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Leukemia & Lymphoma Sep 2007A 31-year-old patient developed chronic myelogenous leukemia (CML) in November, 1983. In November 1984, following a diagnosis of acceleration, he received an autologous...
Simultaneous regression of Philadelphia chromosome and multiple nonrecurrent clonal chromosomal abnormalities with imatinib mesylate in a patient autografted 22 years before for chronic myelogenous leukemia.
A 31-year-old patient developed chronic myelogenous leukemia (CML) in November, 1983. In November 1984, following a diagnosis of acceleration, he received an autologous hemopoietic transplant after conditioning with cyclophosphamide and total body irradiation. The autologous marrow was purged with mafosfamide. Over 20 years, the patient remained in chronic phase of CML. Multiple nonrecurrent clonal chromosomal abnormalities appeared leading to a very complex karyotype, including among others involvement of chromosomes 1, 7, 9, 13, 19, and X. Fluorescent in situ hybridization showed that the two chromosomes 9 were involved. Acute myeloid crisis was diagnosed in February, 2004. Treatment with imatinib mesylate resulted within 6 months in a total disappearance of all chromosomal abnormalities with a complete cytogenetic and molecular response, which persists 3 years later. We question whether the ex vivo purging procedure with mafosfamide has favored the occurrence of these particular cytogenetic abnormalities (with no independent oncogenic potential) within the original leukemic stem cell pool. It remains unclear whether the autologous transplantation has indeed resulted into some prolongation of the duration of the chronic phase, which lasted for 20 years. At time of acute crisis, the dramatic response to imatinib mesylate leading to a complete cytogenetic and molecular response is noteworthy.
Topics: Adult; Antineoplastic Agents; Benzamides; Bone Marrow Transplantation; Chromosome Aberrations; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Philadelphia Chromosome; Piperazines; Pyrimidines; Transplantation, Autologous; Whole-Body Irradiation
PubMed: 17786726
DOI: 10.1080/10428190701534440 -
Current Pharmaceutical Design 2007The oxazaphosphorines including cyclophosphamide (CPA, Cytoxan, or Neosar), ifosfamide (IFO, Ifex) and trofosfamide (Ixoten) represent an important group of therapeutic... (Review)
Review
The oxazaphosphorines including cyclophosphamide (CPA, Cytoxan, or Neosar), ifosfamide (IFO, Ifex) and trofosfamide (Ixoten) represent an important group of therapeutic agents due to their substantial antitumor and immunomodulating activity. However, several intrinsic limitations have been uncounted during the clinical use of these oxazaphosphorines, including substantial pharmacokinetic variability, resistance and severe host toxicity. To circumvent these problems, new oxazaphosphorines derivatives have been designed and evaluated with an attempt to improve the selectivity and response with reduced host toxicity. These include mafosfamide (NSC 345842), glufosfamide (D19575, beta-D-glucosylisophosphoramide mustard), S-(-)-bromofosfamide (CBM-11), NSC 612567 (aldophosphamide perhydrothiazine) and NSC 613060 (aldophosphamide thiazolidine). Mafosfamide is an oxazaphosphorine analog that is a chemically stable 4-thioethane sulfonic acid salt of 4-hydroxy-CPA. Glufosfamide is IFO derivative in which the isophosphoramide mustard, the alkylating metabolite of IFO, is glycosidically linked to a beta-D-glucose molecule. Phase II studies of glufosfamide in the treatment of pancreatic cancer, non-small cell lung cancer (NCSLC), and recurrent glioblastoma multiform (GBM) have recently completed and Phase III trials are ongoing, while Phase I studies of intrathecal mafosfamide have recently completed for the treatment of meningeal malignancy secondary to leukemia, lymphoma, or solid tumors. S-(-)-bromofosfamide is a bromine-substituted IFO analog being evaluated in a few Phase I clinical trials. The synthesis and development of novel oxazaphosphorine analogs with favourable pharmacokinetic and pharmacodynamic properties still constitutes a great challenge for medicinal chemists and cancer pharmacologists.
Topics: Animals; Antineoplastic Agents; Apoptosis; Clinical Trials as Topic; Drug Design; Humans; Lethal Dose 50; Molecular Structure; Neoplasms; Phosphoramide Mustards
PubMed: 17430192
DOI: 10.2174/138161207780414296 -
Cancer Research Jan 2007Monocytes and dendritic cells are key players in the immune response. Because dendritic cells drive the tumor host defense, it is important that monocytes and dendritic...
