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At least 19 recordsLinked to original sources
PubMed1992

[Measurement of busulfan concentration in plasma and spinal fluid from transplant patients pretreated with busulfan and cyclophosphamide].

Busulfan (BU) concentrations in the blood and spinal fluid of 7 patients pretreated with BU for bone marrow transplantation (BMT) were measured using gas chromatography. The data from these periodically obtained samples were used to study the relationship between the BU concentration and complications (e.g. vomiting), indicating that vomiting leads to a lower maximum BU level. The trough level of BU concentration at 6 hours after administration was stable at around 500 ng/ml, not showing little effect of vomiting. The BU concentrations in the spinal fluid were virtually the same as those in plasma collected at the same time and the spinal fluid/plasma ratio of the BU concentration averaged 1.06. No veno-occlusive disease (VOD) was noted. Failure of engraftment occurred in one case of myelofibrosis, however, as the plasma BU concentration in this case was not lower than the others, the graft failure was not considered to be due to the preconditioning regimen including BU.

Adolescent↗
PubMed1992

Growth retardation and depigmentation of hair after high-dose busulfan and congenic hematopoietic cell transplantation in mice.

Busulfan, a myeloablative but non-immunosuppressive alkylating agent, is used extensively in clinical bone marrow transplantation (BMT), but the effects of high-dose administration have not been previously evaluated in preclinical BMT settings with young murine recipients. We compared the survival and growth of C57BL/6 mice given graded single doses of busulfan (10-100 mg/kg) or total body irradiation (TBI; 900 cGy) at age 9 days and hematopoietic cell transplantation (HCT; transplantation of congenic bone marrow and spleen cells) 24 h later. The 30-day survival was 87-100% in mice transplanted after 10-40 mg/kg busulfan and 79% after TBI, but fell to 54% and 33%, respectively, after 80 mg/kg and 100 mg/kg busulfan, suggesting that this latter dosage range represents the LD50 for single-dose busulfan in young C57BL/6 mice given stem cell rescue. The weights of 10-week-old mice given HCT after lower doses of busulfan ranged from 87% of control at 10 mg/kg to 64-69% of control in mice conditioned with 35-65 mg/kg busulfan or TBI. Impairment of weight gain was most striking (approximately 50% of control) in mice transplanted after 80-100 mg/kg busulfan. Despite retardation of somatic growth, the brain weights of busulfan-conditioned mice remained at least 90% of control, and there were no obvious neuropathological alterations in the brains of these animals. All mice treated with at least 20 mg/kg busulfan or TBI lost hair by 3-4 weeks after transplant.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1975

Dibromomannitol in the treatment of chronic granulocytic leukemia: a prospective randomized comparison with busulfan.

Dibromomannitol (DBM) is a new agent for the treatment of chronic granulocytic leukemia. A propsective evaluation of the drug was undertaken in a randomized comparison with busulfan. Forty previously untreated, Philadelphia chromosome-positive cases were treated, with 20 patients in each treatment group. The protocol provided for continuous maintenance therapy after remission induction, with a crossover to the opposite drug in patients who became refractory to the primary agent but are without evidence of blastic tranformation. There were 14 remissions in the DBM group and 15 in those treated with busulfan. The rate of decrease of the elevated leukocyte count was more rapid with DBM, but prolonged disease control off treatment occurred in only three of 14 cases as opposed to nine of fifteen busulfan-treated patients who required a median delay of 12 mo before maintenance could be initiated. Hypoplasia occurred in one DBM patient and two busulfan cases. Following recovery, crossover to the opposite drug in two cases again resulted in hypopllasia. Increased skin pigmentation, amenorrhea, pulmonary fibrosis, and cytologic dysplasia, commonly associated with busulfan adminstration, were also noted with DBM. The median duration of disease control with busulfan was 34 mo and 26 mo with DBM. There was no signigicant difference in the incidence of blastic transformation, and median survival for both groups was 44 mo. DBM appears to be as effective as busulfan in the treatment of the chronic phase of CGL but with a more predictable myelosuppressive action. The principal advantage of busulfan over DBM is the fact that more than half the busulfan-treated patients experienced prolonged disease control off treatment.

Amenorrhea↗
PubMed1978

Spontaneous regression of syngeneic transplanted tumors in rats pretreated with the antileukemia drug busulfan.

