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PubMed1988

In vitro chemical eradication of small cell lung cancer: application in autologous bone marrow transplantation.

Autologous bone marrow transplantation raises the question of the possible reinjection of tumour cells together with marrow. This paper investigates the ability of chemical compounds other than cyclophosphamide derivatives to eradicate small cell lung cancer (SCLC) in bone marrow. The responsiveness of SCLC lines to cis-platinum, doxorubicin, VP16, Celiptium (an ellipticine derivative), Ditercalinium, a new drug belonging to the pyridocarbazole series, and Asta Z were measured in an agar-agar clonogenic assay. Cis-platinum and Ditercalinium exhibited a high tumouricidal effect. The low cloning efficiencies of SCLC lines in an agar-agar clonogenic assay did not allow tumour cells to be detected among bone marrow cells with sufficient sensitivity. Therefore cis-platinum and Ditercalinium were tested on bone marrow-tumour cell mixtures cultured in a liquid medium allowing the detection of one tumour cell per 10(4) bone marrow cells. As cis-platinum exhibited a low myelotoxicity, it is proposed for purging bone marrows of patients with SCLC.

Antineoplastic Agents↗
PubMed1989

Cytotoxic effects of 6-hydroxydopamine, merocyanine-540 and related compounds on human neuroblastoma and hematopoietic stem cells.

6-Hydroxydopamine(6-OHDA) and Merocyanine-540(MC-540) have been used clinically for purging of neuroblastoma cells prior to autologous bone marrow transplantation. Both substances were found to be more toxic against neuroblastoma cells than against hematopoietic stem cells. The more pronounced cytotoxic effects of 6-OHDA against neuroblastoma cells were not caused by its selective uptake; the rapid autooxidation at physiological pH leads to the formation of H2O2 already in the incubation medium. Cytotoxic effects were not detected in short-time test systems (4 hour chromium-51 release assay) but only after longer incubation periods. In contrast, MC-540 proved to be toxic almost equally in short- and long-time test systems. 4-Hydroxynonenal(4-HNE) that may be formed in the plasma membrane subsequently to photoactivation of MC-540 was only slightly more toxic to neuroblastoma cells than to hematopoietic cells. Although the use of 6-OHDA and MC-540 in bone marrow purging has some limitations, the sensitivity of neuroblastoma cells against reactive oxygen compounds may be exploited more generally for therapy of this tumor.

Aldehydes↗
PubMed1990

Immunophenotyping of acute myeloid leukemia cells.

This article considers the expression of myeloid cell-associated antigens on both normal and malignant myeloid cells. Progress in the use of monoclonal antibodies to myeloid cell surface antigens for the diagnosis, subclassification, and treatment of acute myeloid leukemia is discussed. The results of bone marrow purging with monoclonal antibodies to remove leukemia cells for the purpose of autologous bone-marrow transplantation are promising.

Antigens, Differentiation↗
PubMed1993

Autologous BMT in high risk patients with CALLA-positive ALL: possible efficacy of ex vivo marrow leukemia cell purging with monoclonal antibodies and complement.

Autologous BMT (auto-BMT) has been conducted for 17 high-risk common ALL antigen (CALLA)-positive non-T cell type ALL patients. Ex vivo purging of leukemia cells from infused BM cells was performed using complement and three kinds of mouse monoclonal antibodies reactive to CALLA-positive leukemia cells: NL-1 (IgG2a), NL-22 (IgM), and HL-47 (IgM). Minimal residual leukemia cells in BM were examined by PCR method in Philadelphia chromosome (Ph1)-positive ALL cases. BCR/ABL chimeric transcript, which was positive in BM samples before purging, was shown to be absent after ex vivo purging in all three cases tested. Among four Ph1-positive cases transplanted in first CR, three cases survived in CR remission 77, 29 and 26 months after BMT, and one case died without relapse 4 months after BMT. The other four Ph1-negative cases transplanted in the first CR also remained in CR except one who relapsed. The results of minimal residual leukemia cell studies and clinical data indicate the effectiveness of our ex vivo leukemia cell purging method and auto-BMT in the early stage of CR for patients with high risk ALL.

