Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study aimed to evaluate the effect of melphalan on both terminal divisions and self-renewal capacity of acute myeloblastic leukemia (AML) progenitors (colony-forming units, CFU-L) grown in methylcellulose. Terminal divisions and self-renewal were assayed by primary (PE1) and secondary (PE2) colony formation, respectively. Thirteen cases of AML, were tested. Melphalan induced a negative exponential dose-effect on CFU-L survival. Moreover, melphalan was equally effective in inhibiting CFU-L growth in both PE1 and PE2 assays, with D10 values of 1.53 +/- 0.17 micrograms/ml and 1.59 +/- 0.21 micrograms/ml for PE1 and PE2, respectively (p = 0.48). Cytotoxicity of melphalan on CFU-L did not differ significantly from that observed for normal hemopoietic granulocyte-macrophage colony-forming units, erythroid burst-forming units, and granulocyte-erythroid-macrophage-megakaryocyte progenitors. Mafosfamide-lysine, a stable cyclophosphamide congener, strongly inhibited primary colony formation (PE1) with a D10 value of 14.46 +/- 1.76 micrograms/ml, but was much less efficient in the PE2 assay. Our findings suggest that the self-renewal capacity of AML progenitors can be differentially affected by alkylating agents. Moreover, since it is now considered that chemotherapy should be preferentially directed against the self-renewal of leukemic progenitors, melphalan might offer a greater potential than cyclophosphamide or cyclophosphamide derivatives in the therapy of AML.
Leukemia 1992 Mar
PMID:Effect of melphalan against self-renewal capacity of leukemic progenitors in acute myeloblastic leukemia. 156 57

Recently, the principles of density gradient cell separation have been transferred to the marrow fractionation, and the Ficoll technique by using a COBE 2991 blood cell processor has been developed and widely employed as well. This method is particularly useful in view of a chemical antineoplastic purging intended for autologous marrow transplantation. Forty marrows, which derived from patients suffering with leukemia and lymphoma, were fractionated with Ficoll on a COBE machine and in vitro purged with Mafosfamide at a dose of 50 micrograms/ml/1 x 10e7 MN cells. The density gradient separation enables to reduce the initial volume to 10%, the contaminating RBC to less than 1%, the total nucleated cells to 25% (greater than 80% of MNC) sparing about 80% of the CFU-GM. After purging, the surviving hemopoietic progenitor cells were 2.5%. The clinical effects of the fractionated purged cells were studied in 11 autotransplanted patients and compared with 14 transplants performed with untreated buffy-coat marrow derived cells. Ficoll cells produced less adverse effects at the time of reinfusion, while, as expected, the time of hematopoietic recovery was delayed in these patients (mafosfamide treated cells). These results confirm the usefulness of the gradient density cell separation to reduce the side effects of the DMSO and to make reliable the Mafosfamide purging manoeuvre, preventing the interference of contaminating RBC aldehyde dehydrogenase.
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PMID:Density gradient separation of hematopoietic stem cells in autologous bone marrow transplantation. 167 10