Lethal growth of a syngeneic transplanted tumor (KMT-17) was inhibited in WKA rats pretreated with the antileukemia drug busulfan. The effect of busulfan was short-lasting, and administration of the drug after tumor challenge had little effect on the lethal growth of the tumor. After spontaneous regression of the tumor in rats pretreated with busulfan, specific transplantation resistance to identical tumor was acquired. Busulfan did not exhibit its effect in rats irradiated before tumor challenge. As shown by the Winn test, spleen cells from rats immunized with inactivated tumor cells after busulfan treatment inhibited growth of admixed tumor cells more strongly than did spleen cells from rats immunized without busulfan treatment. Enhancement of immune response to tumor cells rather than tumoricidal activity by busulfan was suggested.

Animals↗
PubMed1992

Preclinical activity of hepsulfam and busulfan in solid human tumor xenografts and human bone marrow.

Hepsulfam (1,7-heptanediol disulfamate, NSC 329680) is a new antineoplastic alkanesulfonate agent which has demonstrated a broader preclinical activity than busulfan. The compound is currently undergoing clinical trials. We have studied the activity of hepsulfam and busulfan simultaneously in human tumor xenografts in vitro in a clonogenic assay and in vivo in tumor-bearing animals in order to assess the activity of both compounds in model systems of slowly growing malignancies. In a total of 37 different tumors of various histologies, both agents demonstrated broad spectrum in vitro activity. The median IC50 of hepsulfam and busulfan was determined as 0.93 and 3.31 micrograms/ml, respectively. At a concentration of 1.0 micrograms/ml, hepsulfam was active in eight of 37 tumors (22%) in the clonogenic assay, whereas busulfan effected inhibition of colony formation in one of 37 lines (3%). At the same concentration, however, hepsulfam demonstrated a clear in vitro toxicity to human bone marrow cells (CFU-GM) from healthy donors, whereas busulfan did not reveal a myelosuppressive effect. Evaluation of equitoxic concentrations in vitro revealed a higher activity of hepsulfam, especially in non-small cell lung cancer. In tumor-bearing nude mice, the approximate LD10 dose was determined as 150 mg/kg single bolus injection given i.p. on day 1 for both compounds. Hepsulfam demonstrated superior in vivo activity in a large cell lung cancer xenograft and a gastric carcinoma model. The preclinical activity of hepsulfam suggests a possible role of this compound in the treatment of solid human malignancies. However, the increased bone marrow toxicity of hepsulfam as compared with busulfan might be critical for further clinical application.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

High-performance liquid chromatographic-mass spectrometric assay of busulfan in serum and cerebrospinal fluid.

A liquid chromatographic-mass spectrometric method has been developed to determine busulfan concentrations in the cerebrospinal fluid and serum of some children undergoing bone marrow autotransplantation. After two liquid-liquid extraction steps with dichloromethane on a biological matrix, the separation of busulfan was carried out by isocratic reversed-phase chromatography. The mass spectrometric system was operated in electron-impact mode. Principal ions at m/z 175, 111 and 79 were observed for busulfan, but only m/z 175 was chosen for the quantification of the analyte. The retention time of busulfan was 2.5 min. The detection limit of 100 ng/ml allowed the determination of cerebrospinal fluid and serum busulfan concentrations during the four days of high-dose (1 mg/kg) treatment prior to autotransplantation in five child patients.

Busulfan↗
PubMed1977

Busulfan lung.

An uncommon, but lethal, toxic side effect of busulfan (Myleran) therapy for chronic myelogenous leukemia is pulmonary fibrosis. A 16-month-old male infant treated for 11 months with busulfan for chronic myelogenous leukemia is, we believe, the first case of "busulfan lung" in the pediatric age group to be reported. Progressive roentgenographic changes in the lung of a diffuse intra-alveolar and interstitial pattern were noted. The patient died after a four-day episode of cough, fever, and progressive dyspnea. At autopsy, no evidence of infection or leukemic infiltrates were seen in the lungs. Characteristic histologic findings as a result of busulfan therapy were observed in the lung and pancreas.

Busulfan↗
PubMed1978

[Varying course of pancytopenia after busulfan treatment of chronic myelocytic leukemia (CML)].

