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Anticancer Research Jul 2012Mafosfamide (4-thioethane sulfonic acid salt of 4-hydroxy-cyclophosphamide, MAF) belongs to a new generation of the oxazaphosphorine agents. MAF is a cyclophosphamide... (Review)
Review
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.
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Drug Evaluation, Preclinical; Humans
PubMed: 22753738
DOI: No ID Found -
Vaccines May 2023Chronic hepatitis B infection remains a significant worldwide health burden, placing persons at risk for hepatocellular cancer and hepatic fibrosis. Chronic hepatitis B...
Chronic hepatitis B infection remains a significant worldwide health burden, placing persons at risk for hepatocellular cancer and hepatic fibrosis. Chronic hepatitis B virus (CHB) infection is characterized by elevated levels of immunosuppressive regulatory T cells (Tregs), which can inhibit the function of effector T cells and lead to an insufficient immune clearance response against HBV. Theoretically, suppression of Treg cell functionality and percentage could increase anti-HBV reactivity in CHB-infected patients, although this has not yet been explored. We attempted to enhance our previously established anti-CHB protocol utilizing the GM-CSF+IFN-α+rHBVvac regimen (GMI-HBVac) by incorporating mafosfamide (MAF), which has been utilized in anticancer therapy in the past. Intravenous administration of MAF to rAAV8-1.3HBV-infected mice resulted in a dose-dependent reduction of Tregs in the blood, rebounding to pretreatment levels 10 days later. To assess the potential benefit of adding MAF to the anti-CHB protocol, 2 μg/mL MAF was combined with the GMI-HBVac as an anti-Treg treatment in an HBV-infected animal model. When rAAV8-1.3HBV-infected mice were immunized with MAF+GMI-HBVac, peripheral blood Tregs decreased significantly, leading to dendritic cell activation, HBV-specific T cell proliferation, and the upregulation of IFN-gamma-producing CD8T cells. In addition, MAF+GMI-HBVac vaccination stimulated T cell infiltration in HBV-infected livers. These effects may contribute to an enhanced immune response and the clearance of HBV-associated antigens, including serum HBsAg, serum HBcAg, and HBcAg hepatocytes. Overall, this is the first indication that MAF can act as an adjuvant with GMI-HBVac to deplete Tregs in mice with an established CHB infection. This unique therapeutic vaccine regimen produced a functional cure, as revealed by the remarkable clearance of HBsAg.
PubMed: 37376415
DOI: 10.3390/vaccines11061026 -
Bone Marrow Transplantation Apr 2023Post-transplantation cyclophosphamide (PTCy) has decreased GVHD incidence. Endothelial damage in allo-HCT is caused by multiple factors, including conditioning...
Post-transplantation cyclophosphamide (PTCy) has decreased GVHD incidence. Endothelial damage in allo-HCT is caused by multiple factors, including conditioning treatments and some immunosupressants, and underlies HCT-complications as GVHD. Nevertheless, the specific impact of PTCy on the endothelium remains unclear. We evaluated the effect of mafosfamide (MAF), an active Cy analog, on endothelial cells (ECs) vs. cyclosporine A (CSA), with known damaging endothelial effect. ECs were exposed to MAF and CSA to explore changes in endothelial damage markers: (i) surface VCAM-1, (ii) leukocyte adhesion on ECs, (iii) VE-cadherin expression, (iv) production of VWF, and (v) activation of intracellular signaling proteins (p38MAPK, Akt). Results obtained (expressed in folds vs. controls) indicate that both compounds increased VCAM-1 expression (3.1 ± 0.3 and 2.8 ± 0.6, respectively, p < 0.01), with higher leukocyte adhesion (5.5 ± 0.6, p < 0.05, and 2.8 ± 0.4, respectively). VE-cadherin decreased with MAF (0.8 ± 0.1, p < 0.01), whereas no effect was observed with CSA. Production of VWF augmented with CSA (1.4 ± 0.1, p < 0.01), but diminished with MAF (0.9 ± 0.1, p < 0.05). p38MAPK activation occurred with both compounds, being more intense and faster with CSA. Both drugs activated Akt, with superior MAF effect at longer exposure. Therefore, the cyclophosphamide analog MAF is not exempt from a proinflammatory effect on the endothelium, though without modifying the subendothelial characteristics.
