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Chronic lymphocytic leukemia (CLL) is a heterogenous disease with an imbalance between apoptosis and cell proliferation. Therefore, the main goal in CLL therapy is to induce apoptosis and effectively support this process in transformed B lymphocytes. In the current study, we have compared differential scanning calorimetry (DSC) profiles of nuclei isolated from CLL cells and normal mononuclear cells exposed to cladribine or fludarabine combined with mafosfamide (CM; FM), and additionally to CM combined with monoclonal antibody-rituximab (RCM) for 48 h, as well as in culture medium only (controls). Under current study, the mononuclear cells from peripheral blood (PBMCs) of healthy individuals have been included. The obtained results have shown the presence of thermal transition at 95 ± 5 °C in most of nuclear preparations (92.2 %) isolated from blood of CLL patients. This thermal characteristic parameter was changed after drug exposure, however, to a different extent. These thermal changes were accompanied by the decrease of cell viability, an elevation of apoptosis rate and the changes in expression/proteolysis of poly(ADP-ribose)polymerase-1-main marker of apoptosis. Importantly, in DSC profiles of nuclear preparations of PBMCs from blood of healthy donors exposed to investigated drug combinations and control CLL cells, the lack of such changes was observed. Our results confirmed that DSC technique complemented with other biological approaches could be helpful in tailoring therapy for CLL patients. [ABSTRACT FROM AUTHOR]

A pilot study to investigate the feasibility of the addition of intrathecal (IT) mafosfamide to a regimen of concomitant multi-agent systemic chemotherapy followed by conformal radiation therapy (RT) for children <3 years with newly diagnosed embryonal CNS tumors was performed. Ninety-three newly diagnosed infants and children (<3 years) with embryonal CNS tumors were enrolled. Twenty weeks of systemic multi-agent chemotherapy commenced within 35 days of surgery. Patients without CSF flow obstruction (n = 71) received IT mafosfamide (14 mg) with chemotherapy. Localized (M) patients with SD or better subsequently received RT followed by 20 additional weeks of chemotherapy. Second look surgery was encouraged prior to RT if there was an incomplete surgical resection at diagnosis. 71 evaluable patients with normal CSF flow received IT Mafosfamide with systemic chemotherapy; patients with M + disease were removed from protocol therapy at 20 weeks and those with PD at the time of progression. One and 5-year progression free survival (PFS) and overall survival (OS) for the cohort of 71 evaluable patients were 52 ± 6.5 % and 33 ± 13 %, and 67 ± 6.2 % and 51 ± 11 %, respectively. The 1-year Progression Free Survival (PFS) for M0 patients with medulloblastoma (MB, n = 20), supratentorial primitive neuroectodermal tumor (PNET, n = 9), and atypical teratoid rhabdoid tumor (ATRT, n = 12) was 80 ± 7 %, 67 ± 15 % and 27 ± 13 % and 5-year PFS was 65 ± 19 %, 37 ± 29 %, and 0 ± 0 %, respectively. The addition of IT mafosfamide to systemic chemotherapy in infants with embryonal CNS tumors was feasible. The PFS for M0 patients appears comparable to or better than most prior historical comparisons and was excellent for those receiving conformal radiotherapy. [ABSTRACT FROM AUTHOR]

Imatinib-refractory chronic myelogenous leukemia (CML) patients can experience long-term disease-free survival with myeloablative therapy and allogeneic hematopoietic cell transplantation; however, associated complications carry a significant risk of mortality. Transplantation of autologous hematopoietic cells has a reduced risk of complications, but residual tumor cells in the autograft may contribute to relapse. Development of methods for purging tumor cells that do not compromise the engraftment potential of the normal hematopoietic cells in the autograft has been a long-standing goal. Since primitive CML cells differentiate more rapidly in vitro than their normal counterparts and are also preferentially killed by mafosfamide and imatinib, we examined the purging effectiveness on CD34+ CML cells using a strategy that combines a brief exposure to imatinib (0.5–1.0 μM for 72 h) and then mafosfamide (30–90 μg/ml for 30 min) followed by 2 weeks in culture with cytokines (100 ng/ml each of stem cell factor, granulocyte colony-stimulating factor and thrombopoietin). Treatment with 1.0 μM imatinib, 60 μg/ml mafosfamide and 14 days of culture with cytokines eliminated BCR-ABL+ cells from chronic phase CML patient aphereses, while preserving normal progenitors. This novel purging strategy may offer a new approach to improving the effectiveness of autologous transplantation in imatinib-refractory CML patients.Bone Marrow Transplantation (2006) 37, 575–582. doi:10.1038/sj.bmt.1705284; published online 23 January 2006 [ABSTRACT FROM AUTHOR]

