4hc

Rodents given cyclosporine (CSP) for several weeks after autologous or syngeneic bone marrow transplantation develop a syndrome that mimics allogeneic graft-versus-host disease (GVHD). Autologous GVHD has also been reported after administration of CSP in patients who have received autologous bone marrow transplantation (ABMT) with untreated marrow for lymphoma or acute myeloid leukemia (AML). Our study was designed to determine whether CSP administration is associated with appearance of autologous GVHD in patients with AML receiving ABMT with 4-hydroperoxycyclophosphamide (4HC)-purged marrow and whether there was a dose-dependent effect of CSP on development of the syndrome...

The antileukemic activities of the lysosomotropic compounds, such as phenylalanine methyl ester (PME), have received little attention. In this study, a 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay was used to investigate the antileukemic activity of PME. Leukemic specimens from untreated patients that contained greater than or equal to 75% blasts were used. Leukemic cells were treated with PME at 37 degrees C and 22 degrees C in concentrations ranging from 0.5 to 50 mM. Normal blood mononuclear cells served as controls...

Tumor contamination of hematopoietic stem cell grafts may influence the outcome of breast cancer patients treated with high-dose chemotherapy. The goals of this study were: (a) to evaluate the prevalence of tumor contamination of bone marrow (BM) harvests in patients responding to systemic chemotherapy; (b) to evaluate reduction of BM tumor contamination by ex vivo purging with 4-hydroperoxycyclophosphamide (4HC); and (c) to compare the tumor contamination of peripheral blood progenitor cell collections and BM in advanced-stage breast cancer patients designated for peripheral blood progenitor cell infusion...

Glutathione (GSH) and glutathione S-transferases (GSTs) play an important role in the protection of cells against toxic effects of many electrophilic drugs and chemicals. Modulation of cellular GSH and/or GST activity levels provides a potentially useful approach to sensitizing tumor cells to electrophilic anti-cancer drugs. In this study, we describe the interactions of four representative alkylating agents (AAs), melphalan, 4-hydroperoxy-cyclophosphamide (4HC), an an activated form of cyclophosphamide, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and cisplatin, with GSH and GST in the human breast cancer cell line MCF-7...

We examined 4-hydroperoxycyclophosphamide (4HC) and phosphorodiamidic mustard (PM)-mediated cytotoxicity and DNA interstrand cross-link (ISC) induction in a 4HC-resistant subline, B5-180(3), that was derived from the subcloned human myeloid leukemia cell line KBM-7/B5. Based on the ratio of the 50% inhibitory concentration values, B5-180(3) cells were approximately 35-fold resistant to 4HC compared with the parental cells. 4HC-induced ISC levels (as measured by alkaline elution) were approximately 9-fold lower in the 4HC-resistant line than the parent line...

A cyclophosphamide congener, 4-hydroperoxycyclophosphamide (4HC), has been used to purge bone marrow (BM) of residual leukemia cells ex vivo for use in support of high-dose chemotherapy for patients with acute myeloid leukemia (AML) undergoing autologous BM transplantation (ABMT). The efficacy and toxicity of 4HC are dose-related. The maximally tolerated concentration, 60-100 micrograms/ml, is toxic to tumor cells but also to normal committed hematopoietic progenitor cells. The anti-CD15 monoclonal antibody (mAb) PM-81 has also been employed for purging BM in patients with AML...

Thirty-one marrows were harvested from 29 patients and donors in the first year after startup of a six-bed pediatric bone marrow transplant unit at Children's Memorial Hospital in Chicago. Twenty-seven patients were infused, 13 with allogeneic marrow. Eight of the 14 autologous marrows were purged with 4HC. This paper presents cell processing results from the first year of operation, describes a yield-enhancing change made to the buffy coat procedure, and shows which of various parameters significantly influenced final cell recoveries...

Most malignant gliomas grow despite treatment by standard chemotherapeutic agents. The authors explored the use of an innovative drug, 4-hydroperoxycyclophosphamide (4HC), delivered via a controlled-release biodegradable polymer to determine whether local delivery would enhance efficacy. This drug is an alkylator-type chemotherapeutic agent derived from cyclophosphamide. Unlike the parent drug, which requires activation by hepatic microsomes, 4HC is active in vitro. Two rat glioma cell lines, 9L and F98, were treated in cell culture with medium containing 4HC...

Human natural killer (NK) cells play an important role in first-line defence against primary and metastatic tumours. Their stimulation after autologous bone marrow transplantation (ABMT) may be useful to eradicate residual tumour cells. Human NK cells originate in bone marrow (BM) but little is known about their progenitors and lineage development. We studied NK cell ontogeny from BM progenitors obtained by 'purging' normal BM with 4-hydroperoxycyclophosphamide (4HC); this agent is known to destroy all but the most primitive BM progenitors...

Aldehyde dehydrogenase (ALDH) is well known for its involvement in the resistance of tumor cells to cyclophosphamide (CPA) and its activated derivatives, such as 4-hydroperoxy-CPA (4HC). The role of other drug-metabolizing enzymes such as glutathione S-transferase (GST) in CPA resistance is, however, less certain. In the present study of a human breast cancer cell line (MCF-7) exhibiting about 6-fold resistance to 4HC (MCF/HC), cellular levels of glutathione (GSH) were increased 1.4-fold, while cytosolic GST and ALDH activities were increased 2...