Topics: Humans; Endothelial Cells; Vascular Cell Adhesion Molecule-1; Proto-Oncogene Proteins c-akt; von Willebrand Factor; Graft vs Host Disease; Cyclophosphamide; Cyclosporine; Hematopoietic Stem Cell Transplantation
PubMed: 36639572
DOI: 10.1038/s41409-023-01912-w -
Journal of Neuro-oncology 1998The treatment of childhood brain tumors with cerebrospinal fluid (CSF) dissemination is limited by the relative inaccessibility of the CSF to drugs administered... (Clinical Trial)
Clinical Trial
The treatment of childhood brain tumors with cerebrospinal fluid (CSF) dissemination is limited by the relative inaccessibility of the CSF to drugs administered systemically and the paucity of available agents for intrathecal therapy. Mafosfamide is a cyclophosphamide derivative, which does not require hepatic activation and thus can be utilized for regional therapy. Between May 1994 and December 1996, 16 patients 2 to 19 (median 12) years old with various disseminated brain tumors were treated with intraventricular mafosfamide via an indwelling subcutaneous reservoir. The patients received mafosfamide at a dose of 20 mg once or twice weekly until remission was achieved, followed by weekly administrations as consolidation therapy, and every 3 to 4 weeks thereafter for maintenance therapy. Except for transient headaches, nausea and vomiting during and immediately after mafosfamide administration no toxicities were observed. Nine of the 16 patients were evaluable for response by CSF cytology. Eight had complete responses and one patient did not respond. In addition to mafosfamide all patients received systemic chemotherapy as well. However, 4 of the 8 responding patients had developed CSF dissemination under concurrent systemic therapy and cleared their CSF only after administration of intrathecal mafosfamide. At a median follow-up of 21 months, 7 patients are in complete and 4 in partial remission, 2 have stable disease and 3 died of tumor progression. We conclude that mafosfamide at a dose of 20 mg can be safely administered into the CSF and may produce responses and prolong remission of the leptomeningeal disease.
Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Brain Neoplasms; Cerebellar Neoplasms; Child; Child, Preschool; Cisplatin; Cyclophosphamide; Ependymoma; Etoposide; Female; Glioblastoma; Humans; Ifosfamide; Injections, Spinal; Male; Medulloblastoma; Meningeal Neoplasms; Neuroectodermal Tumors, Primitive
PubMed: 9696374
DOI: 10.1023/a:1005940405165 -
Methods in Molecular Biology (Clifton,... 2019A cell's genomic integrity is at risk when DNA-damaging stress, evoked by mitogenic oncogenes or genotoxic treatment modalities such as radiation or chemotherapy, apply....
A cell's genomic integrity is at risk when DNA-damaging stress, evoked by mitogenic oncogenes or genotoxic treatment modalities such as radiation or chemotherapy, apply. If the DNA repair machinery fails to fix the damaged site during a temporary cell-cycle arrest, or if massive genotoxic stress overwhelmed the repair capacity, cellular failsafe programs such as apoptosis or senescence will be triggered to limit aberrant propagation of these damaged and potentially harmful cells. After decades of scientific focusing on apoptosis, cellular senescence is increasingly recognized as an equally important but biologically and fundamentally different type of ultimate cell-cycle exit program, because of its lastingly persistent nature and cell-intrinsic and extrinsic roles within the tissue and tumor microenvironment. We established primary apoptosis-compromised, Bcl2-expressing Eμ-myc transgenic mouse lymphomas as a versatile and clinically relevant model system to study therapy-induced senescence (TIS). Given the lack of a single specific senescence-defining marker, we previously exploited co-staining of senescence-associated β-galactosidase (SA-β-gal) activity with immunohistochemical detection of trimethylated histone H3 lysine 9 (H3K9me3), an established S-phase gene expression-controlling, repressive chromatin mark, and the proliferation marker Ki67. This biomarker panel is instrumental to characterize cells as senescent via their high SA-β-gal activity, strong nuclear H3K9me3 expression and Ki67-negative profile. In this chapter, we demonstrate the detection of viable senescent cells by novel methods based on a fluorescent version of the SA-β-gal (fSA-β-gal) assay, combined with immuno-fluoroscence staining of H3K9me3 or Ki67, or analysis of the DNA replication status by incorporating 5-ethynyl-2'-deoxyuridine (EdU) detection into the protocol. Notably, while most senescence markers, irrespective of their specificity and sensitivity, may only be assessed in endpoint assays, we would like to emphasize here the strength of viable fSA-β-gal to track single-cell fate in senescent populations over time.
