Showing papers on "Mitoxantrone published in 1986"

Mitoxantrone: a new anticancer drug with significant clinical activity.

Abstract: Clinical studies using mitoxantrone, an anthraquinone, were begun in the United States in 1979. Subsequent phase II and III trials have shown that mitoxantrone has significant clinical activity in patients with breast cancer, acute leukemia, and lymphoma. The drug has antiviral, antibacterial, antiprotozoal, immunomodulating, and antineoplastic properties and is mutagenic in some animal systems. Its mechanism of action seems to involve both DNA intercalation and nonintercalative electrostatic interactions. The dose-limiting toxicity is myelosuppression when the drug is given on a single-dose, every-3-week schedule and mucositis when it is given daily for 5 days. Other toxicities include gastrointestinal and cardiac effects, the gastrointestinal toxicity being less severe and less frequent than that with the anthracycline anticancer drugs. Because of its low incidence of serious toxicities and effectiveness in treating certain solid tumors and leukemias, mitoxantrone is a promising new agent in the treatment of cancer.

Selective immunomodulation by the antineoplastic agent mitoxantrone. I. Suppression of B lymphocyte function.

Abstract: Novantrone mitoxantrone, an antineoplastic agent with antiproliferative properties, is under investigation as an immunomodulating agent The impact of mitoxantrone treatment on B lymphocyte reactivity is presented here Administered ip in H2O at a dose of 05 mg/kg, daily for 14 days, mitoxantrone abrogated both the in vivo antibody response (to ovalbumin) and the in vitro plaque-forming cell (PFC) response (to SRC) In addition to the effects on thymus-dependent reactivity, PFC responses to the thymus-independent antigens TNP-LPS and TNP-Ficoll were also inhibited when tested in vivo or in vitro B cells were identified as a target for the suppressive activity of mitoxantrone by using T cell-replacing factor to reconstitute the in vitro anti-SRC PFC response of a T lymphocyte-depleted spleen cell preparation LPS-induced B cell mitogenesis was largely inhibited by mitoxantrone treatment However, depletion of Sephadex G-10-adherent cells significantly restored the proliferative response Flow cytometric analysis revealed a dramatic decrease in splenic B lymphocyte content Therefore, mitoxantrone exerted a potent suppressive influence on the humoral immune system through a direct reduction in B cell number augmented by macrophage-mediated inhibition of B cell proliferation

Selective immunomodulation by the antineoplastic agent mitoxantrone. II. Nonspecific adherent suppressor cells derived from mitoxantrone-treated mice.

Abstract: Mitoxantrone exerts a potent suppressive influence upon humoral immune responses. The B cell is a likely target for this inhibitory effect, and we have reported evidence supporting this possibility. The impact of mitoxantrone upon T lymphocyte reactivity was assessed as a second mode of action of this novel antineoplastic drug. TH and TS lymphocyte induction were tested in the in vitro anti-sheep erythrocyte response, and a surprising differential effect of mitoxantrone was observed. Helper activity was abrogated and suppressor function was enhanced. In apparent disagreement with this result, mitoxantrone inhibited the in vivo induction of TS cells using trinitrophenylated spleen cells. Macrophages were investigated as potential mediators of these effects upon immunoregulatory function. Replacement of macrophages in mitoxantrone-treated spleen cell preparations by normal adherent cells allowed the induction and complete expression of TH lymphocyte function. Conversely, replacement of mitoxantrone-treated macrophages with normal adherent cells before induction of TS cells failed to generate TS cell function. Thus, TH cells were resistant and TS cells were completely susceptible to mitoxantrone. Furthermore, supplementation of normal TH cell cultures with splenic macrophages from mitoxantrone-treated mice inhibited the induction of helper function. Production of the lymphokines IL 2 and TRF in mitoxantrone-treated mice was normal. This is consistent with the retention of functional TH cells in drug-treated spleens. Macrophages in the spleens of mitoxantrone-treated mice were responsible for the abrogated helper function and the enhanced suppressor activity. Although TS cell induction was directly inhibited by the drug, the effect upon TH cell function was secondary to the action of mitoxantrone-induced suppressor macrophages. Mitogen-stimulated lymphokine production was normal. Thus, mitoxantrone is a selective immunomodulator. The macrophage-mediated suppression of TH cell induction and humoral immunity investigated in spleens from mitoxantrone-treated mice is an intriguing finding that may have significant implications for immunotherapy.

