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Pediatric Hematology and Oncology 2005A large number of patients affected by acute myeloid leukemia (AML) achieve complete remission following induction chemotherapy based on high-dose aracytin and...
A large number of patients affected by acute myeloid leukemia (AML) achieve complete remission following induction chemotherapy based on high-dose aracytin and anthracyclines. However, a postremission consolidation treatment appears to be essential to maintain the remission status. Sixteen patients with newly diagnosed AML received induction chemotherapy according to the AIEOP LAM 92P/Mod protocol. All patients were HLA-typed, and if no donor was identified within the family, patients underwent autologous stem cell transplantation (autoSCT) with mafosfamide-purged bone marrow. Patients with very high-risk AML (cytogenetics with t(9;22), hyperleukocytosis (540x10(9)/L), and AML-M7 with trilineage myelodysplasia) underwent unrelated donor transplantation. One patient relapsed before autoSCT. Eleven patients underwent autoSCT with purged bone marrow, 3 patients underwent unrelated donor transplantation (UD), and 1 patient underwent HLA-identical, matched familiar donor transplantation (MFD). All patients achieved complete remission following one course. No treatment-related deaths occurred during first-line treatment. The median interval between diagnosis and transplant was 175 days (129-277). Three patients relapsed following autoSCT; none relapsed after alloSCT. Taking stem cell transplantation as the starting point, overall survival was 93%, disease-free survival (according to the chosen treatment) was 80%, the relapse rate was 20%, and transplant-related mortality was 0%.
Topics: Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Child; Child, Preschool; Cytarabine; Disease-Free Survival; Etoposide; Female; Humans; Idarubicin; Infant; Leukemia, Myeloid, Acute; Male; Recurrence; Remission Induction; Retrospective Studies; Stem Cell Transplantation; Transplantation, Autologous; Transplantation, Homologous
PubMed: 16166053
DOI: 10.1080/08880010500198871 -
Drug Resistance Updates : Reviews and... Oct 2005The oxazaphosphorines cyclophosphamide, ifosfamide and trofosfamide remain a clinically useful class of anticancer drugs with substantial antitumour activity against a... (Review)
Review
The oxazaphosphorines cyclophosphamide, ifosfamide and trofosfamide remain a clinically useful class of anticancer drugs with substantial antitumour activity against a variety of solid tumors and hematological malignancies. A major limitation to their use is tumour resistance, which is due to multiple mechanisms that include increased DNA repair, increased cellular thiol levels, glutathione S-transferase and aldehyde dehydrogenase activities, and altered cell-death response to DNA damage. These mechanisms have been recently re-examined with the aid of sensitive analytical techniques, high-throughput proteomic and genomic approaches, and powerful pharmacogenetic tools. Oxazaphosphorine resistance, together with dose-limiting toxicity (mainly neutropenia and neurotoxicity), significantly hinders chemotherapy in patients, and hence, there is compelling need to find ways to overcome it. Four major approaches are currently being explored in preclinical models, some also in patients: combination with agents that modulate cellular response and disposition of oxazaphosphorines; antisense oligonucleotides directed against specific target genes; introduction of an activating gene (CYP3A4) into tumor tissue; and modification of dosing regimens. Of these approaches, antisense oligonucleotides and gene therapy are perhaps more speculative, requiring detailed safety and efficacy studies in preclinical models and in patients. A fifth approach is the design of novel oxazaphosphorines that have favourable pharmacokinetic and pharmacodynamic properties and are less vulnerable to resistance. Oxazaphosphorines not requiring hepatic CYP-mediated activation (for example, NSC 613060 and mafosfamide) or having additional targets (for example, glufosfamide that also targets glucose transport) have been synthesized and are being evaluated for safety and efficacy. Characterization of the molecular targets associated with oxazaphosphorine resistance may lead to a deeper understanding of the factors critical to the optimal use of these agents in chemotherapy and may allow the development of strategies to overcome resistance.
Topics: Animals; Antineoplastic Agents, Alkylating; DNA Damage; DNA Repair; Drug Resistance, Neoplasm; Humans; Neoplasms; Phosphoramide Mustards
PubMed: 16154799
DOI: 10.1016/j.drup.2005.08.003 -
BMC Cancer Aug 2005A common sequence polymorphism at codon 72 of the p53 gene encoding either arginine or proline was recently shown to be functionally relevant for apoptosis induction in...
