Showing papers on "Mitoxantrone published in 1993"

Induction of DNA strand breaks associated with apoptosis during treatment of leukemias.

Abstract: A new flow cytometric method is described to detect DNA strand breaks associated with apoptosis, by labeling the 3'-OH termini in the breaks with biotinylated dUTP in a reaction employing exogenous terminal deoxynucleotidyl transferase. The method has been applied in studies on leukemic HL-60 and MOLT-4 cell lines to reveal whether it is specific to apoptotic cells, and whether it can be used in the clinic to detect DNA breakage in leukemic cells during chemotherapy. There was labeling of mononuclear cells in peripheral blood of all 11 patients studied during chemotherapy for acute lymphoblastic, acute myelogenous, or chronic myelogenous leukemia (ALL, AML, or CML) in blastic crisis, indicating induced DNA damage; the number of labeled cells increased from 1-8% before treatment up to 80% during the course of treatment. The DNA topoisomerase inhibitors mitoxantrone, VP-16 (etoposide), and m-AMSA (amsacrine) were more effective in inducing DNA breaks than was hydroxyurea or cytosine arabinoside (AraC). Cells with DNA breaks were identified in peripheral blood for up to 5 days following administration of Mitoxantrone and VP-16. In the case of DNA aneuploid leukemias, the DNA breaks were predominant in the aneuploid cell subpopulations, whereas presumably non-neoplastic diploid cells were unlabeled. In one case of ALL there were two distinct subpopulations of aneuploid cells: one responded to the treatment (by DNA breakage) and the other was non-responding. Thus, cells undergoing apoptosis can be detected by this method of labeling DNA strand breaks and the technique is applicable for analysis of response of leukemic cells to chemotherapy. With this method it may be possible to identify tumor cell sensitivity or resistance to particular drugs early in the course of treatment.

Therapy-related myelodysplasia and acute myeloid leukemia. Cytogenetic characteristics of 115 consecutive cases and risk in seven cohorts of patients treated intensively for malignant diseases in the Copenhagen series.

Abstract: Therapy-related acute myeloid leukemia (t-AML), often presenting as myelodysplasia (t-MDS), has become the most serious long-term complication of cancer therapy and offers a unique opportunity to study chemical leukemogenesis. Seven cohorts of patients treated for six different types of primary tumor have been followed closely for leukemic complications, and 115 consecutive patients with t-MDS or t-AML, including 45 cases from the cohorts, have been investigated cytogenetically at our institutions during the past 16 years. In patients primarily treated with alkylating agents, the risk of t-MDS and t-AML increased by approximately 1% per year from 2 to at least 8 years after start of treatment. In most cases, the disease presented as t-MDS with loss of a whole chromosome 5 or 7, or various parts of their long arms, and the leukemias were of FAB-subtypes M1, M2, or M4. In patients treated with drugs targeting at DNA-topoisomerase II, such as etoposide, doxorubicin, 4-epidoxorubicin, or mitoxantrone combined with drugs reacting directly with DNA, such as cisplatin or alkylating agents, the risk of leukemia increased much more steeply from only one year after start of therapy. These early onset cases often presented as overt leukemia of FAB-subtypes M4 or M5 with balanced translocations to chromosome bands 11q23 and 21q22, whereas later onset cases often shared characteristics with cases observed after therapy with alkylating agents alone. Both alkylation of DNA and poisoning of DNA-topoisomerase II may result in development of t-AML with different clinical and cytogenetic characteristics. There may be a synergistic leukemogenic effect between the two types of drug, and in patients with germ cell tumors treated with etoposide, cisplatin and bleomycin, reassessment suggested the risk of leukemia to increase exponentially with increasing doses of cisplatin and etoposide.

Topoisomerase II alpha co-amplification with erbB2 in human primary breast cancer and breast cancer cell lines: relationship to m-AMSA and mitoxantrone sensitivity.