Monocytes and dendritic cells are key players in the immune response. Because dendritic cells drive the tumor host defense, it is important that monocytes and dendritic cells survive cytotoxic tumor therapy. Although most of the anticancer drugs target DNA, the DNA repair capacity of monocytes and dendritic cells has not yet been investigated. We studied the sensitivity of monocytes and monocyte-derived dendritic cells against various genotoxic agents and found monocytes to be more sensitive to overall cell kill and apoptosis upon exposure to methylating agents (e.g., N-methyl-N'-nitro-N-nitrosoguanidine, methyl methanesulfonate, and the anticancer drug temozolomide). On the other hand, upon treatment with the cross-linking chemotherapeutics fotemustine, mafosfamide, and cisplatin, monocytes and dendritic cells responded in the same way. Monocytes were also more sensitive than lymphocytes. The data indicate a defect in the repair of DNA methylation damage in monocytes. Because the expression of the repair protein O(6)-methylguanine-DNA methyltransferase was higher in monocytes than in dendritic cells, and because its inhibition by O(6)-benzylguanine had no effect on the sensitivity of monocytes, we investigated the base excision repair (BER) pathway. In contrast to dendritic cells, monocytes are unable to perform BER following exposure to methylating agents. Expression studies revealed that monocytes lack XRCC1 and ligase IIIalpha, whereas dendritic cells, similar to human lymphocytes, express these repair proteins at a high level. The data revealed a DNA repair defect in a specific human cell population. The BER defect in monocytes may cause them to be selectively killed during tumor therapy with alkylating agents, provoking hematotoxicity and sustained immunosuppression.
Topics: Alkylating Agents; Cell Survival; Cells, Cultured; DNA Methylation; DNA Repair; Dacarbazine; Dendritic Cells; Drug Hypersensitivity; Humans; Methyl Methanesulfonate; Methylnitronitrosoguanidine; Monocytes; Mutagens; Temozolomide
PubMed: 17210680
DOI: 10.1158/0008-5472.CAN-06-3712 -
Oncology Reports Dec 2006We examined in vitro sensitivity of B-CLL cells exposed to cladribine, mafosfamide, mitoxantrone and combinations ofcladribine with mafosfamide and/or mitoxantrone. The...
We examined in vitro sensitivity of B-CLL cells exposed to cladribine, mafosfamide, mitoxantrone and combinations ofcladribine with mafosfamide and/or mitoxantrone. The results revealed that each applied treatment of leukemic cells, besides having a cytotoxic effect, affected the events associated with apoptosis. All drugs used alone, and cladribine combinations with mafosfamide and/or mitoxantrone induced DNA fragmentation and the changes in expression/proteolysis level of caspase-3, caspase-9 precursors, PARP-1, lamin B, Bax and Bcl-2; however, each to a different degree. The exposure of leukemic cells to both cladribine combinations induced stronger effects. Moreover, the data showed that the expression of regulatory antiapoptotic protein Bcl-2 generally decreased in drug-treated B-CLL cells, whereas proapoptotic polypeptide Bax increased, resulting in enhancement of Bax-Bcl-2 ratios in comparison with untreated cells. Drug-treatment of the studied cells induced the translocation of Bax protein from the cytosol to the cellular pellet, containing mitochondria, where this polypeptide indicated the capacity for oligomerization. These observations suggest that the examined drugs are able to induce apoptosis of B-CLL cells via the mitochondria pathway.
Topics: Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Caspases; Cladribine; Cyclophosphamide; DNA Fragmentation; Female; Humans; In Vitro Techniques; Lamin Type B; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Mitochondria; Mitoxantrone; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Protein Transport; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured; bcl-2-Associated X Protein
PubMed: 17089066
DOI: No ID Found -
Cytotherapy 2006Multiple studies have demonstrated that 'purging' of autografts with 4-hydroperoxycyclophosphamide (4HC) or the related compound mafosfamide (Mf), to eradicate residual... (Clinical Trial)
Clinical Trial
BACKGROUND
Multiple studies have demonstrated that 'purging' of autografts with 4-hydroperoxycyclophosphamide (4HC) or the related compound mafosfamide (Mf), to eradicate residual leukemia, produces the best results associated with autologous blood and marrow transplantation for AML. However, 4HC purging results in prolonged aplasia. Therefore, we evaluated the potential of ex vivo expansion of Mf-treated CD34+ cells from mobilized PBPC.