BACKGROUND
A common sequence polymorphism at codon 72 of the p53 gene encoding either arginine or proline was recently shown to be functionally relevant for apoptosis induction in vitro. In B-type chronic lymphocytic leukemia (B-CLL), p53 gene mutations occur in a subset of patients and are associated with impaired survival and drug resistance. Here, we address the functional relevance of the codon 72 single nucleotide (SNP) polymorphism for cell death sensitivity following exposure to clinically employed cytotoxic drugs and gamma-irradiation.
METHODS
138 B-CLL samples were analysed by SSCP-PCR and sequencing for single nucleotide polymorphism at codon 72 of the p53 gene. The in vitro cytotoxicity assay (DiSC-assay) was performed with 7 drugs (chlorambucil, mafosfamide, fludarabine phosphate, methylprednisolone, doxorubicin, vincristine) or gamma-irradiation.
RESULTS
Of the 138 B-CLL samples, 9 samples were homozygous for proline (Pro/Pro), 78 samples homozygous for arginine (Arg/Arg), and 49 samples heterozygous (Arg/Pro). No differences were found for patient survival and cell death triggered by 7 cytotoxic drugs or gamma-irradiation.
CONCLUSION
These data indicate that polymorphic variants of p53 codon 72 are not clinically relevant for apoptosis induction or patient survival in B-CLL.
Topics: Aged; Antineoplastic Agents; Apoptosis; Arginine; Chlorambucil; Codon; Cyclophosphamide; DNA Mutational Analysis; Doxorubicin; Drug Resistance, Neoplasm; Female; Gamma Rays; Gene Expression Regulation, Neoplastic; Genes, p53; Homozygote; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Methylprednisolone; Middle Aged; Mutation; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Polymorphism, Single-Stranded Conformational; Prognosis; Proline; Vidarabine Phosphate; Vincristine
PubMed: 16109171
DOI: 10.1186/1471-2407-5-105 -
Methods and Findings in Experimental... May 2005Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from...
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 3-AP, Adalimumab, adefovir dipivoxil, AeroDose albuterol inhaler, agalsidase alfa, alemtuzumab, aminolevulinic acid methyl ester, anidulafungin, anthrax vaccine, anti-CTLA-4 MAb, azimilide hydrochloride; Bevacizumab, BG-12, bimatoprost, bortezomib, bosentan, botulinum toxin type B; Caspofungin acetate, ceftobiprole, certolizumab pegol, CG-53135, cilansetron; Darbepoetin alfa, degarelix acetate, dimethylfumarate, duloxetine hydrochloride, dutasteride; Eicosapentaenoic acid/docosahexaenoic acid, eletriptan, entecavir, esomeprazole magnesium, exatecan mesilate, exenatide, ezetimibe; Falecalcitriol, fampridine, fondaparinux sodium, fontolizumab; Gefitinib, gepirone hydrochloride; Human insulin; IDEA-070, imatinib mesylate, iodine (I131) tositumomab; Lanthanum carbonate, lubiprostone; Mafosfamide cyclohexylamine salt, melatonin; NC-531, nemifitide ditriflutate, neridronic acid, nolatrexed dihydrochloride; Oral insulin; Palifermin, parecoxib sodium, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, plerixafor hydrochloride, posaconazole, pramlintide acetate, pregabalin, PT-141; Quercetin; Ranibizumab, renzapride hydrochloride, RSD-1235; Sabarubicin hydrochloride, semapimod hydrochloride, Semax, SHL-749; Tegaserod maleate, tenatoprazole, tetrodotoxin, tolevamer sodium, trabectedin, travoprost, travoprost/timolol; Valdecoxib, visilizumab, Xcellerated T cells, XP-828L; Zoledronic acid monohydrate.
Topics: Clinical Trials as Topic; Humans
PubMed: 16082427
DOI: No ID Found -
Klinische Padiatrie 2005Supratentorial primitive neuroectodermal tumors (stPNETs) are malignant tumors. We saw within three years six children with stPNETs. In four of the six children radical... (Comparative Study)
Comparative Study
Supratentorial primitive neuroectodermal tumors (stPNETs) are malignant tumors. We saw within three years six children with stPNETs. In four of the six children radical resection could be achieved. All had craniospinal irradiation and chemotherapy according to the HIT-91 protocol. The two children with incomplete resection died due to tumor progression after 7 and 10 months. Two of the 4 children with complete tumor resection had local relapses 8 months after diagnosis and died after 14 and 18 months. One child had a diffuse meningeal relapse 12 months after diagnosis. Despite (high-dose) systemic chemotherapy and intraventricular mafosfamide, he died 21 months after diagnosis due to tumor although remission could be achieved. Only one child is still in remission 86 months after diagnosis.
