Showing papers on "Mitoxantrone published in 1983"

Mitoxantrone in Patients with Acute Leukemia in Relapse

Abstract: Twenty-six patients with acute leukemia in relapse were treated with mitoxantrone (dihydroxyanthracenedione dihydrochloride). The drug was given as a rapid i.v. infusion for 5 days, and doses were escalated from 8 mg/sq m daily for 5 days to 20 mg/sq m daily for 5 days. Five of 12 patients with acute lymphoblastic leukemia were induced into complete remission; one patient was induced into complete remission twice. The marrow response lasted from 3 to 50+ weeks. Among 12 patients with acute myelogenous leukemia, there was one complete and one partial remission, with response duration lasting 8 and 2 weeks. One patient with chronic myelogenous leukemia in blastic crisis also had a partial remission lasting 17 weeks. Remissions occurred at doses ranging from 8 to 14 mg/sq m daily for 5 days. All responders had been treated previously with anthracyclines. Drug-induced side effects included dose-limiting oral mucositis, sporadic nausea and vomiting, and transient elevations of the hepatic enzymes. Approximately one-third of the patients had septic complications during the myelosuppressive phase following treatment. We believe that mitoxantrone has definite utility in the treatment of acute leukemia in relapse.

Phase II trial of mitoxantrone in refractory acute leukemia.

Abstract: Mitoxantrone was administered to 41 adults with refractory acute leukemia. The initial dose employed was 4 mg/m2/day X 5 days. Eventually a starting dose of 10 mg/m2/day X 5 days was used, with some patients receiving a subsequent course at 12 mg/m2/day X 5 days. Three patients had a complete response, one a partial response, and one hematologic improvement. Although antileukemia effect was more frequent at the higher doses, so was death following treatment.

Cardiac evaluation of mitoxantrone.

Abstract: Mitoxantrone is a synthetic anthraquinone that was developed through the doxorubicin analog program in hopes of retaining anticancer activity with less cardiotoxicity. This study evaluated 18 patients receiving mitoxantrone with serial noninvasive tests of left ventricular function and with endomyocardial biopsy. The echocardiograms and systolic time intervals demonstrated a trend to deterioration that did not achieve statistical significance. However, the nuclear angiographic ejection fraction significantly decreased from 61% +/- 6% (means +/- SD) at baseline to 58% +/- 5% (P less than 0.05) after 48 mg/m2 of mitoxantrone. The endomyocardial biopsies revealed tubular swelling, degeneration of mitochondria, minimal chromatin clumping, and myofibrillar lysis. This study has revealed mild but definite impairment of cardiac function and mild changes of myocardial morphology during mitoxantrone therapy. Although mitoxantrone is an effective chemotherapeutic agent, a direct comparison of mitoxantrone with doxorubicin is necessary to compare relative therapeutic to cardiotoxic ratios.

Comparative Cytotoxicity of Bisantrene, Mitoxantrone, Ametantrone, Dihydroxyanthracenedione, Dihydroxyanthracenedione Diacetate, and Doxorubicin on Human Cells in Vitro

Abstract: The cytotoxic efficacies of several substituted anthraquinones, ametantrone, dihydroxyanthracenedione, dihydroxyanthracenedione diacetate, mitoxantrone, bisantrene, and doxorubicin, were evaluated on an established human colon adenocarcinoma cell line by the method of inhibition of colony formation. The concentration-dependent survival curve following treatment for 1 hr was biphasic exponential for all agents. At concentrations below 1 µg/ml, mitoxantrone was about twice as active as both hydroxylsubstituted anthracenediones and doxorubicin, about 14 times more efficacious than ametantrone, and about 22 times more powerful than bisantrene. At higher concentrations, these differences in efficacy became even more pronounced. Treatment in stationary phase decreased the lethal efficacy of doxorubicin but not that of the other agents. No recovery of potentially lethal or sublethal damage was noted for any agent, but for anthracenedione derivatives, there was a small but statistically significant increase in cell kill during fractionated exposure. Continuous treatment with mitoxantrone or bisantrene resulted in marked degrees of cell killing, reaching 99.95 and 99.5%, respectively, after 24 hr. For doxorubicin, cell kill efficacy declined after 4 hr. Mitoxantrone was 10-fold more active on cells in G2 phase than on those in mid- to late-S phase. Sensitivity in G1 phase was intermediate. Thus, mitoxantrone appears as the most active compound while bisantrene and ametantrone are the least active agents. The cytotoxic efficacy of bisantrene increases during prolonged continuous exposure, while that of mitoxantrone increases in fractionated administration. These characteristics could be exploited in clinical strategies designed to improve the performance of these agents.