A comparison of mitoxantrone and doxorubicin in breast cancer.

Abstract: Ninety patients with breast cancer refractory to cyclophosphamide/fluorouracil/methotrexate (CMF) have been randomized in their treatment, receiving either doxorubicin or mitoxantrone. Seventy-nine have received two full courses of therapy. Twelve of the 40 (30%) who initially received doxorubicin responded, whereas eight of the 47 (17%) who received mitoxantrone responded. These rates are not statistically different. The degree of myelosuppression was equivalent. Patients who received mitoxantrone had less nausea, vomiting, alopecia, and fatigue. Controllable clinical congestive heart failure developed in seven patients, and four others had a deterioration of noninvasive measures of cardiac function without clinical failure. One patient with clinical heart failure developing received only doxorubicin and one, only mitoxantrone, whereas the others received both agents. The duration of remission and time lapsed before disease progression were almost identical for the two regimens. This study included a crossover design. Two of 22 (10%) patients receiving doxorubicin and five of 24 (21%) receiving mitoxantrone as secondary therapy responded. This suggests that there is not absolute cross-resistance between these agents. We conclude that the efficacy of these two drugs is comparable in patients refractory to CMF, though the nonhematologic side effects of mitoxantrone are less.

Use of in vitro dose response effects to select antineoplastics for high-dose or regional administration regimens.

Abstract: Several preclinical and clinical studies have documented that dose or dose intensity of chemotherapeutic agents are important factors for response of patients' tumors. This finding has prompted empiric trials of certain chemotherapeutic agents in high-dose or regional administration treatment regimens. The present study was performed to identify agents that would be particularly good candidates for high-dose or regional administration regimens against particular types of tumors. Using a human tumor cloning technique, we constructed dose in vitro response lines for ten different chemotherapeutic agents against seven different histologic types of malignancies. Slopes of the lines indicated the agents with the greatest increases of in vitro response per increment in dose of the agent. Tumors against which the agents gave the steepest dose response lines included lymphoma, head and neck cancer, ovarian cancer, and small-cell lung cancer, while the dose response lines for non-small-cell lung cancer, breast cancer, and colon cancer were quite flat. Suggestions for clinical trials based on these findings include the use of high-dose melphalan for patients with lymphoma, head and neck, and ovarian cancer; the use of mitoxantrone in high-dose regimens for patients with breast cancer; high-dose cisplatin regimens for patients with small-cell lung cancer; high-dose bleomycin regimens for patients with non-small-cell lung and head and neck cancer; and regional perfusion of liver metastases from colorectal cancer with cisplatin. Prospective testing of high-dose or regional administration regimens suggested by this new model should indicate its use for prediction of the best agent to use in high-dose regimens against a particular tumor type.

Human autopsy tissue concentrations of mitoxantrone.

Abstract: A sensitive high-performance liquid chromatography method was used to measure mitoxantrone in autopsy tissue samples of 11 patients who had received the drug iv 10-272 days antemortem. Mitoxantrone was readily detectable in tissues from all patients. Tissue concentrations were proportional to lifetime cumulative dose of mitoxantrone, and decreased very slowly with time. The thyroid and the liver had the highest mitoxantrone concentrations, followed by the heart. These high cardiac concentrations of mitoxantrone could be partially responsible for the occasional case of cardiotoxicity seen with mitoxantrone. The brain had the lowest mitoxantrone concentrations. Organ mitoxantrone concentrations did not conform to a flow-limited model. Tumor mitoxantrone concentrations varied quite markedly from one site to another in the same patient. Tumors generally had lower mitoxantrone concentrations than did surrounding normal tissues. Mitoxantrone concentrations were consistently highest in intrahepatic tumors and lowest in intracerebral tumors. It is unclear whether the low concentrations in brain tumors were due to a partially intact blood-brain barrier or to the fact that most brain tumors had been irradiated prior to mitoxantrone administration. Further studies are warranted to more fully explore the relationship between human tissue mitoxantrone concentrations and efficacy and toxicity.

Pharmacokinetics of Mitoxantrone in Man and Laboratory Animals

Abstract: (1986). Pharmacokinetics of Mitoxantrone in Man and Laboratory Animals. Drug Metabolism Reviews: Vol. 17, No. 3-4, pp. 311-329.