Adolescent↗
PubMed1994

A combination of anti-CD15 monoclonal antibody PM-81 and 4-hydroperoxycyclophosphamide augments tumor cytotoxicity while sparing normal progenitor cells.

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. In some patients, all tumor cells may not be lysed due to antigenic heterogeneity. Because the two agents used individually are associated with potential limitations in terms of toxicity to normal cells and efficacy of tumor cell purging, using these agents together might have advantages. In fact, in this study the use of these two agents together in subtherapeutic concentration ranges as single agents revealed killing of cells from the HL60 and NB4 promyelocytic leukemia cell lines in addition to cells from patients with AML while sparing normal progenitor cells. Surprisingly, not only did the combination enhance killing of tumor cells, but the order of addition of the two agents was important in maximizing toxicity to tumor cells. Adding mAb+complement (C') first or simultaneously to 4HC was less effective than adding 4HC first followed by mAb + C'. This combination regimen was toxic to HL60 and NB4 leukemia cells that may not be killed by the mAb alone due to antigen-negative tumor cells or by low concentrations of 4HC.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1991

Interaction of various cytokines with interleukin 2 in the generation of killer cells from human bone marrow: application in purging of leukemia.

We have shown that incubation of bone marrow (BM) with interleukin 2 (IL-2) generates activated bone marrow cells (ABM) with potent tumoricidal activity in vitro and in vivo. The present study was carried out to define the interaction of other cytokines with IL-2 in generation of ABM. Our data show that interleukin 1 (IL-1), interferon (IFN)- both gamma and alpha, and tumor necrosis factor (TNF-alpha) significantly increased the cytolytic potential of ABM. Interleukin 3, interleukin 4, transforming growth factor-beta and adherent cells were reduced, while granulocyte-macrophage colony-stimulating factor had no influence on the generation of cytolytic activity. IL-1 was enhanced while TNF-alpha depressed the BM progenitor cell activity in vitro. The IL-2-induced purging ability of BM contaminated with leukemic cells was increased by IL-1, TNF-alpha and IFN-gamma. This study shows that biomodulation of BM with combination of cytokines in vitro can be useful in purging a large leukemic burden.

Bone Marrow↗
PubMed1995

Autologous PBSC transplant for late onset AML after mafosfamide-purged and TBI-containing autologous BMT.

The prognosis of AML patients who fail autologous BMT and lack a donor for a salvage allogeneic BMT is very poor. We administered an alternative drug treatment including autologous PBSC transplant to a child who relapsed with AML 4 years after a mafosfamide-purged and TBI-containing BMT for second remission AML. Treatment comprised induction-consolidation with 'short' ICE courses (idarubicin-Ara C-etoposide for 2 days), high-dose CY plus G-CSF with collection of CD34+ PBSC and myeloablative treatment with high-dose mitoxantrone/BEAM supported by autologous PBSC reinfusion. The outcome was complete response, lasting 24 months. The patient died in remission of drug-related cardiotoxicity. This report emphasizes the possibility of a secondary AML after mafosfamide-purge autologous BMT, and documents the feasibility of an autologous PBSC transplant in such a high risk setting.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

New approaches to management of multiple myeloma.

A new era of multiple myeloma (MM) management includes new approaches such as genetic marking and gene therapy, immunotherapy, stimulation of graft versus myeloma effect, etc. Intensive clinical research is also focused on the detection of minimal residual disease and bone marrow purging. Autoregulatory loop of myeloma cells and detection of genes responsible for pathological transformation of B-line cells is of great research interest. Clinical trials have begun and the first results are promising, though preliminary. The safety of the patients and the public must be major concern of all investigators. The combinations of new types of therapeutical approaches with the most efficient regimens used until now could form a new type of MM management strategy that better involves minimal residual disease.

Bone Marrow Purging↗
PubMed1989

Autologous bone marrow transplantation with immunotoxin-purged marrow for advanced multiple myeloma.