METHODS
CD34+ cells were isolated from PBPC products and treated with 30 microg/mL Mf. The Mf-treated CD34+ cells were washed and cultured for 14 days in StemLine II-defined media containing recombinant human (rh) SCF, G-CSF and thrombopoietin (Tpo).
RESULTS
Treatment with Mf resulted in 90% killing of progenitor cells (GM-CFC) but maintenance of SCID-repopulating cells (SRC). Ex vivo culture of the Mf-treated CD34+ cells resulted in decreased cell numbers (10-20% of the starting cell dose) during the first week. Nevertheless, in the second week of culture the total cell numbers expanded to approximately 20-fold above starting cell numbers and progenitor cells returned to approximately pre-treatment levels.
DISCUSSION
These studies demonstrate the potential of ex vivo culture to expand both total cell numbers and progenitor cells following treatment of PBPC CD34+ cells with Mf. Clinical studies are currently being initiated to evaluate the engraftment potential of these purged and expanded products.
Topics: Adjuvants, Immunologic; Animals; Antigens, CD34; Bone Marrow Purging; Cells, Cultured; Cyclophosphamide; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Mice; Mice, SCID; Peripheral Blood Stem Cell Transplantation; Transplantation, Autologous; Transplantation, Heterologous
PubMed: 17050250
DOI: 10.1080/14653240600905353 -
Cancer Investigation 2006Intrathecal administration of chemotherapy, with or without radiation therapy, is the primary treatment modality for the prevention and treatment of central nervous... (Review)
Review
Intrathecal administration of chemotherapy, with or without radiation therapy, is the primary treatment modality for the prevention and treatment of central nervous system (CNS) metastases in patients with leukemia or lymphoma. Although this treatment strategy has been very effective for patients with hematological malignancies, currently available intrathecal agents are relatively ineffective for patients with neoplastic meningitis resulting from an underlying solid or CNS tumor effective. This article provides an overview of some of the practical considerations and limitations associated with intrathecal chemotherapy, and is followed by a comprehensive review of some of the preclinical and early phase clinical trials of novel anticancer agents and treatment strategies using the intrathecal route.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Busulfan; Central Nervous System Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Deoxycytidine; Etoposide; Humans; Immunologic Factors; Injections, Spinal; Interferon-gamma; Interleukin-2; Leukemic Infiltration; Meninges; Rituximab; Topotecan; Gemcitabine
PubMed: 16939963
DOI: 10.1080/07357900600815166 -
Bone Marrow Transplantation Mar 2006Imatinib-refractory chronic myelogenous leukemia (CML) patients can experience long-term disease-free survival with myeloablative therapy and allogeneic hematopoietic...
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 microM for 72 h) and then mafosfamide (30-90 microg/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 microM imatinib, 60 microg/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.
Topics: Antigens, CD; Antigens, CD34; Antineoplastic Agents; Benzamides; Bone Marrow Purging; Cell Separation; Cell Survival; Cyclophosphamide; Flow Cytometry; Humans; Imatinib Mesylate; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplastic Cells, Circulating; Piperazines; Pyrimidines; Stem Cell Transplantation; Transplantation, Autologous
PubMed: 16435011
DOI: 10.1038/sj.bmt.1705284 -
Drug Metabolism Reviews 2005The oxazaphosphorines including cyclophosphamide (CPA), ifosfamide (IFO), and trofosfamide represent an important group of therapeutic agents due to their substantial... (Review)
Review
The oxazaphosphorines including cyclophosphamide (CPA), ifosfamide (IFO), and trofosfamide represent an important group of therapeutic agents due to their substantial antitumor and immuno-modulating activity. CPA is widely used as an anticancer drug, an immunosuppressant, and for the mobilization of hematopoetic progenitor cells from the bone marrow into peripheral blood prior to bone marrow transplantation for aplastic anemia, leukemia, and other malignancies. New oxazaphosphorines derivatives have been developed in an attempt to improve selectivity and response with reduced toxicity. These derivatives include mafosfamide (NSC 345842), glufosfamide (D19575, beta-D-glucosylisophosphoramide mustard), NSC 612567 (aldophosphamide perhydrothiazine), and NSC 613060 (aldophosphamide thiazolidine). This review highlights the metabolism and transport of these oxazaphosphorines (mainly CPA and IFO, as these two oxazaphosphorine drugs are the most widely used alkylating agents) and the clinical