Clinical pharmacology of mitoxantrone.

Abstract: A pharmacokinetic study on mitoxantrone was performed within the framework of a phase II clinical trial. Serum concentrations and urinary excretion were measured using a high-performance liquid chromatography method. Four metabolites were separated in urine and three in serum. The two major metabolites cochromatographed with the synthesized monocarboxylic and dicarboxylic acids of mitoxantrone. Within 48 hours, 4.4% of the administered dose was excreted in urine as mitoxantrone, 0.5% as Metabolite 1, and 0.3% as Metabolite 2. The pharmacokinetic parameters are adequately described by a three-compartment model with a terminal half-life of 214.8 hours and a volume of distribution of 2248 L/m2. The total-body clearance was 217 ml/min/m2 and the renal clearance was 15 ml/min/m2. These results suggest that mitoxantrone is sequestered in a deep tissue compartment and only slowly released.

Pharmacokinetics of mitoxantrone in humans following single-agent infusion or intra-arterial injection therapy or combined-agent infusion therapy.

Abstract: This study describes the pharmacokinetics of mitoxantrone determined by a sensitive and specific HPLC-method.

High-dose cytosine arabinoside and mitoxantrone: A highly effective regimen in refractory acute myeloid leukemia

Abstract: In a clinical phase I/II study, high-dose cytosine arabinoside and mitoxantrone (HAM) were given in combination to 40 patients with refractory acute myeloid leukemia. All patients had received a 9-day combination of thioguanine, Ara-C, and daunorubicin (TAD-9) as standardized first-line treatment. Refractoriness was defined as (a) nonresponse against two TAD-9 induction cycles, (b) early relapse within the first 6 months on monthly maintenance or after TAD-9 consolidation, (c) relapse after 6 months with nonresponse against one additional TAD-9 cycle, and (d) second and subsequent relapses after successful TAD-9 therapy at the preceding relapse. Therapy consisted of HD-Ara-C 3 g/m2 every 12 hours on days 1 through 4; mitoxantrone was started at 12 mg/m2/day on days 3, 4, and 5 and was escalated to 4 and 5 doses of 10 mg/m2/day on days 2 through 5 and 2 through 6. Of the 40 patients, 21 achieved a complete remission (53%), 1 patient had a partial remission, and 5 patients were nonresponders. Thirteen patients died in aplasia due to infections (n = 11), pericardiac effusion, or acute cardiomyopathy. Nonhematologic side effects consisted predominantly of nausea and vomiting, mucositis, and diarrhea. Central nervous system (CNS) symptoms were observed during six treatment courses. Recovery of blood counts occurred at a median of 27 days from the onset of treatment; the median time to complete remission was 36 days. Two of the 21 responders underwent successful bone marrow transplantations. The median remission duration for the remaining 19 patients is 4.5 months, and the median survival time is 9 months. These data emphasize that HAM has high antileukemic activity in refractory AML and strongly suggest starting the combination at earlier stages in AML therapy.

Lack of experimental vesicant activity for the anticancer agents cisplatin, melphalan, and mitoxantrone

Abstract: Cisplatin and L-PAM are DNA-crosslinking anticancer agents which have not been systematically studied for vesicant potential. Mitoxantrone is a new active anthracene-based, DNA intercalator which is undergoing widespread clinical testing for antitumor efficacy in man. These three agents were tested for vesicant activity in dehaired BALB/c mice given ID injections equivalent to human clinical doses. Neither cisplatin (up to 150 mg/m2) nor L-PAM (up to 71 mg/m2) produced any skin necrosis in the mice. The L-PAM solvent (acid/alcohol in propylene glycol) was ulcerogenic if injected undiluted. Mitoxantrone (up to 14 mg/m2) was not ulcerogenic in the mice, although the skin site retained a blue drug discoloration for several weeks. It is concluded that in clinically relevant doses, cisplatin, L-PAM, and mitoxantrone are not vesicants.

Mitoxantrone and hepatic toxicity.

Abstract: Excerpt To the editor: The use of mitoxantrone as an antineoplastic drug was reviewed recently by Shenkenberg and Von Hoff (1), who described its biochemistry, pharmacology, activity, and associate...

Reversible bilateral lateral rectus muscle palsy associated with high-dose cytosine arabinoside and mitoxantrone therapy.