Intraventricular administration of chemotherapy is one approach to overcoming the limited distribution of anticancer drugs and their active metabolites into the CNS. This form of regional chemotherapy has led to effective treatment of occult and overt meningeal leukaemia in humans. In contrast, the efficacy of this therapy is extremely limited in the treatment of leptomeningeal dissemination of various solid tumours. Pharmacokinetic studies of the commonly intraventricularly applied anticancer agents in humans have demonstrated that, using low drug doses, very high drug concentrations can be achieved in the cerebrospinal fluid (CSF) and relatively high concentrations in the leptomeninges but not in the brain tissue and the plasma. Therefore, this approach is not an effective treatment for bulky disease of brain tissue, and results in minimal systemic toxicity. In comparison with intralumbar administration, lower interpatient variability of CSF drug concentrations and improved clinical efficacy were observed. ‘Concentration × time’ schedules, i.e. frequent small drug doses over a short period, enable long-term CSF exposure to cytotoxic drug concentrations while avoiding excessively high and potentially neurotoxic drug concentrations. The technique of ventriculolumbar cerebrospinal perfusion delivers continuously high drug concentrations throughout the CSF for several hours, but its widespread use is limited by the technical complexities of this approach. In this article, the dosages, schedules and pharmacokinetic data of routinely used intraventricular agents in humans, e.g. methotrexate, cytarabine, glucocorticoids and thiotepa, are outlined in detail. In addition, pharmacokinetic data of investigational agents for intraventricular administration (diaziquone, DTC 101, mercaptopurine, mafosfamide, etoposide, topotecan, nimustine [ACNU] and bleomycin) are presented. Better understanding of the CSF pharmacology of these drugs is an essential prerequisite for safe, effective administration of these drugs. Investigational efforts are underway to verify the feasibility and efficacy of different dosages, schedules and combination therapies of these new intra-CSF agents. Current and future clinical research should also focus on methods allowing the delivery of tumoricidal drug concentrations for extended periods into the CSF and the brain tissue while minimising neurotoxicity and systemic toxicity (e.g. liposomal drug preparations, monoclonal antibodies, immunotoxins and gene therapy). [ABSTRACT FROM AUTHOR]

Neoplastic meningitis is an increasingly recognized complication of advanced metastatic cancer and, if left undiagnosed or untreated, is characterized by rapid neurologic deterioration and death. Thus, the diagnosis and treatment of neoplastic meningitis present challenges for the clinical oncologist. The diagnosis of neoplastic meningitis is based on clinical signs and symptoms, laboratory analysis of cerebrospinal fluid to determine cell count and cytology, and analysis of neuroimaging studies for evidence of leptomeningeal or cranial nerve enhancement. Once diagnosed, conventional treatment regimens may include radiotherapy combined with systemic or intrathecal chemotherapy, often with the antimetabolites cytarabine and/or methotrexate. However, the prognosis for neoplastic meningitis secondary to an underlying solid tumor or recurrent leukemia is poor with conventional treatment regimens. Therefore, novel agents for intrathecal administration, including DepoCyttrade mark, mafosfamide, and topotecan, or novel therapeutic approaches, including conjugated monoclonal antibodies and immunotoxins or gene therapy, are currently under investigation. Such new agents and therapeutic approaches will facilitate the development of effective treatment strategies and will ultimately improve the outcome for patients with this devastating disease. This article provides an overview of the approaches to the diagnosis, evaluation, and treatment of neoplastic meningitis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mafosfamide (Mafo) is an analog of cyclophosphamide that does not require hepatic activation and therefore has in vitro activity. The present study was conducted to determine the effects of in vitro treatment with Mafo on the generation and growth of cytotoxic T lymphocytes (CTL) from tumor-bearing host mice (TBH). In contrast to early (day-11) TBH splenocytes, splenocytes from late (days 18-20) P815 TBH mice suppress the in vitro generation of CTL. Treatment of late TBH splenocytes in vitro with 5-15 µM Mafo resulted in a reduced ability of these cells to suppress in vitro CTL generation. Treatment of late TBH splenocytes with 10 µM Mafo also inhibited their ability to suppress adoptive immunotherapy of intradermal tumors with immune splenocytes. These doses of Mafo were selectively toxic to the suppressive effects of late TBH splenocytes, since treatment of early TBH splenocytes with 1-10 µM Mafo did not significantly inhibit CTL generation. Spleen cells from early (days 10-12) TBH mice, carried in long-term in vitro sensitization cultures in the presence of tumor cells and 20 U/ml human recombinant interleukin-2, did not increase in cell number over time. However, when pretreated with 3 µM Mafo, this population of tumor-sensitized lymphocytes demonstrated 450-fold growth over 6 weeks as compared to the static cell numbers for the untreated controls. High levels of tumor-specific cytolytic activity were maintained in these expanded cells. These results suggest that Mafo pretreatment markedly and selectively inhibits suppressor cells that limit long-term expansion of splenic CTL in culture and inhibit adoptive immunotherapy of solid tumors. [ABSTRACT FROM AUTHOR]