implications. Both CPA and IFO are prodrugs that require activation by hepatic cytochrome P450 (CYP)-catalyzed 4-hydroxylation, yielding cytotoxic nitrogen mustards capable of reacting with DNA molecules to form crosslinks and lead to cell apoptosis and/or necrosis. Such prodrug activation can be enhanced within tumor cells by the CYP-based gene directed-enzyme prodrug therapy (GDEPT) approach. However, those newly synthesized oxazaphosphorine derivatives such as glufosfamide, NSC 612567 and NSC 613060, do not need hepatic activation. They are activated through other enzymatic and/or non-enzymatic pathways. For example, both NSC 612567 and NSC 613060 can be activated by plain phosphodiesterase (PDEs) in plasma and other tissues or by the high-affinity nuclear 3'-5' exonucleases associated with DNA polymerases, such as DNA polymerases and epsilon. The alternative CYP-catalyzed inactivation pathway by N-dechloroethylation generates the neurotoxic and nephrotoxic byproduct chloroacetaldehyde (CAA). Various aldehyde dehydrogenases (ALDHs) and glutathione S-transferases (GSTs) are involved in the detoxification of oxazaphosphorine metabolites. The metabolism of oxazaphosphorines is auto-inducible, with the activation of the orphan nuclear receptor pregnane X receptor (PXR) being the major mechanism. Oxazaphosphorine metabolism is affected by a number of factors associated with the drugs (e.g., dosage, route of administration, chirality, and drug combination) and patients (e.g., age, gender, renal and hepatic function). Several drug transporters, such as breast cancer resistance protein (BCRP), multidrug resistance associated proteins (MRP1, MRP2, and MRP4) are involved in the active uptake and efflux of parental oxazaphosphorines, their cytotoxic mustards and conjugates in hepatocytes and tumor cells. Oxazaphosphorine metabolism and transport have a major impact on pharmacokinetic variability, pharmacokinetic-pharmacodynamic relationship, toxicity, resistance, and drug interactions since the drug-metabolizing enzymes and drug transporters involved are key determinants of the pharmacokinetics and pharmacodynamics of oxazaphosphorines. A better understanding of the factors that affect the metabolism and transport of oxazaphosphorines is important for their optional use in cancer chemotherapy.
Topics: Animals; Antineoplastic Agents, Alkylating; Biological Availability; Biological Transport; Clinical Trials as Topic; Humans; Molecular Structure; Neoplasms; Phosphoramide Mustards
PubMed: 16393888
DOI: 10.1080/03602530500364023 -
Cancer Letters Aug 2006DNA double-strand breaks (DSBs) are potent killing lesions, and inefficient repair of DSBs does not only lead to cell death but also to genomic instability and...
DNA double-strand breaks (DSBs) are potent killing lesions, and inefficient repair of DSBs does not only lead to cell death but also to genomic instability and tumorigenesis. DSBs are repaired by non-homologous end-joining and homologous recombination (HR). A key player in HR is Xrcc2, a Rad51-like protein. Cells deficient in Xrcc2 are hypersensitive to X-rays and mitomycin C and display increased chromosomal aberration frequencies. In order to elucidate the role of Xrcc2 in resistance to anticancer drugs, we compared Xrcc2 knockout (Xrcc2-/-) mouse embryonic fibroblasts with the corresponding isogenic wild-type and Xrcc2 complemented knockout cells. We show that Xrcc2-/- cells are hypersensitive to the killing effect of the simple methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). They undergo apoptosis after MNNG treatment while necrosis is only marginally enhanced. Complementation of Xrcc2 deficient cells by Xrcc2 cDNA transfection conferred resistance to the cytotoxic and apoptosis-inducing effect of MNNG. The hypersensitivity of Xrcc2-/- cells to MNNG prompted us to investigate their killing and apoptotic response to various methylating, chloroethylating and crosslinking drugs used in anticancer therapy. Xrcc2 deficient cells were found to be hypersensitive to temozolomide, fotemustine and mafosfamide. They were also hypersensitive to cisplatin but not to taxol. The data reveal that Xrcc2 plays a role in the protection against a wide range of anticancer drugs and, therefore, suggest Xrcc2 to be a determinant of anticancer drug resistance. They also indicate that HR is involved in the processing of DNA damage induced by simple alkylating agents.
Topics: Antineoplastic Agents, Alkylating; Apoptosis; Cisplatin; Cyclophosphamide; DNA-Binding Proteins; Dacarbazine; Humans; Methylnitronitrosoguanidine; Mitomycin; Mutagens; Nitrosourea Compounds; Organophosphorus Compounds; Temozolomide
PubMed: 16298473
DOI: 10.1016/j.canlet.2005.08.036 -
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