Topics: Animals; Apoptosis; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cellular Senescence; Cyclophosphamide; DNA Damage; Fluorescence; Humans; Lymphoma; Mice; Mice, Transgenic; beta-Galactosidase
PubMed: 30474843
DOI: 10.1007/978-1-4939-8931-7_10 -
Anticancer Research Mar 2021Breast cancer (BC) may be affected by diabetes and anti-diabetic medication, as well as its therapeutic agents. Low-dose metronomic chemotherapy (LDMC) is an available...
BACKGROUND/AIM
Breast cancer (BC) may be affected by diabetes and anti-diabetic medication, as well as its therapeutic agents. Low-dose metronomic chemotherapy (LDMC) is an available treatment option in BC. We investigated the impact of insulin on low-dose metronomic vinorelbine and mafosfamide in BC cell lines.
MATERIALS AND METHODS
Human BC cell lines T-47D, MCF-7, MDA-MB-231, BT-549 and non-tumorigenic breast cell line MCF-10A were exposed to 0.01 μg/ml and 10 μg/ml insulin in combination with low-dose metronomic vinorelbine or mafosfamide. The cell viability was determined after 24-72 hours using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.
RESULTS
Insulin, especially at a concentration of 10 μg/ml, seemed to increase viability of vinorelbine-treated hormone receptor-positive BC cells, whereas low-dose mafosfamide treatment tended to be potentiated by insulin in triple-negative cells.
CONCLUSION
Our findings suggest that insulin may influence the cytotoxic activity of LDMC depending on insulin concentration, type of cytotoxic drug used and BC cell line.
Topics: Administration, Metronomic; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Cyclophosphamide; Female; Humans; Insulin; Vinorelbine
PubMed: 33788715
DOI: 10.21873/anticanres.14881 -
Blut Nov 1989Autologous bone marrow transplantation (ABMT) is increasingly used to consolidate remissions, primarily in hematological disease. Various purging strategies have been... (Review)
Review
Autologous bone marrow transplantation (ABMT) is increasingly used to consolidate remissions, primarily in hematological disease. Various purging strategies have been developed to minimize the risk of reimplantation of tumor cells with the bone marrow autotransplant. Pharmacological purging with the oxazaphosphorine derivative mafosfamide has been studied extensively, and recent clinical data suggest that purging with mafosfamide may translate into superior remission duration if compared to nonpurged ABMT in acute leukemia. Chemical and experimental data relevant to mafosfamide-purging and clinical results are reviewed, with special emphasis on safety aspects.
Topics: Animals; Bone Marrow; Bone Marrow Transplantation; Chemical Phenomena; Chemistry; Colony-Forming Units Assay; Combined Modality Therapy; Cyclophosphamide; Humans; Hydrolysis; Leukemia; Mice
PubMed: 2684298
DOI: 10.1007/BF00349064 -
Journal of Clinical Oncology : Official... Oct 2005
Topics: Antineoplastic Agents; Cyclophosphamide; Humans; Injections, Spinal; Meningeal Neoplasms; Meningitis; Treatment Outcome
PubMed: 16234539
DOI: 10.1200/JCO.2005.02.8373 -
Immunopharmacology Jun 1995Cyclophosphamide, an alkylating agent belonging to the family of nitrogen mustards, is commonly used to treat progressive autoimmune diseases in humans. At the molecular...