Abstract: Topoisomerase II alpha (topo II alpha) is a key enzyme in DNA replication and a target for many anti-cancer drugs. High levels are associated with sensitivity to topoisomerase II inhibitors. Because its chromosome location is similar to erbB2 (17q21-22), which is frequently amplified in breast cancer, co-amplification of these genes was assessed. In 117 primary breast cancers, 25 were amplified for erbB2. Three of these cases showed co-amplification of topo II alpha. Topo II beta was not amplified. Four human breast cancer cell lines were assessed for erbB2 and topo II alpha co-amplification. They were also analysed for sensitivity to the topoisomerase inhibitors m-AMSA and mitoxantrone. The most sensitive cell line was SKBr3, which was the only one with erbB2 amplification. Topo II alpha was co-amplified to a similar extent as in tumours. This suggests that patients whose tumours show topo II alpha amplification should be assessed specifically for therapy with topoisomerase inhibitors.

An open-trial evaluation of mitoxantrone in the treatment of progressive MS

Abstract: We treated 13 patients with progressive MS with mitoxantrone. All patients received a standard IV dose of mitoxantrone (8 mg/m2) every 3 weeks for a total of seven infusions, with dosage adjustments depending on the hematologic profile at the nadir. The treatment was well tolerated, with the most common side effect being mild nausea. Four of seven women developed transient secondary amenorrhea. The postenrollment clinical behavior of these patients was generally more favorable than during the 18 months prior to enrollment (only three of 13 patients developed an increase in the Expanded Disability Status Scale of more than 0.5 points), suggesting a possible treatment effect, but comparison with two historical control groups (both the active and placebo groups from the Canadian Cooperative Trial of Cyclophosphamide and Plasma Exchange) does not suggest that mitoxantrone was efficacious. Eight of 12 patients had evidence of MRI activity on 13 of 29 follow-up visits. This small, open-labeled pilot study did not provide strong support for proceeding with a randomized, controlled trial of this dosage regimen of mitoxantrone in patients with progressive MS.

Cytochrome P-450-induced Cytotoxicity of Mitoxantrone by Formation of Electrophilic Intermediates

Abstract: Recent studies of our group have shown that the oxidation of the substituted anthraquinone skeleton is involved in the biotransformation of mitoxantrone. In this report the importance of this process with regard to the mode of action of the drug is investigated. This communication describes a new high performance liquid chromatography separation for mitoxantrone and its metabolites allowing the direct coupling of high performance liquid chromatography to mass spectrometry. Application of this technique to bile of mitoxantrone-treated pigs reveals the formation of several metabolites in addition to the drug-derived compounds found in urine. Seven biliary metabolites are identified as thioether derivatives of mitoxantrone and its side chain oxidation products. Independent synthesis and structural elucidation of 3 thioether conjugates of the drug provides unequivocal evidence that the hydroquinone moiety of mitoxantrone is the site of reaction with glutathione. Furthermore, the formation of the thioether conjugates in HepG2 hepatoma cells and in rat hepatocytes during cell incubations is demonstrated. Inhibition of cytochrome P-450 with metyrapone prevents the formation of the thioether conjugates and leads to a complete loss of the cytotoxicity of mitoxantrone in HepG2 cells and rat hepatocytes up to concentrations of 200 to 400 µm thereby indicating that mitoxantrone has a negligible effect by itself. Rat hepatocytes were found to be more susceptible for the oxidation-induced cytotoxicity than HepG2 cells. These results demonstrate that the acute cytotoxicity of mitoxantrone depends on prior oxidation of its 1,4-dihydroxy-5,8-diaminoanthraquinone moiety.

Clinical features and prognosis of follicular large-cell lymphoma: a report from the Nebraska Lymphoma Study Group

Abstract: PURPOSEOur purpose was to describe the treatment outcome of patients with follicular large-cell lymphoma (FLCL) and to identify prognostic factors that affect the treatment outcome.PATIENTS AND METHODSBetween 1980 and 1991, 107 newly diagnosed, previously untreated patients with FLCL were prospectively treated using treatment plans of the Nebraska Lymphoma Study Group (NLSG). Most stage I/II patients received two to three cycles of one of four closely related six-drug combination chemotherapy regimens (cyclophosphamide, doxorubicin or mitoxantrone, and procarbazine, plus bleomycin, vincristine, and prednisone or dexamethasone [CAP/BOP I-IV]) plus involved-field radiotherapy; 10 patients received involved-field irradiation only. Stage III/IV patients received six to eight cycles of CAP/BOP.RESULTSForty-four percent of patients had stage I/II disease. Stage I/II patients were older and more often female than stage III/IV patients. Cytogenetic studies were available on 35 patients: seven were normal; the mos...