Background : Determinants of cellular sensitivity to anticancer drugs include enzymes that catalyze their biotransformation. Coordinated induction of some of these enzymes is known to be caused by a number of dietary constituents, environmental contaminants, phar macological agents and other xenobiotics, e.g. 3-methylcholanthrene and catechol. Despite the potential for inducing simultaneous changes in tumor cell sensitivity to a wide range of drugs, scant attention has been paid to the impact that dietary constituents and other xenobiotics might have on the therapeutic outcome of cancer chemotherapy. Purpose: The aim of this investigation was to demonstrate the potential of xenobiotic-induced multienzyme-mediated stable and transient multidrug resistance/collateral sensitivity in a model system. Methods: Human breast adenocarcinoma MCF-7/0 cells and a stably oxazaphosphorine-resistant subline thereof, MCF-7/OAP, were grown in the presence of 3-methylcholanthrene (3 μ M ), catechol (30 μ M ), or vehicle for 5 days. Spectrophotometric and spectrofluorometric assays were used to quantify catalytic activities and thus cellular levels of cytosolic class 3 aldehyde dehydrogenase, glutathione S-transferase, DT-diaphorase, UDP-glucuronosyl transferase and cytochrome P450 1A1. A colony-forming assay was used to quantify cellular sensitivities to several anticancer drugs. Results: Relative to their untreated counterparts, MCF-7/0 and MCF-7/OAP cells treated with 3-methylcholanthrene or catechol transiently expressed elevated levels of cytosolic class 3 aldehyde dehydrogenase, glutathione S-transferase, DT-diaphorase and UDP-glucuronosyl transferase, and were transiently, more resistant to mafosfamide, melphalan, and mitoxantrone, and more sensitive to EO9. Further, MCF-7/0 and MCF-7/OAP cells treated with 3-methylcholanthrene, but not those treated with catechol, transiently expressed elevated levels of cytochrome P450 1A1 and were transiently more sensitive to ellipticine. Relative to MCF-7/0 cells, MCF-7/OAP cells stably overexpressed all but cytochrome P450 1A1 and were stably, more resistant to mafosfamide, melphalan and mitoxantrone, and more sensitive to EO9. Inclusion of relatively specific inhibitors of, or alternative substrates for, the enzymes of interest during drug exposure negated the influence of enzyme overexpression on cellular sensitivities to these agents. Untreated, and 3-methylcholanthrene- or catechol-treated, MCF-7/0 and MCF-7/OAP cells were equisensitive to vincristine and nearly so to doxorubicin. Conclusions: Collectively, these experiments illustrate the potential for both stable and transient xenobiotic-induced multienzyme-mediated multidrug resistance/collateral sensitivity that, although also the result of a single event, is mechanistically different from, and pertains to a largely different group of anticancer agents than does, the multidrug resistance caused by cell surface multidrug transporters. [ABSTRACT FROM AUTHOR]

The present studies showed that nude mice xenotransplanted with L5222 leukemia responded as did syngeneic BD IX rats to low doses of mafosfamide or cyclophosphamide. Unlike rats, nude mice rarely showed resistance to a second tumor challenge. The observation that concurrent treatment of rats with cyclosporin A did not alter the rate of survival clearly indicated a T-cell-independent mechanism of tumor defense. The incidence of lung colonies from i. v. injected Lewis lung-tumor cells could be enhanced by a high-dose pretreatment with mafosfamide or cyclophosphamide, whereas pretreatment at low doses was inhibitory. Since identical experiments carried out in NK-cell-deficient C57Bl/6 'beige' mice did not show such an effect, NK cells appeared to represent a possible effector cell in oxazaphosphorine-mediated antitumor effects. This assumption was further supported by the fact that enhanced NK cell activity could be observed in the Cr release assay using spleen cells from mafosfamide-treated L5222-bearing rats. The transplantation of the unrelated syngeneic ovarian carcinoma OV-342 to animals that had previously been cured of L5222 leukemia did not lead to the rejection of this tumor. This indicates that a specific resistance against L5222 leukemia had developed. In contrast, a T-cell-dependent antitumor effect was demonstrated for mafosfamide in the MOPC-315 mouse plasmocytoma. Therefore, we conclude that the effector cell for tumor rejection depends on the type of tumor. This, of course, does not exclude a common target cell for the immunopharmacological activity of oxazaphosphorines. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Three phase I/II trials were performed in patients with metastatic colorectal cancer using immunochemotherapy - a combination of recombinant interferon β und γ with low doses of cytostatic drugs. The third regimen, consisting of a cytostatic component containing 5-fluorouracil plus carboplatin plus mitomycin C besides the interferons, produced a high remission rate of 47%: 14/30 patients responded. The tolerability of this protocol was good and it could be administered on an out-patient basis. [ABSTRACT FROM AUTHOR]