Four hundred eleven women with metastatic breast cancer were randomly assigned to receive either 60 mg/m2 doxorubicin (130 patients), 320 mg/m2 bisantrene (146 patients), or 14 mg/m2 mitoxantrone (135 patients) [13].

Chemical compound and disease context of Novantron

• INTERPRETATION: The Bezwoda study should not be used as the basis for further trials to test the efficacy of the cyclophosphamide, mitoxantrone, etoposide regimen for high-dose chemotherapy in women with high-risk primary breast cancer [14].
• Enforced expression of the full-length BCRP cDNA in MCF-7 breast cancer cells confers resistance to mitoxantrone, doxorubicin, and daunorubicin, reduces daunorubicin accumulation and retention, and causes an ATP-dependent enhancement of the efflux of rhodamine 123 in the cloned transfected cells [15].
• Patients with T-cell acute lymphoblastic leukemias (T-ALLs) within the Leucemies Aigues Lymphoblastiques de l'Adulte-94 (LALA-94) prospective trial were treated with a 4-drug per 4-week induction, with intermediate-dose cytarabine and mitoxantrone salvage treatment for patients not achieving complete remission (CR) in 1 course [16].
• High-dose cytosine arabinoside and mitoxantrone: a highly effective regimen in refractory acute myeloid leukemia [17].
• In vitro evaluation of fludarabine in combination with cyclophosphamide and/or mitoxantrone in B-cell chronic lymphocytic leukemia [18].

Biological context of Novantron

• Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo [19].
• High-dose mitoxantrone induces programmed cell death or apoptosis in human myeloid leukemia cells [20].
• From another patient in blast crisis (of myeloblastic phenotype), only Ph1-positive lines were established initially; however, five months later, after the patient had been treated with mitoxantrone, only Ph1-negative lines were derived from this patient [21].
• In this report, we show that 1-hour exposure of human myeloid leukemia HL-60 and KG-1 cells to mitoxantrone concentrations ranging between 0.1 and 10.0 mumol/L induced internucleosomal DNA fragmentation of approximately 200-bp integer multiples, characteristic of cells undergoing programmed cell death (PCD) or apoptosis [20].
• Transfection and enforced expression of BCRP in drug-sensitive cells confer resistance to mitoxantrone, doxorubicin, daunorubicin, and topotecan [22].

Anatomical context of Novantron

• It is likely that BCRP is the putative "mitoxantrone transporter" hypothesized to be present in these cell lines [4].
• Granulocyte-colony stimulating factor (filgrastim) accelerates granulocyte recovery after intensive postremission chemotherapy for acute myeloid leukemia with aziridinyl benzoquinone and mitoxantrone: Cancer and Leukemia Group B study 9022 [23].
• Using 2 myeloid cell lines, HL60 and NB4, evidence is presented that prior incubation with the CD44-specific monoclonal antibody (mAb) A3D8, reported to induce differentiation of AML blasts, significantly decreases apoptosis induced by 3 drugs used in AML chemotherapy: daunorubicin (DNR), mitoxantrone, and etoposide [24].
• The exposure of bone marrow transplant to the plasma residual concentration of mitoxantrone was correlated with the limiting hematological toxicity of the regimen (P < 0.001) [25].
• Furthermore, at later time points, e.g., 120 and 180 min, mitoxantrone accumulation in the MX2 cells exceeded that in HL-60 cells by 8.5 and 6.4%, respectively [26].

Associations of Novantron with other chemical compounds

• BCRP can render tumor cells resistant to the anticancer drugs topotecan, mitoxantrone, doxorubicin, and daunorubicin [11].
• We have analyzed the effect in vitro of the combination of fludarabine with cyclophosphamide and/or mitoxantrone on cells from 20 B-CLL patients [18].
• Salvage therapy consisted of oral ATRA for 30 days followed by 4 daily courses of chemotherapy (CHT) with cytarabine 1 g/m(2)/d and mitoxantrone 6 mg/m(2)/d. Second molecular remission was obtained in 12 of 14 patients (86%) [27].
• Antileukemic treatment differed according to age, but for remission induction, all patients received a combination of cytosine arabinoside and an anthracycline or mitoxantrone [28].
• Comparison of daunorubicin and mitoxantrone fluorescence emission profiles revealed significantly higher drug efflux from leukemic SP cells than from non-SP cells [29].

Gene context of Novantron

• We examined the role of multidrug resistance protein (MRP) 1 (ABCC1) in the emergence of mitoxantrone (MX) cross-resistance in a MCF7 breast cancer cell line selected for resistance to etoposide [30].
• Lastly, the defective P-gp in the mutant mdr1a(-/-) mice was associated with increased abcg2 mRNA at the BBB and a greater export of prazosin and mitoxantrone from the brain, as measured in the P-gp-deficient mice versus the wild-type mice [31].
• Mitoxantrone resistance in a small cell lung cancer cell line is associated with ABCA2 upregulation [32].
• c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for mitoxantrone- and anisomycin-induced apoptosis in HL-60 cells [33].
• Here, we found that mitoxantrone and anisomycin stimulated a dose- and time-dependent induction of JNK/SAPK activity, and to a lesser extent p38 activity, that preceded the appearance of apoptosis as measured by internucleosomal DNA fragmentation [33].
• This review provides an outline on relevant preclinical as well as clinical studies, places mitoxantrone in the context of other therapeutic approaches against multiple sclerosis (MS), and discusses relevant side effects [34].

Analytical, diagnostic and therapeutic context of Novantron

• Cardiotoxicity, determined by serial radionuclide ventriculography, occurred in 10 patients (37%) at a mean total mitoxantrone dose of 83.0 mg/m2 [2].
• Comparison of short-term and continuous chemotherapy (mitozantrone) for advanced breast cancer [35].
• Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial [36].
• The nature of the PEG-PE component also determined the antitumor efficacy of mitoxantrone-loaded PFV in murine and human in murine and human xenograft tumor models [37].
• Controlled destabilization of a liposomal drug delivery system enhances mitoxantrone antitumor activity [37].

References