Phase I clinical and pharmacokinetic evaluation of high-dose mitoxantrone in combination with cytarabine in patients with acute leukemia.

Abstract: PURPOSETo determine the maximally tolerated dose of mitoxantrone in combination with cytarabine in patients with acute leukemia and advanced phases of chronic myelogenous leukemia (CML), and to assess the pharmacokinetics of high-dose mitoxantrone in this patient population.PATIENTS AND METHODSIn a phase I study, 68 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and accelerated- and blastic-phase CML received induction therapy consisting of cytarabine 3 g/m2 by infusion over 3 hours daily for 5 days, with escalating doses of mitoxantrone 40 to 80 mg/m2 over 1 to 2 days by intravenous infusion over 15 minutes. Mitoxantrone pharmacokinetics were evaluated by high-performance liquid chromatography (HPLC) in 15 patients given a single dose of mitoxantrone ranging from 40 to 80 mg/m2 in combination with cytarabine.RESULTSSevere, but reversible hyperbilirubinemia (> three times normal) was considered the dose-limiting toxicity, and was observed in 25% of all patients and in ...

Granulocyte-macrophage colony-stimulating factor in association to timed-sequential chemotherapy with mitoxantrone, etoposide, and cytarabine for refractory acute myelogenous leukemia.

Abstract: Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), given intravenously 5 micrograms/kg per day, was administered on days 4-8 of timed-sequential chemotherapy (TSC) with mitoxantrone, 12 mg/m2 per day on days 1-3, etoposide, 200 mg/m2 per day on days 8-10 and cytarabine, 500 mg/m2 per day on days 1-3 and 8-10, in 22 patients aged < 60 years with refractory acute myelogenous leukemia in an attempt to increase recruitment of leukemic cells in S phase before the second sequence of TSC. Thirty-eight patients treated with TSC without GM-CSF in a previous trial served as historical controls. In GM-CSF-treated patients, median duration of neutropenia < 0.5 x 10(9)/1 was 33 days and of platelet transfusion requirement 30 days, without any increase by comparison with controls. WHO grade 3 or more extra-hematologic toxicity included sepsis in 60% of patients, vomiting in 30%, diarrhea in 15%, hyper-bilirubinemia in 15%, and mucositis in 10%, without any difference with controls. Among 20 evaluable patients six individuals (30%), with a 95% confidence interval (CI) ranging from 12-54% achieved complete remission, 11 (55%, CI 31-77%) did not respond to therapy and three (15%, CI 3-38%) died from infection. There was no demonstrable in vivo proliferation of leukemic cells during the 5 days of administration of GM-CSF. The average percentage of bone marrow cells in S phase in five patients was 4.0 +/- 2.8 on day 4 and 7.0 +/- 7.2 on day 8 (p = NS). In this cohort of patients refractory to cytarabine, addition of GM-CSF did not increase efficacy of TSC by comparison with historical controls.

Late cardiac toxicity of doxorubicin, epirubicin, and mitoxantrone therapy for Hodgkin's disease in adults.

Abstract: Cardiotoxicity is a well recognized side effect of anthracyclines (doxorubicin and epirubicin) or antracenadiones (mitoxantrone) at cumulative or high doses. However the side effects have not been evaluated in adults with Hodgkin's disease who received therapeutic doses of these drugs. We analyzed the cardiac function studying the left ventricular ejection fraction (LVEF) at rest in 136 patients with Hodgkin's disease treated with doxorubicin, epirubicin or mitoxantrone used in combination with vinblastine, bleomycin and decarbazine. No other risk factors, such as radiation therapy to the mediastinum, were considered. The follow-up is 5 to 8 years for patients in complete remission. Forty-five patients received doxorubicin (from 325 to 685 mg/ m2, median 475 mg/m2), 51 patients received epirubicin (from 310 to 610 mg/ m2, median 510 mg/m2) and 40 patients were treated with mitoxantrone (from 70 to 165, median 125 mg/m2). The median time between the end of treatment and the evaluation was 6.7 years. Thirty...