In 84 patients with chronic myeloid leukaemia receiving a cytostatic monotherapy with busulfan, an aplastic syndrome developed which was confirmed by a biopsy of the pelvis crest and examination of the sternal marrow. The time interval until pancytopenia was detected varied considerably in each case, ranging between 6 and 126 months. There are no correlations to the initial doses of busulfan. 3 patients died of the immediate effects of the bone-marrow damage caused by busulfan. In 4 from 6 of the following pancytopenic patients the leukocyte values lay between 12,800/microliter and 80,400 microliter when busulfan adminstration was interrupted. Thus, it is scarcely possible to give any reliable informations about a leukocyte limit value as a standard for an interruption of therapy in order to prevent bone-marrow aplasia. Taking this into account, the conclusion may be drawn that relatively short control intervals have to be made in this monochemotherapy of CML which often can be used successfully for many years.

Adolescent↗
PubMed1976

Erythroleukemia-like syndrome due to busulfan toxicity in polycythemia vera.

Over a 19-year period, a patient with polycythemia vera who had undergone a splenectomy received six courses of busulfan for recurrent thrombocytosis. The total dose of busulfan given for the sixth course was greater than that used for the previous ones. Severe pancytopenia followed, which persisted for 4 months. During this period there was marked erythroid hyperplasia in the bone marrow with striking dyserythropoiesis; PAS-positive red cell precursors, as well as moderate numbers of circulating normoblasts and evidence of chronic and acute hemolysis, were present. All of these findings reverted to normal without therapy, and the polycythemic state eventually recurred. These events are interpreted as an unusual marrow reaction following busulfan overdosage rather than a transient erythroleukemia.

Adult↗
PubMed1979

Cytogenetic effects of busulfan in vivo on bone marrow cells and oocytes of adult mice and liver cells of transplacentally exposed embryos.

Adult female mice were twice treated orally with 15, 30, or 60 mg busulfan per kg of body weight. In bone marrow, a dose-dependent linear increase in the frequency of chromosome aberrations was observed. Similar to the effects of other alkylating agents, busulfan induced all types of aberrations, including exchanges. In metaphase II oocytes, only a few chromosome aberrations were observed. An intervening round of DNA-replication seems to be necessary to translate busulfan-induced lesions in oocytes into chromosome aberrations. In embryonic liver cells of transplacentally exposed mice, chromosome aberrations were induced.

Animals↗
PubMed1992

Treatment of recurrent and refractory pediatric solid tumors with high-dose busulfan and cyclophosphamide followed by autologous bone marrow rescue.

PURPOSE: The purpose of this study was to determine the toxicities of and responses to high-dose busulfan and cyclophosphamide with autologous bone marrow transplant (ABMT) in patients with recurrent or refractory pediatric solid tumors. PATIENTS AND METHODS: We treated 18 patients (ages, 2 to 38 years; median, 14) who had tumors that were resistant to conventional chemotherapy and radiotherapy with busulfan 16 mg/kg and cyclophosphamide 200 mg/kg. Seventeen patients received bone marrow purged with 4-hydroperoxycyclophosphamide; one received unpurged marrow. RESULTS: Despite extensive prior treatment, including radiotherapy in 16 patients, toxicity generally was acceptable. For seven patients with measurable disease, there were three partial responses of 2, 10, and 20 months' duration, three patients with stable disease (SD), and one early, toxic death. Of the 11 patients with no measurable disease at the time of transplantation, one patient with osteosarcoma continues in remission at 57+ months and one third of the patients survived for at least 16 months. Mucositis was the predominant nonhematopoietic toxicity. CONCLUSION: Although the high-dose busulfan and cyclophosphamide combination showed modest activity, changes in the preparative regimen should be considered to improve the response rate in refractory tumors.

Adolescent↗
PubMed1979

[Effect of calusterone on the stem cell compartment after suppression with busulfan in mice].

