Disease relevance of ASTA 6496

• Autologous bone marrow transplantation in patients with acute nonlymphocytic leukemia, using ex vivo marrow treatment with 4-hydroperoxycyclophosphamide [1].
• Amifostine (WR-2721) shortens the engraftment period of 4-hydroperoxycyclophosphamide-purged bone marrow in breast cancer patients receiving high-dose chemotherapy with autologous bone marrow support [2].
• Two commonly used methods of BM purging for patients with acute myeloid leukemia have been the drug 4-hydroperoxycyclophosphamide (4-HC) and (MoAbs) directed to myeloid antigens such as CD14, CD15, and CD33 [3].
• A lymphoblast progenitor cell assay was used to evaluate the antileukemic efficacy of marrow-purging protocols that employed intact ricin immunotoxins (IT) and 4-hydroperoxycyclophosphamide (4-HC) against clonogenic primary T-lineage marrow blasts freshly obtained from 12 T-lineage acute lymphoblastic leukemia (ALL) patients [4].
• In vitro restoration of polyclonal hematopoiesis in a chronic myelogenous leukemia after in vitro treatment with 4-hydroperoxycyclophosphamide [5].

High impact information on ASTA 6496

• Antisense-oligonucleotide-mediated downregulation of p27 in EMT-6 mammary tumor cell spheroids reduced intercellular adhesion, increased cell proliferation, sensitized tumor cells to 4-hydroperoxycyclophosphamide, and restored drug- or radiation-induced cell-cycle perturbations repressed in spheroid culture [6].
• In vitro effects of 4-hydroperoxycyclophosphamide on human immunoregulatory T subset function. I. Selective effects on lymphocyte function in T-B cell collaboration [7].
• In vitro, addition of 4-hydroperoxycyclophosphamide, a metabolite of cyclophosphamide decreased IL-12 production in mononuclear cell cultures [8].
• Pretreatment of marrow cells with two chemotherapeutic agents, 5-fluorouracil and 4-hydroperoxycyclophosphamide facilitated detection of CFU-B1 derived colonies, while diminishing or totally inhibiting colony formation by other hematopoietic progenitor cells [9].
• Differential effect of 4-hydroperoxycyclophosphamide and antimyeloid monoclonal antibodies on T and natural killer cells during bone marrow purging [3].

Chemical compound and disease context of ASTA 6496

• The effects of 4-hydroperoxycyclophosphamide (4-HC), an analogue of cyclophosphamide, on the blast progenitors from eight acute myeloblastic leukemia patients were studied in methylcellulose and suspension cultures [10].
• Light-density cells isolated from the grafts of 26 patients with acute leukemia or lymphoblastic lymphoma were treated with 4-hydroperoxycyclophosphamide (4-HC; 30 to 60 micrograms/mL), vincristine (Vcr; 1.5 to 3.0 micrograms/mL), and methylprednisolone sodium succinate (MP; 5 mg/mL) [11].
• DNA repair initiated in chronic lymphocytic leukemia lymphocytes by 4-hydroperoxycyclophosphamide is inhibited by fludarabine and clofarabine [12].
• Compared with the wild-type human mammary adenocarcinoma cell line (MCF-7wt), the isotope incorporation rate was increased 1.6-, 2.4-, and 5.3-fold in the etoposide-resistant MCF-7 cell line (MCF-7vp), doxorubicin-resistant MCF-7 cell line (MCF-7adr), and 4-hydroperoxycyclophosphamide-resistant MCF-7 cell line (MCF-7hc), respectively [13].
• Identification of glutathione S-transferase as a determinant of 4-hydroperoxycyclophosphamide resistance in human breast cancer cells [14].

Biological context of ASTA 6496

• 4-Hydroperoxycyclophosphamide depleted GSH by greater than 95% before inducing cell death in SEC [15].
• The exposure of embryonic murine limbs in vitro to an activated analog of cyclophosphamide, 4-hydroperoxycyclophosphamide (4OOH-CPA), induced limb malformations and apoptosis [16].
• Four patients received allogeneic transplants from histocompatibility locus antigen (HLA)-compatible siblings and the fifth patient received an autologous marrow treated with 4-hydroperoxycyclophosphamide [17].
• We studied the neurotoxicity and pharmacokinetics of i.t. 4-hydroperoxycyclophosphamide (4-HC) in the rabbit and the activity of i.t. 4-HC in a VX2 rabbit model of leptomeningeal carcinomatosis to evaluate the potential use of 4-HC in the treatment of leptomeningeal tumors [18].
• H69/CDDP was also resistant to cadmium chloride (2-fold), cis-diammine(glycolato)platinum (4-fold), 4-hydroperoxycyclophosphamide (3-fold) and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosour ea (4-fold) if the drug concentrations that inhibit cell growth by 50% from growth inhibition assay were compared [19].