Mitoxantrone hydrochloride (NSC-310739) in lymphoma. A Southwest Oncology Group study.

Abstract: The members of the Southwest Oncology Group have treated thirteen patients with Hodgkin's disease and thirty-seven with non-Hodgkin's lymphoma with mitoxantrone on the every three week schedule While the result (\313 responses in Hodgkin's; \937 responses in non-Hodgkin's lymphoma) is not striking, there is a definite antitumor activity in a very heavily pretreated group of patients Toxicity was acceptable Additional trials in lymphoma are planned using mitoxantrone in combination with BCNU

Inhibitory effects of anthracenedione antineoplastic agents on hepatic and cardiac lipid peroxidation.

Abstract: The effects of mitoxantrone, ametantrone and a monohydroxylated anthracenedione on hepatic microsomal, cardiac sarcosomal and cardiac mitochondrial lipid peroxidation were examined and compared with those of doxorubicin and daunorubicin. Rabbit microsomal NADPH-dependent lipid peroxidation was inhibited by the anthracenediones in a concentration-dependent manner, whereas doxorubicin caused a concentration-dependent enhancement of peroxidation. Mitoxantrone and ametantrone (200 microM) completely inhibited microsomal malondialdehyde production while an identical concentration of doxorubicin caused a 2.5-fold stimulation. Rabbit cardiac sarcosomal NADPH-dependent malondialdehyde production was also abolished by 100 microM anthracenedione. Mitochondria isolated from rabbit hearts were found to support NADH-dependent lipid peroxidation. Doxorubicin produced a maximal 3-fold enhancement of mitochondrial malondialdehyde production at 25 microM. The anthracenediones however, completely inhibited mitochondrial lipid peroxidation Drug-stimulated lipid peroxidation was also effectively diminished by mitoxantrone and ametantrone in a concentration-dependent manner. Half-maximal inhibition of doxorubicin-stimulated rabbit microsomal malondialdehyde production was achieved by 4 anal 6 microM mitoxantrone and ametantrone, respectively. Furthermore this effect was not limited to anthracycline-induced lipid peroxidation. Mitoxantrone and ametantrone also protected against rat microsomal lipid peroxidation produced by nitrofurantoin, paraquat and doxorubicin, decreasing these rates by 80, 90, and 50%, respectively, at 10 microM anthracenedione. The relative inability of the anthracenediones to stimulate lipid peroxidation is consistent with the diminished cardiotoxicity of ametantrone and mitoxantrone relative to doxorubicin and daunorubicin.

Mitoxantrone: modest activity in a phase II trial in advanced prostate cancer.

Abstract: Thirty-seven patients with metastatic prostate cancer refractory to endocrine therapy were treated in a phase II trial of mitoxantrone. Starting doses were 12 and 10 mg/m2 iv every 21 days for good-risk and poor-risk patients, respectively. Of the 35 evaluable patients, two had objective partial regression and five had stable disease. Response duration ranged from 7 to 17+ months. The drug was very well tolerated by these elderly patients; myelosuppression was the major toxic effect. We conclude that mitoxantrone has modest activity and acceptable toxicity in patients with advanced prostate cancer.

Influence of mitoxantrone on nucleic acid synthesis on the T-47D breast tumor cell line

Abstract: Mitoxantrone exerts growth inhibitory effects, suppresses (3H)-thymidine as well as (3H)-uridine incorporation, and induces ultrastructural alterations in T-47D human breast tumor cells At low concentration (10(-9)M) the drug induced little effect on cell proliferation; cell growth kinetics were inhibited at a concentration of 10(-5)M (3H)-thymidine and (3H)-uridine incorporation declined rapidly at the concentrations tested (10(-9), 10(-7), and 10(-5) M), revealing a potent effect on metabolic activity of the cultured cells The sharpest decline in DNA and RNA synthesis occurred within the first 2 hr of drug treatment Serial ultrastructural examinations indicated definitive alterations in chromatin structure, disintegration of nucleolar components as early as 2 hr after drug treatment, and complete segregation of nucleolar components following 8-hr exposure to concentrations of the drug between 10(-5) and 10(-7) M A distinct increase in the density of mitochrondrial matrix was evident The in vitro data presented in this report demonstrate the growth inhibitory and antimetabolic effects of mitoxantrone on human breast tumor cells and suggest that the drug may be a promising antitumor agent