Mitoxantrone, etoposide and intermediate-dose Ara-C (MEC) : an effective regimen for poor risk acute myeloid leukemia

Abstract: A total of 74 patients with poor risk AML (median age 36.7 years, range 4.5-60.6) received a single course of a regimen including mitoxantrone (6 mg/m2 intravenous bolus daily, days 1 to 6), etoposide (80 mg/m2 intravenous over 1 h, daily, days 1 to 6) and intermediate-dose Ara-C (1 g/m2 over 6 h, daily days 1 to 6). 28 patients had failed initial remission induction with daunorubicin and conventional doses of Ara-C, 16 patients had secondary AML and 30 patients had relapsed from initial remission (five within six months, 15 over six months and ten after autologous or allogeneic bone marrow transplantation). Overall 41/74 patients (55%) achieved complete remission, 26 (35%) had resistant disease and seven (10%) died of infection during marrow hypoplasia. A 4-day course of the same regimen was given as consolidation to patients in complete remission. Subsequent antileukemic therapy was individualized. Profound myelosuppression and pancytopenia were universal resulting in fever or documented infections in almost 100% of patient; major hemorrhagic complications occurred in 39% of patients. Extrahematologic toxicity was mild to moderate consisting mostly of nausea and vomiting, oral mucositis and transient liver and cardiac dysfunction. We conclude that the MEC combination chemotherapy program seems to be an effective antileukemic regimen for secondary and advanced AML, with acceptable toxicity.

Toxicoses and efficacy associated with administration of mitoxantrone to cats with malignant tumors

Abstract: Eighty-seven cats with histologically confirmed malignant tumors were used in a prospective study to determine the toxicity of mitoxantrone, a dihydroxyquinone derivative of anthracene, which was administered at 21-day intervals at dosages ranging from 2.5 to 6.5 mg/m2 of body surface, IV. Eleven of these cats were treated concurrently with radiation but were evaluated separately. Each cat was evaluated for signs of toxicosis for 3 weeks after each dose was administered or until the cat developed progressive disease, or until the cat's quality of life diminished to an unacceptable level as determined by the owner or attending veterinarian. Although the primary purpose of this study was to determine a clinically useful dosage and to characterize the toxicoses associated with mitoxantrone administration, each cat was monitored for response to treatment. Forty-nine cats had been refractory to 1 or more treatment modalities prior to inclusion in this study. The most common signs of toxicosis after treatment with mitoxantrone were vomiting, anorexia, diarrhea, lethargy, sepsis secondary to myelosuppression, and seizures. Two cats died of complications that may have been attributed to mitoxantrone: 1 of cardiomyopathy and the other of pulmonary edema of an undetermined cause. Older cats were more likely to develop signs of toxicosis after the third or fourth mitoxantrone treatment than younger cats (P < or = 0.05). Cats with signs of toxicosis during the 21-day interval after administration of the first dose of mitoxantrone were significantly (P < or = 0.05) more likely to develop signs of toxicosis during the 21-day interval between the second and third doses of mitoxantrone.(ABSTRACT TRUNCATED AT 250 WORDS)

Similar sequence specificity of mitoxantrone and VM-26 stimulation of in vitro DNA cleavage by mammalian DNA topoisomerase II

Abstract: The molecular mechanism of topoisomerase II trapping by antitumor drugs probably involves the formation of a ternary complex DNA-drug-topoisomerase II. Recent studies support the view that a drug molecule might be placed at the DNA cleavage site interacting with the two flanking base pairs and amino acid residues of the enzyme. In this work, the DNA sequence-dependent action of mitoxantrone on topoisomerase II DNA cleavage was investigated in SV40 DNA fragments and short oligonucleotides, in comparison to VM-26, 4-demethoxydaunorubicin, and mAMSA. Mitoxantrone and VM-26 had a much lower degree of selectivity than 4-demethoxydaunorubicin and mAMSA in stimulating DNA cleavage. DNA cleavage at sites that were always stimulated also by VM-26. In contrast, mitoxantrone and 4-demethoxydaunorubicin shared only 7% of cleavage sites, and about 70% of the 4-demethoxydaunorubicin-stimulated sites were also stimulated by VM-26. Unlike what is generally seen with anthracyclines, the structurally related drug, mitoxantrone, stimulated cleavage also at DNA sites observed without drugs. Local base preferences at the cleavage site as determined by statistical analysis showed that mitoxantrone preferentially cleaved the DNA at sites with a cytosine or a thymine at position-1. However, strong DNA cleavage stimulation by mitoxantrone was favored by specific base pairs at the next positions flanking the cleaved bond (positions -2 and +2) and at positions +8 and +9. Effects of base mutations on drug stimulation of DNA cleavage in short DNA oligonucleotides independently showed that a pyrimidine at position -1 is required for mitoxantrone action.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporin A as a modifier agent in the salvage treatment of acute leukemia (AL).