These studies were undertaken to evaluate the effect of Calusterone (a weakly androgenic steroid) on hemopoiesis in mice. Cellular proliferation was suppressed by a single (IP) injection of busulfan (BU) (40 mg/Kg). Calusterone (CA) was administered s.c. SC daily (10 mg/Kg); controls received an equivalent injection of oil vehicle. Hemopoiesis was characterized by measurement of peripheral blood neutrophils, bone marrow cellularity, differentials and stem cell content. This included pluripotent (CFU-S), granulocytic (CFU-C) and erythroid (CFU-E) progenitor cells. Only a minimal decrease in narrow cellularity was observed after busulfan; similar values were obtained in calusterone recipients. Neutrophils fell by day 4, showed an abortive rise on day 8 and subsequently fell to 32% of control values. Calusterone recipients showed a 2 fold higher value (62%) on day 12. CFU-S, CFU-C, and CFU-E were depressed to 20-40% of control values by day 2 after busulfan. Although CFU-S and CFU-C remained depressed through the 14th day, CFU-E recovered by day 8 CA stimulated an overshoot in these cells to 288% of control values. These findings correlated with an increase in marrow erythroid cells to 182% on day 10. CFU-S remained low (20%) by day 14 and gradually increased to 50% of control by day 24. A delayed 10 day course of CA more than doubled the CFU-S recovery. These findings show that BU markedly suppress hemopoietic stem cells: a differential recovery is noted between CFU-E and the other progenitor cells. CA increase the recovery of all 3 hemopoietic stem cell compartments when given either immediately or in a delayed schedule. This suggests that this compound may be of use in the therapy of bone marrow hypoplasia.

Animals↗
PubMed1978

Myeloschisis in a six weeks embryo of a leukemic woman treated by busulfan.

A case of myeloschisis in a six weeks old human embryo is reported. The 39-year-old mother was treated by busulfan before and during the early stages of gestation for chronic lymphatic leukemia. Additional histological findings consisted in a decrease of mesenchymal elements together with a somitic disorganisation in the affected area of the embryo. In spite of the well known experience that this drug is well tolerated by leukemic pregnant women, a possible interference of busulfan with the oocyte differentiation in this elderly primipara is proposed.

Abnormalities, Drug-Induced↗
PubMed1976

Histopathology and ultrastructure of busulfan-induced cataract.

A 49-year-old man with chronic myelogenous leukemia developed dense posterior subcapsular cataracts and punctate cortical opacities after five years of busulfan (Myleran) therapy. We found that the histopathologic appearance of busulfan-induced cataracts is similar to other forms of human and experimental cataracts, regardless of cause. Ultrastructural examination revealed cortical liquefaction with formation of Morgagnian droplets, involving primarily the region from the equator to the posterior subcapsular space. In contrast to previous findings in rats, we observed posterior migration of equatorial nuclei and bladder cell formation. Also present were socalled crystalloid rays and abundant degenerate lens fiber membranes manifested as mutli-layered, irregularly folded configurations resembling myelin figures.

Busulfan↗
PubMed1977

Effect of busulfan on oncornavirus-like activity in platelets and chromosomes in polycythemia vera and essential thrombocythemia.

The effect of busulfan therapy on the activity of oncornavirus-like particles and chromosome patterns in patients with polycythemia vera and essential thrombocythemia was studied. Three patients had pretreatment platelet counts greater than 1 million/microliter, abnormal bone marrow karyotypes, and electron microscopic and biochemical evidence of oncornavirus. The results demonstrated that in all 3 patients virus-like particles and reverse transcriptase-like activity could no longer be found in the platelets within 2-4 weeks after the initiation of busulfan treatment. The platelet count was still elevated at this point for each patient, although the count returned to normal levels within 2-3 weeks after virus-like activity was no longer detectable. The chromosome patterns, characterized by aneuploidy (30-50%) before treatment, improved after therapy.

Aged↗
PubMed1975

Comparative effects of Yoshi-864 and busulfan on certain transplantable murine tumors.

Yoshi-864 extends markedly the survival times of mice bearing L1210 leukemia or Ehrlich ascites carcinoma. Busulfan, with methanesulfonate leaving groups identical with those of Yoshi-864, is without effect. Tumor cells from mice bearing the Ehrlich tumor and treated with Yoshi-864 have a persistent reduction in ability to synthesize DNA. Synthesis of DNA in cells from mice treated with busulfan is moderately suppresed at 48 hr after treatment, but returns virtually to the control value at 72 hr.

Alkylating Agents↗
PubMed1976

Treatment of busulfan-induced pancytopenia.

A patient with busulfan-induced pancytopenia and recurrent, thrombocytopenic bleeding was treated prophylactically with random-donor platelet transfusions and later with HLA-matched platelets from a sibling. The pancytopenia remitted after five months. The course and alternative modes of therapy of busulfan-induced pancytopenia are discussed. This disorder may be reversible if the patient can be supported through an initial period of severe pancytopenia.

Adult↗