Abstract: A patient with acute myelogenous leukemia in relapse developed reversible bilateral lateral rectus muscle palsy and cerebellar dysfunction after receiving chemotherapy with high-dose cytosine arabinoside and mitoxantrone. The differential diagnosis of this syndrome is reviewed.

First-line mitoxantrone chemotherapy for advanced breast cancer.

Abstract: Results of first-line mitoxantrone chemotherapy for advanced breast cancer are presented. Full dose (14 mg/m2 iv every 3 weeks) was given to 22 patients who had received no previous adjuvant chemotherapy; five (23%) partial responses were seen. No responses were seen in eight patients who had failed adjuvant chemotherapy, of whom seven received full dose. No responses were seen in nine patients receiving lower doses (mean, 10 mg/m2). The overall response rate was 13%. Treatment was well tolerated. Moderate or severe nausea/vomiting and alopecia were infrequent. One patient developed heart failure without predisposing risk factors.

A phase II study of dihydroxyanthracenedione (DHAD, Mitoxantrone, NSC 301739) in advanced malignant melanoma

Abstract: The Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial of Dihydroxyanthracenedione (DHAD, Mitoxantrone, NSC 301739) in 28 patients with advanced malignant melanoma, none of whom had received prior cytotoxic chemotherapy. 27 of 28 patients were ECOG performance status 0 or 1. Mitoxantrone was administered at a dose of 12 mg/M2 as a 30-45 minute intravenous infusion repeated every 3 weeks as toxicity and response permitted. Dose limiting toxicity was myelosuppression. No cardiotoxicity was encountered in this study. In this optimal group of patients, only one partial response to Mitoxantrone was observed. At this dose and schedule, Mitoxantrone has no clinically worthwhile activity against malignant melanomas.

Combination therapy with mitoxantrone and etoposide in refractory acute myelogenous leukemia.

Abstract: We have investigated the efficacy of mitoxantrone in combination with etoposide in patients with refractory acute myelogenous leukemia. The regimen consisted of 10 mg/m2/day of mitoxantrone given iv on Days 1-5; and 100 mg/m2/day of etoposide as short infusion, initially on Days 1-3 and extended to Days 4 and 5 as appropriate. Of the 26 patients treated with this combination, nine (34.6%) have achieved complete remission and two have achieved partial remission. The median duration of continuous complete remission was 85 days (range, 21-183+). Toxicity was mild and only one case of early death was observed. This combination seems to be an active regimen in refractory acute myelogenous leukemia, and its incorporation in front-line therapy seems warranted.

Mitoxantrone, methotrexate, and 5‐fluorouracil combination chemotherapy as first‐line treatment in stage IV breast cancer

Abstract: Fifty patients with Stage IV breast cancer were entered into a prospective Phase II trial of combination chemotherapy that consisted of mitoxantrone (10 mg/m2), methotrexate (40 mg/m2), and 5-fluorouracil (600 mg/m2) given in a 3-weekly schedule. Objective response to treatment was seen in 18 of 48 assessable patients (38%). Responses were seen predominantly in the lung and pleura and the node and soft tissue sites of disease. The median duration of response was 7 months. Toxicity from treatment consisted predominantly of reversible leukopenia. Other toxicities such as nausea and alopecia occurred in less than one half of the patients in the study group. The combination was well-tolerated, and appears to be moderately effective.

Phase II study of novantrone (mitroxantrone hydrochloride) in adults with grade III-IV astrocytomas

Abstract: Sixteen patients with malignant gliomas were trated with mitoxantrone 16 mg/m2 intravenously. One patient responded. Myelosuppression was dose-limiting but tolerable. Mitoxantrone has minimal activity against gliomas.

Possible mitoxantrone-induced amenorrhea.

Abstract: A patient with adenoid cystic carcinoma was treated with mitoxantrone at a dose of 12 mg/m2 every 3 weeks After the fifth dose, she developed amenorrhea accompanied by vasomotor instability (hot flashes) Subsequent serum gonadotropin and estradiol levels confirmed the postmenopausal state The mechanism of mitoxantrone-associated amenorrhea is most likely due to direct toxic effects on the ovary, as is seen with other forms of chemotherapy Ovarian dysfunction with mitoxantrone has not been previously reported The important consequences of chemotherapy-induced ovarian failure are described This toxic effect may be more frequently described as the drug becomes more widely available