Abstract: Sixteen adult patients with relapsed (7 patients) or refractory (9 patients) acute leukemia received mitoxantrone (10 mg/m2 per day for 3 days) and etoposide (200 mg/m2 per day for 3 days) with escalating dose of cyclosporin A (CsA) from a loading dose of 2 mg to 65 mg/kg per 2 h followed by 3 days continuous infusion of 5-15 mg/kg per day The major toxicities were stomatitis and prolonged aplasia, occurring for 15 mg/kg per day of CsA Transient conjugated hyperbilirubinemia occurred in all patients, and was CsA dose-dependent (r = 07) Adequate serum levels of CsA (> 1 microgram/ml) were obtained in 3/6 patients treated with 10 mg/kg per day and 4/4 patients with 15 mg/kg per day The pharmacokinetic of mitoxantrone showed an unusual increase of carboxylic metabolites, parallel to CsA levels We observed six responses (two complete and four partial remissions), and eight resistances Two patients died at days 3 and 8 from sepsis Before treatment, 7/16 patients tested for P-gp with C219 were positive (> 10% positive cells) 3/6 responders were P-gp-positive At time of leukemic regrowth, cells expressing P-gp before therapy reverted to P-gp-negative cells

Synthesis and antitumor properties of an anthraquinone bisubstituted by the copper chelating peptide Gly-Gly-L-His.

Abstract: A new molecule 4 [(GGH-DAE)2DHQ] associating the 1,4,5,8-tetrahydroxyanthraquinone ring (DHQ) of the antitumor drug mitoxantrone (2), two diaminoethylene chains (DAE), and the metal-chelating peptide Gly-Gly-His (GGH) has been synthesized Such a molecule presents characteristics able to induce antitumor activity: compound 4 intercalates into DNA as measured by delta Tm, fluorescence quenching, and viscometry; ESR studies demonstrate that several types of Cu complexes are formed depending on pH; and the production of free radicals, as evidenced by spin-trapping, is enhanced by 4 In vitro, in leukemia cells L1210 and mammary cells MCF7, 4 is slightly less cytostatic than mitoxantrone, but substantially less toxic In vivo, in leukemia P388 on mice, a T/C value of 230 is obtained at 25 mg/kg, higher than the one of mitoxantrone, which is toxic at the same dose

Influence of polybutylcyanoacrylate nanoparticles and liposomes on the efficacy and toxicity of the anticancer drug mitoxantrone in murine tumour models

Abstract: Polybutylcyanoacrylate (PBCA) nanoparticles were prepared and loaded with mitoxantrone, a highly effective anticancer drug. The proportion of mitoxantrone bound to the particles was analysed to be about 15 per cent of the initial drug concentration with the incorporation method and about 8 per cent with the adsorption method. Selected nanoparticle formulations were tested in leukaemia-or melanoma-bearing mice after intravenous injection. Efficacy and toxicity of mitoxantrone nanoparticles were compared with a drug solution and with a mitoxantrone-liposome formulation (small unilamellar vesicles with a negative surface charge). Furthermore, influence of an additional coating surfactant, poloxamine 1508, which has been shown to change body distribution of other polymeric nanoparticles, was investigated. It was shown that PBCA nanoparticles and liposomes influenced the efficacy of mitoxantrone in cancer therapy differently: liposomes prolonged survival time in P388 leukaemia, whereas nanoparticles le...

The role of systemic high-dose cytarabine in the treatment of central nervous system leukemia. Clinical results in 46 patients.