Anatomical context of ASTA 6496

• To develop a model predictive of hematologic recovery, we studied the progenitor cell contents of 4-hydroperoxycyclophosphamide (100 micrograms/mL)-purged bone marrow grafts of 40 consecutive patients undergoing autologous BMT at this center [20].
• We previously found that the myeloid progenitor cell (CFU-GM) content of the marrow grafts after ex vivo purging with 4-hydroperoxycyclophosphamide (4-HC) correlates with time to hematologic recovery after autologous bone marrow transplantation in patients with acute nonlymphoblastic leukemia [21].
• The response of both cell lines to 4-hydroperoxycyclophosphamide was similar [22].
• Administration of human recombinant granulocyte colony-stimulating factor (filgrastim) accelerates granulocyte recovery following high-dose chemotherapy and autologous marrow transplantation with 4-hydroperoxycyclophosphamide-purged marrow in women with metastatic breast cancer [23].
• Human peripheral blood mononuclear cells were incubated for 1 hr in 4-hydroperoxycyclophosphamide (0.5 to 10.0 micrograms/ml), and the adherent, esterase-positive cells (macrophages) were studied [24].

Associations of ASTA 6496 with other chemical compounds

• Chemosensitivity of these lines to three other drugs, 4-hydroperoxycyclophosphamide, Adriamycin, and etoposide, suggested cross-resistance between CDDP and 4-hydroperoxycyclophosphamide [25].
• The combined use of 2'-deoxy-5-azacytidine with cisplatin or 4-hydroperoxycyclophosphamide in vitro frequently resulted in synergistic cytotoxicity against a panel of six human cell lines [26].
• Role for aldehyde dehydrogenase in survival of progenitors for murine blast cell colonies after treatment with 4-hydroperoxycyclophosphamide in vitro [27].
• Inhibitors of aldehyde dehydrogenase activity potentiated the cytotoxic action of 4-hydroperoxycyclophosphamide and mafosfamide toward all of the hematopoietic progenitors; they did not potentiate the cytotoxic action of phosphoramide mustard toward these cells [28].
• Drugs tested included melphalan, cyclophosphamide (4-hydroperoxycyclophosphamide in vitro), iphosphamide (4-hydroperoxyiphosphamide in vitro), phenylketocyclo-phosphamide, phenylketoiphosphamide, Asta Z 7557, and thiotriethyl-enephosphoramide [29].

Gene context of ASTA 6496

• We have previously reported that 20 hours' preincubation of human bone marrow cells with interleukin-1 beta (IL-1) can protect early progenitor cells from 4-hydroperoxycyclophosphamide (4-HC) cytotoxicity [30].
• To analyze the effects of the HGF on gene transfer into more primitive hematopoietic progenitors, CD34+ cells were isolated from marrow samples that were purged of committed progenitor cells by treatment with 4-hydroperoxycyclophosphamide (4-HC) [31].
• The relative abundance of tissue transglutaminase increased 3-4-fold after 6 or 24 h of culture with either concentration of 4-hydroperoxycyclophosphamide; immunoreactive protein in drug-treated limbs decreased to control levels by 48 h [32].
• The abundance of clusterin was increased 3-4-fold in drug-treated limbs; this induction occurred only after 48 h of culture with 4-hydroperoxycyclophosphamide [32].
• Herein we show that hyperthermia, 4-hydroperoxycyclophosphamide, and staurosporine also activate caspase-9, the apical caspase in the mitochondrial apoptotic pathway [33].

Analytical, diagnostic and therapeutic context of ASTA 6496

• The observed disease-free survival after transplantation with autologous marrow treated with 4-hydroperoxycyclophosphamide compares favorably with the results of syngeneic or allogeneic transplantation in similar groups of patients [1].
• Twenty-four patients with acute nonlymphocytic leukemia (ANLL) were treated with high-dose chemotherapy or chemoradiotherapy followed by infusion of autologous marrow purged with 100 micrograms/mL of 4-hydroperoxycyclophosphamide (4HC) [34].
• A monoclonal antibody (MoAb) cocktail of BA-1, BA-2, and BA-3 plus rabbit complement (C') plus 4-hydroperoxycyclophosphamide (4-HC) was used to eliminate residual occult leukemia cells from autografts [35].
• We tested the ability of CD34+lin- precursor cells isolated from marrow after treatment with 4-hydroperoxycyclophosphamide (4HC) to generate colony-forming cells (CFC) [36].
• Use of immunomagnetic purging in combination with 4-hydroperoxycyclophosphamide eliminated up to 5 logs of tumor cells but reduced the recovery of colony forming units-granulocyte-macrophage [37].

References