Topics: Brain Neoplasms; Brain Stem Neoplasms; Cerebellar Neoplasms; Cerebellar Nuclei; Child; Child, Preschool; Combined Modality Therapy; Corpus Callosum; Disease Progression; Frontal Lobe; Humans; Male; Mesencephalon; Neoplasm Recurrence, Local; Neuroectodermal Tumors; Occipital Lobe; Parietal Lobe; Prognosis; Remission Induction; Temporal Lobe; Thalamus; Time Factors
PubMed: 15858707
DOI: 10.1055/s-2005-836505 -
Journal of Clinical Oncology : Official... Mar 2005Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for... (Clinical Trial)
Clinical Trial
PURPOSE
Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials.
PATIENTS AND METHODS
In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs.
RESULTS
The cytotoxic target exposure for mafosfamide was 10 micromol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 micromol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease.
CONCLUSION
The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.
Topics: Animals; Antineoplastic Agents; Child, Preschool; Cyclophosphamide; Feasibility Studies; Humans; Injections, Spinal; Macaca mulatta; Meningeal Neoplasms; Meningitis; Neoplasms; Treatment Outcome
PubMed: 15735131
DOI: 10.1200/JCO.2005.06.053 -
Experimental Hematology Feb 2005Studies of memory T cells transferred with the graft are relevant to better understand the early immune reconstitution of patients given autologous bone marrow...
Bone marrow-resident memory T cells survive pretransplant chemotherapy and contribute to early immune reconstitution of patients with acute myeloid leukemia given mafosfamide-purged autologous bone marrow transplantation.
OBJECTIVE
Studies of memory T cells transferred with the graft are relevant to better understand the early immune reconstitution of patients given autologous bone marrow transplantation (A-BMT). A critical question is whether memory T cells resident in bone marrow (BM) of patients with hematological malignancies are resistant to either pretransplant chemotherapy or ex vivo pharmacological purging.
PATIENTS AND METHODS
To address these issues, we evaluated the frequency of tetanus-toxoid (TT)-specific proliferating T-cell precursors (TT-PTCp) in BM and peripheral blood (PB) of eight patients with acute myeloid leukemia (AML) given A-BMT after in vitro purging of BM with mafosfamide. Patients were studied at the time of BM harvesting and five of them also after A-BMT.
RESULTS
The range of TT-PTCp frequencies found after A-BMT were comparable with those observed in PB and in BM at the time of harvesting and did not differ significantly from those of eight age-matched healthy subjects who donated BM for a human leukocyte antigen-identical sibling. TT-PTCp frequencies in BM, studied before and after ex vivo purging, appeared not to be affected by incubation with mafosfamide. We also compared the T-cell receptor (TCR)-Vbeta-repertoire usage of TT-specific T-cell lines (TT-TCL) in BM of patients at the time of harvesting and in their PB 2 months after transplantation. The same TCR-clonotypes were detected in TT-TCL at time of harvesting and after A-BMT.
CONCLUSION
These data indicate that BM-resident memory T cells of patients with AML are resistant to both pretransplant chemotherapy and ex vivo pharmacological purging and may contribute to immune reconstitution after A-BMT.
Topics: Adjuvants, Immunologic; Adolescent; Bone Marrow; Bone Marrow Purging; Bone Marrow Transplantation; Child; Cyclophosphamide; Female; Humans; Immunologic Memory; Male; T-Lymphocytes; Transplantation, Autologous
PubMed: 15676215
DOI: 10.1016/j.exphem.2004.10.008 -
Journal of Clinical Oncology : Official... Jan 2005A phase I trial of intrathecal (IT) mafosfamide was performed to determine the optimal dose, dose-limiting toxicities, and incidence and severity of other toxicities... (Clinical Trial)
Clinical Trial
Phase I clinical trial of mafosfamide in infants and children aged 3 years or younger with newly diagnosed embryonal tumors: a pediatric brain tumor consortium study (PBTC-001).