Abstract: Background. Given the good penetration of systemic high-dose cytarabine (HDara-C) into the cerebrospinal fluid (CSF), this approach was used to treat patients with central nervous system (CNS) leukemia, either isolated or with concurrent extraneurologic disease (END). Methods. From 1983 to 1991, 46 adults with CNS involvement were treated with systemic HDara-C: 25 had acute lymphoblastic leukemia (ALL), 15 had high-grade non-Hodgkin lymphoma (NHL), 5 had acute myelogenous leukemia (AML), and 1 had lymphoid blast crisis of chronic myelogenous leukemia. Induction consisted of HDara-C 3 g/m2 every 12 hours, by 3-hour infusion, for 8 doses (30 patients), or 6 doses (16 patients), followed by 4 doses at day 21. Results. Of 46 patients, 29 (63%) achieved complete remission (CR): 15/15 with isolated CNS leukemia, and 14/31 (45%) with CNS and concurrent marrow or lymph node disease. Of 17 patients not meeting CR criteria because of persistent END, 11 showed complete CNS response. The first 10 remitters were consolidated with monthly 4-dose courses of HDara-C. The remaining 19 received postinduction multidrug chemotherapy (including vincristine, doxorubicin, cyclophosphamide, Lasparaginase, etoposide plus intermediate-dose ara-C, mitoxantrone plus HDara-C) and intrathecal methotrexate (MTX) ± cranial radiation therapy. One patient underwent autologous and one allogeneic bone marrow transplant. Median CR duration was 7 months (range, 2–56+): 8 months for patients with isolated CNS leukemia, and 4 months for those with concurrent END. In only two patients was CNS the primary site of relapse. Three patients with isolated CNS leukemia are disease-free at 23, 40, and 56 months. The main toxicity was myelosuppression. No patient showed dose-limiting neurologic toxicity. Conclusions. Systemic HDara-C appears effective therapy for CNS leukemia, maximally in cases with isolated CNS involvement. HDara-C may be combined safely with cranial radiation therapy and intrathecal MTX. This approach for CNS leukemia, however, needs to be combined with additional treatments to eradicate residual disease in extraneurologic compartments.

Myocyte cell damage after administration of doxorubicin or mitoxantrone in breast cancer patients assessed by indium 111 antimyosin monoclonal antibody studies.

Abstract: PURPOSETo compare myocyte cell damage induced by doxorubicin or mitoxantrone, we performed left ventricular ejection fraction (LVEF) measurements and indium 111 antimyosin antibody studies in a group of patients with advanced breast cancer who had been treated with these anthracycline derivatives.PATIENTS AND METHODSWe studied 35 patients eligible to receive chemotherapy including the anthracyclines: doxorubicin or mitoxantrone (cumulative dose of doxorubicin, 500 mg/m2; or mitoxantrone, 120 mg/m2). LVEF was measured before and after 10 cycles of chemotherapy. Antimyosin uptake in the myocardium was quantified by means of a heart-to-lung ratio (HLR).RESULTSPatients treated with doxorubicin presented with a significant decrease in LVEF after chemotherapy (before, 60.4% +/- 8.92%; after, 49.8% +/- 9.71%; P = .001). Antimyosin uptake was observed in all patients with a HLR of 2.03 +/- 0.25. Seven of eight patients with a HLR greater than 2.03 had a greater than 10% decrease in LVEF. Patients treated with mit...

A phase II study of mitoxantrone combined with beta‐interferon in unresectable hepatocellular carcinoma

Abstract: BACKGROUND Chemoimmunotherapy is being evaluated in the most common gastrointestinal tumors, but little data are available on hepatocellular carcinoma (HCC). Considering the encouraging objective response rates and the absence of important side effects obtained with mitoxantrone in HCC, we tested the activity and feasibility of a schedule combining beta-interferon (beta-IFN) and mitoxantrone. METHODS Forty patients (ECOG Performance Status 0-1) with unresectable HCC received mitoxantrone (12 mg/m2 intravenously every 3 weeks) plus beta-IFN (3 x 10(6) U on days 1, 2, and 3; 6 x 10(6) from day 4 to day 60; and then 6 x 10(6) U three times a week for 10 months). RESULTS Thirty-eight patients were evaluable for response and toxicity with a median of four administered cycles (range, 2-10 cycles). Nine patients achieved a partial response (23%) (95% confidence interval, 11-40%) with a median duration of response of 4 months. In 15 cases, the disease was stable for at least 2 months; 14 patients had disease progression. The median survival time of the group as a whole was 8 months. Patients who were alpha-fetoprotein positive had a median survival time of 7 months; those who were alpha-fetoprotein negative had a median survival time of 9 months. The most common side effects were hematologic (World Health Organization Grade 3, 15 patients; Grade 4, 3 patients). Mild or moderate flu-like syndrome was present in 50% of treated patients, whereas 10 patients experienced mild or moderate nausea. CONCLUSIONS The schedule was active on advanced tumors with high alpha-fetoprotein values, and side effects were manageable. However, the addition of beta-IFN did not seem to improve significantly the response rate in HCC.