The sensitivity of human myeloblastic leukemic (CFU-L) and normal hemopoietic stem cells (CFU-GM and BFU-e) to Asta Z 7557 (INN Mafosfamide) was studied with regard to autologous bone marrow transplantation (ABMT) with cleansed marrow for consolidation therapy in adult patients with acute leukemia (AL) in remission. Establishment of the dose-response curves for CFU-GM (n = 37), BFUe (n = 11), and myeloblastic CFU-L (n = 9) demonstrated a wide range of sensitivity from patient to patient for all three progenitors. Whereas CFU-L, CFU-GM, and BFU-e grown in semisolid cultures disclosed similar sensitivities to Asta Z 7557, long-term culture (LTC) studies (n = 41) indicated a higher resistance of early progenitors. In an effort to achieve a maximum tumor cell kill and yet spare a sufficient amount of normal stem cells to ensure consistent engraftment, we defined the optimal dose for marrow cleansing as the dose sparing 5% CFU-GM (LD95). This dose was established from a preincubation test (PIT) realized on a 10-mL marrow aspirate taken 15 days before marrow collection in each individual patient. Twenty-four adult patients while in remission of AL (20 in complete remission, four in partial remission) were consolidated by cyclophosphamide 60 mg/kg X 2 and total body irradiation at 10 Gy followed by ABMT with marrow cleansed by Asta Z 7557 according to the specification described above. Patients were divided in two groups: group 1, unfavorable prognosis (11 patients); group 2, standard prognosis [13 patients in first complete remission (CR)]. All patients engrafted on leukocytes (median day for recovery to 10(9)/L: day 30), patients with ALL recovered faster than patients with ANL (median day 19 v 34). Similarly, recovery of platelets to 50.10(9)/L occurred sooner in patients with ALL (median day 67, range day 23 through 90) whereas three patients with acute nonlymphoblastic leukemia (ANLL) in group 2 had to be supported with platelet transfusions for more than one year. In group 1, six patients had recurrent tumor within six months; three patients died from toxicity with no evidence of tumor. Two patients are still disease-free with a short follow-up (nine and ten months). In group 2, two patients died from toxicity with no evidence of leukemia three and 16 months post-ABMT. One patient with a M5 ANLL and one patient with ALL relapsed at six and 15 months, respectively. Nine patients have remained in CR or are disease-free with a median follow-up of 22 months.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Autologous bone marrow transplantation using marrow incubated with Asta Z 7557 in adult acute leukemia. 351 54

Lymphatic leukemia L 1210 cells were treated in vitro with various concentrations of Mafosfamide--a stabilized active derivative of cyclophosphamide (4-hydroxycyclophosphamide). L 1210 cells treated with Mafosfamide (L 1210-MAF cells) were used for vaccination of semisyngeneic CD2F1 mice against L 1210 leukemia. These cells do not grow in vivo but are viable in the test with trypan blue. L 1210-MAF cells, obtained by treatment of L 1210 cells two times with 50 micrograms/ml or 100 micrograms/ml of Mafosfamide, and injected into the mice induced resistance against L 1210 leukemia in these animals. L 1210 cells treated two times with higher concentration of Mafosfamide (200 micrograms/ml or 400 micrograms/ml) did not give this effect.
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PMID:New application of a stabilized active cyclophosphamide derivative (mafosfamide, ASTA Z 7654)--immunogenic properties of lymphatic leukemia L 1210 cells treated in vitro with the drug. 365 51

Leukemia cells were mixed with normal human bone marrow cells to simulate bone marrow from leukemia patients; the mixture was then treated with a combination of stabilized derivative of cyclophosphamide [Mafosfamide (ASTA Z 7557)] and pokeweed antiviral protein-containing immunotoxin. The ability of this protocol for selective elimination of B-ALL cells was evaluated by clonogenic assay. The monoclonal antibody (B43) portion of the immunotoxin was directed against human B-cells and was linked to pokeweed antiviral protein by a disulfide bond. The combination of ASTA Z 7557 and immunotoxin was superior to either ASTA Z 7557 or the immunotoxin alone and produced nearly 7 logs of elimination of leukemia cells from the cell mixtures. About 5 logs of contaminating tumor cells were eliminated from a 200-fold excess of normal marrow under conditions where fewer than 50% of pluripotent stem cells were lost. Moreover, this manipulation did not inhibit subsequent production of pluripotent stem cells in long-term bone marrow cultures, indicating that the more primitive progenitors were not harmed.
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PMID:Increased efficiency in selective elimination of leukemia cells by a combination of a stable derivative of cyclophosphamide and a human B-cell-specific immunotoxin containing pokeweed antiviral protein. 387 Nov 74