Fatal Congestive Heart Failure Following Mitoxantrone Treatment in Two Children Previously Treated With Doxorubicin and Cisplatin

Abstract: Two children, who had received chemotherapy with doxorubicin and cisplatin for disseminated chondrosarcoma and recurrent rhabdomyosarcoma, developed congestive heart failure following treatment with mitoxantrone (DHAD); the total doses of DHAD were 128 and 90 mg/m2, respectively. The patient with chondrosarcoma had relief of his cardiac symptoms with digitalis and furosemide. The patient with rhabdomyosarcoma, whose tumor responded following treatment with DHAD, died 2 weeks after development of congestive heart failure. For patients who have received prior treatment with potentially cardiotoxic agents, administration of DHAD should be followed by careful monitoring of cardiac function.

Mitoxantrone in advanced breast cancer: a phase II trial of the Southwest Oncology Group.

Abstract: 124 patients with metastatic breast cancer were entered into this phase II trial of mitoxantrone (DHAD). Patients were stratified prior to treatment as good or poor risk, and whether they had received previous therapy with an anthracycline derivative. Mitoxantrone was given every 21 days at a starting dose of 12 mg/m2 for good risk patients and 10 mg/m2 for poor risk patients. Among the group who had not received anthracyclines, 12 are fully or partially evaluable for response with five classified as good risk. One complete response, ongoing at 52 weeks was seen in this group. Of the seven poor risk patients, stable disease was seen in two. 103 patients with prior anthracycline exposure are fully or partially evaluable, 31 good risk and 72 poor risk. There were three partial responses in each group. Toxicity was primarily myelosuppression, and was more severe in the poor risk group. Mitoxantrone when used on this schedule has minimal activity among heavily pretreated patients with metastatic breast cancer.

Phase I trial of mitoxantrone by 24-hour continuous infusion.

Abstract: Mitoxantrone (DAD) is a new agent which intercalates into DNA. Preclinical studies have demonstrated activity equal to or greater than that of doxorubicin in all tumor systems tested. In this phase I clinical trial, the schedule of drug administration consisted of a 24-hour continuous iv infusion repeated at 21-day intervals. Twenty-nine patients received a total of 66 courses over a dose range of 4-15 mg/m2. The dose-limiting toxic effect was leukopenia, with a wbc count nadir on Day 12 and resolution prior to Day 21. Other toxic effects were thrombocytopenia, mild phlebitis, and blue discoloration of veins. Objective tumor responses were seen in a patient with adenocarcinoma of the breast and in another patient with clear cell carcinoma of the vagina. An additional six patients with acute leukemia were treated at a dose of 12 mg/m2; a decrease in peripheral blast count was observed in four of these six patients. The toxicity of DAD by 24-hour iv infusion was similar to that previously reported for iv bolus administration. We recommend phase II evaluation of DAD at a dose of 12 mg/m2 by single iv injection at 21-day intervals. Patients with acute leukemia should be evaluated at higher dose levels.

Comparison of in Vitro Methods for Assessing Cytotoxic Activity against Two Pancreatic Adenocarcinoma Cell Lines

Abstract: Several models of pancreatic adenocarcinoma are now available for experimental evaluation of newer chemotherapeutic agents. The present study represents an attempt to develop a rapid in vitro screening technique that would allow prediction of cytotoxic activity (or lack thereof) as reliably as the clonogenic or colony formation assay. To this end, seven drugs (cisplatin, dactinomycin, doxorubicin, 5-fluorouracil, menogarol, mitoxantrone, and streptozocin) were tested against two pancreatic adenocarcinoma cell lines using a standard colony formation assay and a 24-hr microcytotoxicity assay. The cell lines tested were PANC-1, of human poorly differentiated pancreatic adenocarcinoma origin, and WD PaCa, of hamster well-differentiated pancreatic adenocarcinoma origin. The dose-survival curves and resulting determinations of drug dose (µg/ml/1-hr exposure) at which there is a 50% inhibition of survival as compared to controls were compared for the two cell lines by each assay system. Lack of correlation of the two assays and considerable interdrug and inter-cell line variation were found. In addition, the microcytotoxicity assay was felt to underestimate the in vitro drug sensitivity of PANC-1 to three drugs (dactinomycin, doxorubicin, and mitoxantrone) and of WD PaCa to two drugs (5-fluorouracil and mitoxantrone). Despite the possible utility of the microcytotoxicity assay with other experimental models, the colony formation assay technique appears to provide the most reliable in vitro assessment of antineoplastic activity for pancreatic adenocarcinoma cell lines and should continue to be the standard to which other assay systems are compared.