Multicenter phase II trial of mitoxantrone in patients with advanced nasopharyngeal carcinoma in Southeast Asia: an Asian-Oceanian Clinical Oncology Association Group study.

Abstract: PURPOSEPatients with advanced nasopharyngeal carcinoma (NPC) have a high incidence of recurrence and often develop distant metastases despite local control. This prospective multicenter phase II trial was conducted to evaluate the safety and efficacy of Novantrone (mitoxantrone; Lederle Laboratories, Wayne, NJ) in the therapy of patients with advanced NPC.PATIENTS AND METHODSOne hundred eight patients with advanced NPC, namely, those with recurrent or persistent disease following primary radiotherapy, or newly diagnosed metastatic disease, were treated with mitoxantrone. Mitoxantrone was administered intravenously at an initial dose of 12 mg/m2 and repeated every 3 weeks, with dose escalation to a maximum of 14 mg/m2. The distribution of histologic subtypes was representative of NPC, with the majority being (61%) undifferentiated (or anaplastic) carcinoma.RESULTSThe overall response rate (complete response [CR] and partial response [PR]) was 25% (95% confidence interval, 17% to 33%). The median response d...

High-Dose Versus Intermediate Dose Cytosine Arabinoside Combined with Mitoxantrone for the Treatment of Relapsed and Refractory Acute Myeloid Leukemia: Results of an Age Adjusted Randomized Comparison

Abstract: 193 patients with relapsed or refractory acute myeloid leukemia (AML) were entered into a prospective randomized comparison of high-dose versus intermediate dose cytosine arabinoside (AraC) both combined with mitoxantrone (mitox) according to the previously established sequential HD-AraC/mitox regimen (S-HAM). AraC was administered by 3 hr inf. q 12 hrs on days 1, 2, and 8, 9 at randomly assigned doses of cither 3.0 versus 1.0 g/m2 in pts. 18 mths.). From 151 presently evaluable cases 72 pts (48%) achieved a complete remission (CR), 38 cases (25%) were non-responders (NR) and 41 pts. (27%) died within the first 6 weeks after the start of treatment (early death = ED). No significant differences were found in CR rates b...

Plasma and cellular pharmacokinetics of mitoxantrone in high-dose chemotherapeutic regimen for refractory lymphomas.

Abstract: We have studied the plasma and peripheral leukocyte pharmacokinetics of mitoxantrone associated, in a high-dose regimen, with cyclophosphamide, carmustine, and etoposide in patients with refractory lymphoma undergoing autologous bone marrow transplantation. Nineteen patients with refractory lymphoma were involved in a clinical trial with escalated doses (15-90 mg/m2) of mitoxantrone administered by 30-min i.v. infusion 8 days before an autologous bone marrow transfusion. Mitoxantrone was measured by high-performance liquid chromatography in plasma and peripheral lymphocytes. The plasma pharmacokinetics of mitoxantrone was linear between 15 and 90 mg/m2: total body clearance (19.3 +/- 6.2 liter/h/m2) and volume of distribution at steady state (486 +/- 254 liter/m2) were not altered by increasing the dose. 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). At all times, the mitoxantrone concentration in peripheral cells was much higher than in plasma and was retained at a constantly high concentration level. Whereas cellular versus plasma maximum concentration ratio was near 1, the area under the concentration +/- time curve ratio reached 100, suggesting a long elimination half-life from cells. Plasma and cellular pharmacokinetics data of mitoxantrone reinforce the idea that this drug is a good candidate for high-dose chemotherapy regimen.