The 4-hydroperoxycyclophosphamide (4HC)-resistant B5-180(3) subline of the cloned KBM-7/B5 cell line was developed as a model of induced cyclophosphamide resistance in human myeloid leukemia. Based on IC90 values, this subline was approximately 20-fold resistant to 4HC. Furthermore, it was significantly cross-resistant to phosphorodiamidic mustard (PM), whose cytotoxicity is independent of aldehyde dehydrogenase (ADH). Using alkaline elution we found that the resistant line had decreased initial levels of DNA interstrand cross-links (ISCs) following 4HC but not PM treatment...

We tested the ability of CD34+lin- precursor cells isolated from marrow after treatment with 4-hydroperoxycyclophosphamide (4HC) to generate colony-forming cells (CFC). In liquid cultures, recombinant human stem cell factor (SCF), in combination with interleukin-1 (IL-1), IL-3, IL-6, granulocyte-macrophage colony-stimulating factor, or granulocyte colony-stimulating factor caused untreated, but not 4HC-treated, CD34+lin- cells to form CFC. However, generation of CFC from CD34+lin- cells treated with 60 micrograms/mL of 4HC was possible in the presence of an irradiated allogeneic stromal cell layer...

Previous studies have shown that treatment of bone marrow (BM) cells with interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF-alpha) can protect hematopoietic progenitor cells (HPC) from the toxic effects of 4-hydroperoxycyclophosphamide (4HC) or gamma-irradiation. Since doxorubicin (DX) and hydroquinone (HQ) may inhibit hematopoiesis through mechanisms similar to 4HC and gamma-irradiation, it was of interest to determine whether IL-1 beta or TNF-alpha could protect HPC from DX and HQ as well...

This retrospective study was conducted to determine whether the total number of nucleated cells (TNC)/kg collected at marrow harvest was associated with outcome in 151 patients with acute myelogenous leukemia (AML) who received an autologous purged (n = 67) or non-purged (n = 84) marrow transplant. At the time of transplant 33 patients were in first complete remission (CR), 47 in second CR, 54 in first relapse and 17 beyond second CR. Ninety patients received busulfan (BU) 16 mg/kg and cyclophosphamide (CY) 120 or 200 mg/kg, 51 patients received CY 120 mg/kg and total body irradiation (TBI) 12-15...

PURPOSE: (1) To study the ability of mobilized peripheral-blood progenitor cells (PBPC) collected in a single large-volume leukapheresis performed on a predetermined date to accelerate engraftment after high-dose cyclophosphamide and thiotepa; (2) to establish the minimum dose of PBPC associated with early engraftment; and (3) to identify parameters predictive of collection of large numbers of PBPC. PATIENTS AND METHODS: Twenty-three patients with breast cancer received cyclophosphamide (4 g/m2) and granulocyte-macrophage colony-stimulating factor ([GM-CSF] 5 micrograms/kg/d x 15 days) for PBPC mobilization...

We report details of the synthesis and characterization of oligoribonucleotides containing 4-thiouridine or 2-pyrimidinone ribonucleoside (4HC). We have used these probes to examine the roles of the conserved pyrimidines in the central core of the hammerhead ribozyme. The effects on catalysis of singly-substituted hammerhead ribozyme and substrate strands were quantified in multiple-turnover reactions. Various effects were observed on kcat. and Km, with up to a 7-fold decrease and a 3-fold increase respectively...

The mechanics involved in the renal excretion of C14-labeled coumarin (C), 7-hydroxycoumarin (7HC) and 4-hydroxycoumarin (4HC) were studied in unanesthetized chickens by use of the Sperber technique. Analysis of urine collected during unilateral portal infusion of C, 4HC or 7HC indicated that the chicken excreted these coumarins almost entirely in conjugated form. Both 7HC and 4HC appeared in the urine only as the corresponding glucuronide. During C infusion, 84% of excreted radioactivity was identified as 7HC-glucuronide with only 8% appearing as a conjugate of open-ring metabolite o-hydroxyphenylacetic acid (HPAA)...

Cell suspensions of normal rat marrow mixed with rat acute myelogenous leukemic cells were prepared and incubated in vitro with graded doses of 4-hydroperoxycyclophosphamide (4HC). The cell suspensions were injected into rats prepared with a lethal dose of total body irradiation. Animals injected with these cells survived fatal irradiation induced aplasia. In a dose related manner 4HC was able to "purge" tumor cells from the cell mixtures. Thus, animals given cell suspensions incubated with the lower doses of 4HC showed prolonged survival before death from leukemia and animals given cell suspensions incubated with higher doses of 4HC survival lethal irradiation without the subsequent appearance of leukemia...

In vitro growth of erythroid progenitors (BFU-e and CFU-e) from mouse bone marrow (BM) can be influenced by the addition of graded doses of thymocytes (THY). At low THY:BM ratios (1:50), inhibition of erythroid growth occurred, whereas at high THY:BM ratios (20:1), enhancement of erythroid growth was observed. Experiments were designed to examine the sensitivity of the thymocytes to gamma radiation or treatment in vitro with an alkylating agent, 4-hydroperoxycyclophosphamide (4HC), to determine if two subpopulations with different physical characteristics were responsible for these observations...

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