Unusual side effect of mitoxantrone.

Abstract: Ketoconazole To the Editor: Numerous studies attest to the efficacy and relative safety of the antifungal agent ketoconazole when it is administered to adults. I] I wish to report the details of nine patients with fungal infections who received oral therapy with ketoconazole for between four and 16 weeks. In all cases, the diagnosis of dermatophyte infestation was made on the basis of the results of clinical, microscopic and microbiological investigations. Multiple biochemical analyses and full blood examination were performed in all patients before treatment, two weeks after starting treatment, and each month during treatment with ketoconazole. No patient showed changes beyond the stated normal range in any of the parameters measured. Mycological monitoring involved the initial microscopic examination of skin scrapings cleared in a solution of 5% aqueous potassium hydroxide in dimethylsulphoxide and their culture on Sabouraud's medium with chloramphenicol and cycloheximide (Actidione), followed by further microscopic and cultural examination at the point of adjudged clinical cure. Five patients remained symptom-free and fungus-free for between nine and 12 months after stopping the drug. Four patients did not become completely fungus-free but did become symptom-free. Most patients received 200 mg of ketoconazole a day. Three received 400 mg/day after only an insufficient clinical response was achieved by one month of treatment at the lower dosage. One patient was given 600 mg/day when his infection had shown complete clinical resolution, but when microscopic examination of skin scrapings showed the persistence of mycelium. Therapy with ketoconazole was withdrawn from this patient when he developed a gastrointestinal upset after 10 days of treatment. Further cultural and microscopic studies at that stage did not show any evidence of a persisting dermatophyte infection. The conditions of all patients responded quickly to ketoconazole therapy and symptoms of itching disappeared within 48 hours. However, the rate of improvement, particularly when the nails were invaded by fungus, slowed as the course of treatment proceeded. This observation is consistent with the hypothesis that initially a steady state exists between the rate of fungal invasion and that of extrusion of fungus from the body. Administration of ketoconazole slows the invasion rate and, in the glabrous skin, the body probably casts off the fungus before it can adapt to its changed environment. However, in nails, there is sufficient time for the fungus to adapt and, therefore, higher doses and longer courses of treatment with ketoconazole become necessary. No single instance of raised liver enzyme levels was found in these patients. Hepatotoxicity was the first serious side effect noted with the administration of ketoconazole,' and it seems to have occurred even when monitoring has taken place. However, raised levels of liver enzymes are not necessarily an indication for the withdrawal of treatment.' The question remains whether these patients have really been cured. In the case of a patient who has remained symptom-free for many months after the cessation of treatment, one can reasonably claim cure. Recurrence at that stage is more likely to be due to reinfection than to persistence. The efficacy of ketoconazole treatment, therefore, is very great. Even in those in whom the fungus persists in tissue cultures, the absence of symptoms suggests that fungus and host have entered a state of symbiosis in which there is no disruption to the patient's life. Of course, the same sort of \"cure\" and relief may be obtained using griseofulvin, but not all fungal infections respond to griseofulvin and many patients cannot tolerate the drug for one reason or another. Ketoconazole, therefore, -. represents a valuable and welcome addition\" to the anti-fungal armamentarium. . Tom Turner, P.O. Box 754, Norwood, SA 5067.

Synthesis of Potential Antineoplastic Anthracenedione Derivatives. II. 1,2-Dihydroxy Derivatives

Abstract: In continuation of the preceding paper in this series, four derivatives of 1,2-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]-9,10-anthracenedione: a positional isomer of mitoxantrone have been prepared to establish a relationship between the position of the hydroxyl groups on the A ring and antineoplastic activity against experimental leukemia L1210 in mice. Two compounds were found to be fairly active.