Cyclophosphamide, an alkylating agent belonging to the family of nitrogen mustards, is commonly used to treat progressive autoimmune diseases in humans. At the molecular level, its cytotoxicity results from DNA double strand crosslinks and, at higher concentrations, from DNA strand breaks. At the cellular level, cyclophosphamide may selectively affect mature lymphocytes with relative sparing of the respective precursor cells. In this study, we show that 4-hydroxycyclophosphamide (4-OH-CP), the active metabolite of cyclophosphamide, induces apoptosis in mature human lymphocytes at concentrations that are achieved in vivo. Since cyclophosphamide requires enzymatic conversion in the liver to yield its active metabolite, 4-OH-CP was generated in vitro by non-enzymatic hydrolysis of mafosfamide. Apoptotic cell death of lymphocytes was characterized by typical morphological changes, nucleosomal DNA fragmentation, and quantified by 3'-OH end labeling of fragmented DNA. The percentage of apoptotic cells both depended on drug concentration and time of exposure. Cycloheximide or ZnSO4 did not suppress 4-OH-CP induced apoptosis. Etoposide, a topoisomerase II inhibitor known to induce apoptosis in human tumor cell lines like 4-OH-CP, did induce detectable DNA fragmentation in only a minor proportion of T-lymphocytes but suppressed T-cell proliferation.
Topics: Adult; Alkylation; Apoptosis; Cycloheximide; Cyclophosphamide; DNA Damage; DNA Nucleotidyltransferases; Electrophoresis, Polyacrylamide Gel; Growth Inhibitors; Humans; Immunosuppressive Agents; Lymphocyte Activation; Male; Sulfates; T-Lymphocytes; Zinc Compounds; Zinc Sulfate
PubMed: 7591714
DOI: 10.1016/0162-3109(95)00005-e -
Pediatric Blood & Cancer Apr 2008A major barrier to treatment of leptomeningeal disease is the lack of proven combination chemotherapy regimens for intrathecal administration. The purpose of this study...
BACKGROUND
A major barrier to treatment of leptomeningeal disease is the lack of proven combination chemotherapy regimens for intrathecal administration. The purpose of this study was to determine the cytotoxic effects of karenitecin and mafosfamide in vitro against leukemia, medulloblastoma, and neuroblastoma cell lines.
PROCEDURE
A modified methyl tetrazolium (MTT) assay was used to determine the sensitivity of the cells to karenitecin and mafosfamide. Cells were exposed to drug for 72 hr, after which the number of surviving cells was quantitated. For drug combination experiments, cells were exposed to medium alone (controls), single drugs alone (mafosfamide only, karenitecin only) or to different concentrations of the combination of the two drugs (karenitecin + mafosfamide), for a total of 36 concentration pairs per plate. The universal response surface approach (URSA) was used to analyze the cytotoxic effects of the combination of karenitecin and mafosfamide.
RESULTS
The IC(50)s of karenitecin and mafosfamide for the various cell lines were similar. For both drugs nearly complete inhibition of cell growth was demonstrated at higher concentrations in all cell lines. In the neuroblastoma cell lines (SK-N-DZ; SK-N-SH) and the DAOY medulloblastoma cell line, the combination of karenitecin and mafosfamide were synergistic. In the D283 medulloblastoma and both the leukemia cell lines (JM1 and Molt-4), the drug interaction was additive. Antagonism was not seen in any cell line.
CONCLUSIONS
Karenitecin and mafosfamide are additive or synergistic in vitro against tumor types that disseminate to the leptomeninges. These results provide guidance for the choice of potential combination intrathecal regimens.
Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cell Line, Tumor; Child; Cyclophosphamide; Drug Synergism; Humans; Leukemia; Medulloblastoma; Neuroblastoma
PubMed: 17849472
DOI: 10.1002/pbc.21330