PURPOSE
A phase I trial of intrathecal (IT) mafosfamide was performed to determine the optimal dose, dose-limiting toxicities, and incidence and severity of other toxicities when administered in association with concomitant multiagent systemic chemotherapy to children younger than 3 years with newly diagnosed embryonal tumors.
PATIENTS AND METHODS
Twenty-five assessable patients received IT mafosfamide at one of six dose levels ranging from 5 mg to 17 mg. Patients were premedicated with dexamethasone (0.15 mg/kg) and morphine (0.1 mg/kg) before receiving IT mafosfamide. Serial samples of CSF for pharmacokinetic studies were obtained in a subset of patients with Ommaya reservoirs.
RESULTS
Irritability, presumably secondary to pain or headache during mafosfamide administration, was dose limiting in two of three patients at the 17-mg dose level. The maximum-tolerated dose of IT mafosfamide following premedication with dexamethasone and morphine was 14 mg.
CONCLUSION
The maximum tolerated dose and recommended phase II dose of IT mafosfamide in patients younger than 3 years with newly diagnosed embryonal CNS tumors is 14 mg. A trial to assess the efficacy of regional therapy with IT mafosfamide administered with intensive systemic chemotherapy in children younger than 3 years with primary intracranial embryonal tumors is now in progress.
Topics: Affect; Age Factors; Analgesics, Opioid; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Child, Preschool; Cyclophosphamide; Dexamethasone; Female; Glucocorticoids; Headache; Humans; Infant; Injections, Spinal; Male; Maximum Tolerated Dose; Morphine; Neoplasms, Germ Cell and Embryonal; Pain
PubMed: 15659498
DOI: 10.1200/JCO.2005.06.544 -
Clinical Pharmacokinetics 2005Intraventricular administration of chemotherapy is one approach to overcoming the limited distribution of anticancer drugs and their active metabolites into the CNS.... (Review)
Review
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 x 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).
Topics: Adolescent; Adult; Animals; Antineoplastic Agents; Cerebrospinal Fluid; Child; Drug Administration Schedule; Humans; Infusion Pumps, Implantable; Injections, Intraventricular; Injections, Spinal; Meningeal Neoplasms; Metabolic Clearance Rate
PubMed: 15634030
DOI: 10.2165/00003088-200544010-00001 -
European Journal of Gynaecological... 2004The endogenous estradiol metabolite, 2-methoxyestradiol (2ME), has been shown to be a potent inhibitor of cell growth and a strong anti-angiogenic substance. We...
PURPOSE OF INVESTIGATION
The endogenous estradiol metabolite, 2-methoxyestradiol (2ME), has been shown to be a potent inhibitor of cell growth and a strong anti-angiogenic substance. We investigated for the first time whether in vitro combinations of 2ME with various chemotherapeutic compounds may result in an additive inhibitory effect on the proliferation of human ovary cancer cells.
METHOD
As a model two different human ovary cancer cell lines were used. All cell lines were incubated with equimolar concentrations of 2ME (0.8-25 microM) and the chemotherapeutics epirubicine, doxorubicine, paclitaxel, docetaxel, carboplatin, vinorelbine, 5-fluorouracil and mafosfamide. Proliferation was measured after four days using the ATP-chemosensitivity test.
RESULTS
For both ovary cancer cell lines a significant additive effect of 2ME with epirubicine and carboplatin was observed at the lower concentration range of these chemotherapeutic substances.
CONCLUSION
2ME is able to enhance the antiproliferative activity of certain chemotherapeutics at pharmacological relevant concentrations. This estradiol metabolite is currently in a phase II trial in patients with refractary metastatic breast cancer and the tolerability has been shown to be very good. The combination of 2ME with chemotherapeutics may therefore offer a new clinically relevant treatment regimen for hormone-dependent cancer.
Topics: 2-Methoxyestradiol; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cell Line, Tumor; Cell Proliferation; Cyclophosphamide; Docetaxel; Dose-Response Relationship, Drug; Doxorubicin; Drug Administration Schedule; Epirubicin; Estradiol; Female; Fluorouracil; Humans; Ovarian Neoplasms; Paclitaxel; Taxoids; Vinblastine; Vinorelbine
PubMed: 15597845
DOI: No ID Found