Mafosfamide (ASTA-Z 7557) is a chemotherapeutic agent currently used for purging human bone marrow cells prior to autologous bone marrow transplantation. Adoptive cell-mediated immunotherapy has been shown to have a positive effect on the control of minimal residual disease and reinduction of remission post-bone marrow transplantation. Large granular lymphocytes and natural killer (NK) cells are believed to play a role in this effect. In the present work, we assessed the effect of ASTA-Z on the cytotoxic and proliferative capabilities of large granular lymphocytes (LGLs). The ASTA-Z significantly inhibited peripheral blood and bone marrow-derived LGL proliferation and cytotoxic capabilities, while this effect was less pronounced post-IL-2 treatment. We conclude that ASTA-Z purging may significantly impair the NK cell-mediated graft versus leukemia effect and therefore should be preceded by IL-2 therapy.
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PMID:ASTA-Z 7557 impairs human natural killer (NK) cell activity. 862 16

Several prospective randomized trials in acute myelocytic leukemia (AML) documented a lower relapse rate with autologous bone marrow transplantation (ABMT) than with conventional chemotherapy. However, they also identified some transplant difficulties, such as failure to collect sufficient numbers of stem cells, slow kinetics of engraftment, and a high transplant-related mortality that diminished or negated positive impact on overall survival. Data for ABMT are inconclusive in acute lymphocytic leukemia (ALL) in adults. We retrospectively analyzed patients with acute leukemia autografted with marrow purged with mafosfamide after January 1983 in our institution. The population comprised 229 consecutive patients; 165 with AML [123 in first remission (CR1), 32 in second remission (CR2)]; 61 with ALL (46 in CR1, 4 in CR2); and 3 with undifferentiated acute leukemia. All patients were autografted with marrow purged with mafosfamide. Mafosfamide was given at a constant dose of 50 microg/mL in 103 and adjusted individually to produce a CFU-GM LD 95 (5% residual CFU-GM post purging) in 126. The outcome was analyzed for correlation with patient characteristics, the disease including cytogenetics, and the graft itself. Prognostic factors identified by multivariate analysis were used to derive a prognostic classification. Patients receiving higher doses of marrow submitted to purging (>5.46 x 10(4) CFU-GM/kg) experienced a lower treatment-related mortality (RR = 0.11, p = 0.005) and a higher leukemia-free (RR = 0.5, p = 0.005) and overall survival (RR = 0.4, p = 0.001). Patients receiving <0.004% CFU-GM of marrow actually infused post purging had a lower relapse rate (RR = 0.51, p = 0.003). Modeling of prognostic groups identified good-, intermediate-, and poor-risk categories. Patients receiving a stem cell dose evaluated before purging of >5.46 x 10(4) CFU-GM/kg and doses actually infused post purging of < or =0.02 x 10(4)/kg had a treatment-related mortality of only 2+/-2%, a leukemia-free survival of 70%, and an overall survival of 77+/-7% at 10 years. In this study of autotransplantation for acute leukemia using mafosfamide-purged marrow, the stem cell dose used for purging and the intensity of purging were the most important factors predicting outcome.
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PMID:Importance of marrow dose on posttransplant outcome in acute leukemia: models derived from patients autografted with mafosfamide-purged marrow at a single institution. 1064