A system to purge the bone marrow of myeloma cells has been developed in our laboratories with the aim of treating with myeloablative radiochemotherapy patients suffering from advanced multiple myeloma. This system is based on the ex vivo incubation of the marrow with an immunotoxin composed of the 8A monoclonal antibody--that recognizes plasma cells and B-cell precursors--and the ribosome-inactivating protein momordin. 8 patients have so far been treated. 4 are surviving from 4 to 18 months after ABMT, whereas 4 died after 1 to 6 months, 2 from infections, 1 from relapsing disease and 1 from veno-occlusive disease. A marked tumour reduction was observed in all evaluable patients; however, none has achieved complete disappearance of the disease. The haemopoietic reconstitution was significantly delayed in 3 patients. These preliminary results show the feasibility of this approach in advanced MM patients with heavily infiltrated marrow. The place of ABMT in the treatment of MM remains to be determined; the selection of patients with still responding and less advanced disease would probably produce better results.

Adult↗
PubMed1996

Purging of autografts: methods and clinical significance.

High-dose chemoradiotherapy with autologous haematopoietic progenitor cell support is being used with increasing frequency to treat patients with a variety of malignancies. The most common reason for the ultimate failure in patients treated with high-dose therapy with stem cell support is not lack of engraftment, toxicity of therapy, or infection, but rather relapse of disease. There is solid evidence that reinfusion of autografts containing clonogenic tumour cells can contribute to relapse and influence patient outcome after high-dose treatment. In patients undergoing high-dose treatment, tumour cell contamination can be observed in histologically normal bone marrow or peripheral blood by sensitive micrometastatic detection techniques. Consequently, methods for detection of minimal residual disease in the autografts, together with techniques to remove tumour cells from the harvest are considered to be important in patients receiving high-dose therapy with stem cell support.

Antineoplastic Agents↗
PubMed1997

Effects of phosphodiester and phosphorothioate antisense oligodeoxynucleotides on cell lines which overexpress c-myc: implications for the treatment of Burkitt's lymphoma.

The product of the c-myc proto-oncogene is a highly conserved nuclear phosphoprotein whose expression is closely linked to cellular proliferation and differentiation. We have been interested in developing an antisense oligodeoxynucleotide (ODN) strategy to inhibit the proliferation of c-myc-dependent malignancies for use in future specific therapies and bone marrow purging regimens. Our experimental approach was to incubate either antisense or sense ODNs, spanning the 5' cap region of the c-myc gene, with c-myc overexpressing cell lines (HL-60) Raji, MJBL, CA-46) for up to seven days. Proliferation assay to test the inhibitory effect of an unmodified antisense ODN 15-mer (GCACAGCTCGGGGGT) showed that concentrations as low as 50 micrograms/ml significantly decreased proliferation of HL-60 cells by approximately 40% (P < 0.0001; n = 6) compared to controls. Clonogenic assays showed that the same antisense ODN inhibited colony formation by MJBL (40%0 and Raji (52%) cells. Subsequent experiments to study the effect of a more nuclease-stable, phosphorothioate-modified antisense ODN 18-mer (GCAGCACAGCTCGGGGGT) revealed 66% inhibition of HL-60 cell proliferation at 96 and 120 hours at 50 micrograms/ml, whereas sense ODN control had no effect. However, tenfold less of the modified antisense ODN (1 micrograms/ml) was required to inhibit proliferation of HL-60 cells by 50% compared to the unmodified antisense ODN. A decrease in the HL-60 native c-myc protein level was also observed with 100 micrograms/ml of modified antisense ODN, but not with the sense ODN control, by immunoblot analysis. Additionally, concentrations up to 10 micrograms/ml of either modified antisense or sense ODN did not decrease CFU-GM formation (145 +/- 35%, P = 0.27) in human bone marrow, suggesting that these levels of ODN would have a negligible effect on normal hematopoietic cells. These pilot data suggest that modified antisense ODN directed at the cap region of the c-myc gene could specifically inhibit c-myc expression at a single, lower dose than unmodified ODN and may play a future role in inhibiting the growth of c-myc-dependent malignant cells.