Characterization of Experimental Mitoxantrone Cardiotoxicity and Its Partial Inhibition by ICRF-187 in Cultured Neonatal Rat Heart Cells

Abstract: Mitoxantrone cardiotoxicity was investigated in isolated neonatal rat heart myocytes treated for 3 h in the presence or absence of the metal chelator ICRF-187. Electron microscopy studies of mitoxantrone-treated myocytes showed disorganized myofibrillar structures, swollen mitochondria, and extensive vacuolization. Cardiotoxicity, reflected as the ratio of intracellular ATP/protein and the loss of spontaneous beating, was only partially reduced by continuous ICRF-187 concentrations up to 50 µg/ml. ICRF-187 induced myocyte protection which was dependent on the dose and duration of exposure. ICRF-187 also reduced the cardiotoxicity of doxorubicin to a lesser extent and reduced the toxicity of a postulated cyclic mitoxantrone metabolite. However, the cardiotoxicity of ametantrone, a nonmetal-binding analogue of mitoxantrone, was unaltered with ICRF-187. The antitumor activity of mitoxantrone was unaltered by ICRF-187 in human tumor cells and in P-388-bearing mice. In addition, ICRF-187 allowed for 50% greater cumulative dosing in normal mice that, nonetheless, showed extensive histological heart damage 7 wk after dosing. These studies show that ICRF-187 provides partial protection from mitoxantrone cardiotoxicity in vitro without impairing the drug9s antitumor activity in vitro or in vivo. This facilitates greater cumulative drug dosing in normal mice. The postulated mechanism of cardioprotection is metal chelation, because ICRF-187 did not alter the toxicity of a nonchelating mitoxantrone analogue.

Sequence selectivity of topoisomerase II DNA cleavage stimulated by mitoxantrone derivatives: relationships to drug DNA binding and cellular effects.

Abstract: Mitoxantrone, a DNA intercalator, is an effective antitumor drug known to interfere with topoisomerase II function through stimulation of enzyme-mediated DNA cleavage. To clarify the drug structural requirements for stimulation of topoisomerase II DNA cleavage, the cytotoxic activity and molecular effects of mitoxantrone, ametantrone, and a new derivative (BBR2577), bearing a modification on one of the side chains, were examined in relation to their DNA binding affinities and modes of drug-DNA interaction. The results showed a good correlation between cytotoxicity and topoisomerase II DNA cleavage. The modification of one side chain did not influence the cytotoxic potency or the ability of the drug to stimulate DNA cleavage. In contrast, removal of the hydroxyl substituents in the planar aromatic moiety (ametantrone) markedly affected the efficacy of the drug. Ametantrone showed a markedly lower capacity, compared with the other two compounds, to induce cleavable complexes both in intact cells and in SV40 DNA, which suggests a critical role of these substituents in the formation of the ternary topoisomerase II-DNA-drug complex. The poor efficacy of ametantrone is likely due to low stability of the ternary complex. This is possibly related to a different orientation of the drug chromophore intercalated into DNA, compared with those of mitoxantrone and BBR2577. The DNA cleavage efficiencies of the tested drugs at low concentrations correlated with the DNA binding affinity. Identical DNA cleavage patterns were observed with the three compounds, which suggests that all tested drugs share a similar specificity for interaction with sites recognized by the enzyme.

Bleomycin and mitoxantrone in the treatment of malignant pleural effusions. A comparative study.

Abstract: Effusions are common in advanced cancer. Intracavitary instillation of various agents such as bleomycin has achieved control rates varying between 20% and 60%. However, serious side effects have also been observed, and cases of death due, for instance, to bleomycin have been reported. Mitoxantrone has been tested recently in the treatment of effusions, and preliminary results suggest high efficacy of this drug in the treatment of peritoneal, pericardial, and pleural effusions. Nevertheless, certain results have been conflicting. In the present study, 29 patients with pleural effusions were treated either with intracavitary bleomycin or intracavitary mitoxantrone. Effusions were controlled almost equally by both agents; 67% with mitoxantrone and 64% with bleomycin. We conclude that both agents can be used successfully in the treatment of pleural effusions.