The oxazaphosphorines including cyclophosphamide (CPA, Cytoxan, or Neosar), ifosfamide (IFO, Ifex) and trofosfamide (Ixoten) represent an important group of therapeutic agents due to their substantial antitumor and immunomodulating activity. However, several intrinsic limitations have been uncounted during the clinical use of these oxazaphosphorines, including substantial pharmacokinetic variability, resistance and severe host toxicity. To circumvent these problems, new oxazaphosphorines derivatives have been designed and evaluated with an attempt to improve the selectivity and response with reduced host toxicity. These include mafosfamide (NSC 345842), glufosfamide (D19575, beta-D-glucosylisophosphoramide mustard), S-(-)-bromofosfamide (CBM-11), NSC 612567 (aldophosphamide perhydrothiazine) and NSC 613060 (aldophosphamide thiazolidine). Mafosfamide is an oxazaphosphorine analog that is a chemically stable 4-thioethane sulfonic acid salt of 4-hydroxy-CPA. Glufosfamide is IFO derivative in which the isophosphoramide mustard, the alkylating metabolite of IFO, is glycosidically linked to a beta-D-glucose molecule. Phase II studies of glufosfamide in the treatment of pancreatic cancer, non-small cell lung cancer (NCSLC), and recurrent glioblastoma multiform (GBM) have recently completed and Phase III trials are ongoing, while Phase I studies of intrathecal mafosfamide have recently completed for the treatment of meningeal malignancy secondary to leukemia, lymphoma, or solid tumors. S-(-)-bromofosfamide is a bromine-substituted IFO analog being evaluated in a few Phase I clinical trials. The synthesis and development of novel oxazaphosphorine analogs with favourable pharmacokinetic and pharmacodynamic properties still constitutes a great challenge for medicinal chemists and cancer pharmacologists.
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PMID:Design of new oxazaphosphorine anticancer drugs. 1743 Jan 92

Differential scanning calorimetry (DSC) and complementary techniques were utilized to evaluate the sensitivity of B-cell chronic lymphocytic leukemia (B-CLL) cell samples in vitro exposed to cladribine or fludarabine in combination with mafosfamide. Mafosfamide, the active in vitro form of cyclophosphamide with both purine analogs produced the cytotoxic effect on mononuclear cell probes, however, to a different degree. Our results indicated that higher sensitivity of examined leukemic cell samples to the used drug combinations was usually accompanied by a marked decrease or even a complete loss of thermal transition at 95+/-3 degrees C in DSC scans of nuclear preparations as well as by more significant reduction of cell viability, higher extent of DNA damage estimated by the comet assay and by dropping/disappearance of anti-apoptotic protein Mcl-1 in comparison with untreated cells. We have also observed that the reduction of transition at 95+/-3 degrees C in thermal scans of nuclear preparations isolated from blood of B-CLL randomized patients who showed response to cladribine or fludarabine combined with cyclophosphamide, i.e., CC and FC, respectively, corresponded with the decrease or disappearance of anti-apoptotic proteins Bcl-2 and/or Mcl 1. In conclusion, these in vitro and in vivo studies revealed that quick DSC technique, usually supplemented by other methods, is a potent tool to distinguish efficacy of B-CLL treatment and could be helpful in choosing the most effective manner of treatment for this type of leukemia.
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PMID:Calorimetric study as a potential test for choosing treatment of B-cell chronic lymphocytic leukemia. 1867 14

Mafosfamide (4-thioethane sulfonic acid salt of 4-hydroxy-cyclophosphamide, MAF) belongs to a new generation of the oxazaphosphorine agents. MAF is a cyclophosphamide analog which spontaneously degrades to 4-hydroxy-cyclophosphamide. The effects of MAF on various types of cancer cells were determined during preclinical investigations and clinical trials. The positive results from in vitro and in vivo anticancer studies promoted MAF to a good candidate for phase I trials. Clinical experience with intrathecal MAF, used for patients with neoplastic meningitis due to leukemia, lymphoma, and solid tumors, indicated good tolerability and efficacy. The recommended phase II doses of intrathecally administered MAF were determined. Clinical trials using intrathecal MAF are now underway. To obtain a better therapeutic index, a strategy to alternate dosing between the intraventricular and intralumbar routes is also being tested. MAF is an attractive agent for regional cancer therapy. The current available knowledge on MAF as a new anticancer agent is based on a collection of the original published studies, conference abstracts and relevant articles.
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PMID:Mafosfamide as a new anticancer agent: preclinical investigations and clinical trials. 2275 38


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