Blotting, Southern↗
PubMed2002

[The effect of multi-unit ribozymes on the growth inhibition and apoptosis induction of CML K562 cells].

OBJECTIVE: To investigate the possibility of multi-unit ribozymes to purge bone marrow of chronic myelocytic leukemia (CML), its in vitro cleavage ability and the reversal effect on CML cell's malignant phenotype. METHODS: As bcr-abl fusion gene plays an important role in CML pathology, three single-unit ribozymes were designed and synthesized in 44 base pairs near the fusion point, two enzyme cleavage sites on bcr gene and one on abl gene. Multi-unit ribozymes' in vitro transcription and retroviral vector through gene recombination were constructed. Then, its in vitro cleavage ability was tested and the retroviral vector was transfected into K562 cell. Through MTT assay, the incorporation rate of (3)H-TdR, RT-PCR, Southern and Northern blot hybridization, flow cytometry, transmission and scanning electron microscopy were used to study the effect of multi-unit ribozymes on CML cell proliferation, cell structure, cell cycle and the induction of apoptosis. RESULTS: Multi-unit ribozymes had in vitro cleavage efficiency of 70.8%. After the transfection of multi-unit ribozymes retroviral vector into K562 cell, cell proliferation and DNA synthesis were greatly reduced with an inhibition rate of about 50% after 96 hours of transfection. Multi-unit ribozymes could cleave K562 cell's RNA with a reduction rate about one 1 000 th of the original. By flow cytometry (FCM), 18.4% cells underwent apoptosis after 72 hours transfection with most of the cells blocked in the G phase. Here, the ratio in S phase was lowered by 41.9%. Under transmission and scanning electron microscope, compaction of nuclear chromation and apoptosis bodies were observed in the transfected cells. CONCLUSION: Multi-unit ribozymes possess high cleavage ability in vitro. The ribozymes, whose retroviral vector being transfected into CML cell, are able to express a lasting ability to cleave the fusion gene, induce apoptosis, reduce cell proliferation, revert the malignant phenotype. It is possible to make use of multi-unit ribozymes to purge CML bone marrow. Therefore, multi-unit ribozymes may very well be valuable in the gene therapy of CML.

Apoptosis↗
PubMed2002

Autologous versus allogeneic unrelated donor transplantation for acute lymphoblastic leukemia: comparative toxicity and outcomes.

For patients with high-risk or relapsed acute lymphoblastic leukemia (ALL) lacking a related histocompatible donor, autologous (Auto) and unrelated donor (URD) transplantation are available options. We compared outcomes and toxicities in 712 patients with ALL (517 URD, 195 Auto) in first complete remission (CR1) or second complete remission (CR2) who underwent transplantation. All patients were <50 years old, although URD patientswere younger (median age, 14 versus 18 years, P < .002). The proportion of patients in CR1 versus CR2 was similar (36% versus 38%, P = .57), but more URD recipients than Auto recipients had high-risk karyotypes (25% versus 13%, P = .003) and white blood cell (WBC) counts > or =50 x 10(9)/L (33% versus 14%, P < .001). Engraftment was similar in URD and Auto recipients. Ex vivo purging delayed but did not prevent engraftment after Auto transplantation. Transplantation-related mortality was higher after URD transplantation (42%+/-8%) than after Auto transplantation (20%+/-12%) in CR1 (P = .004) and also in CR2. Conversely, relapse was more frequent after Auto transplantation in CR1 (Auto, 49%+/-12% versus URD, 14%+/-5%) and CR2 (64%+/-8% versus 25%+/-5%) (P < .0001). These findings showed net similar outcomes for these 2 transplantation choices. Transplantation in CR1 yielded similar 3-year survival rates for URD (51%+/-7%) and Auto (44%+/-12%), as did transplantation in CR2 (40%+/-6% versus 32%+/-9%, respectively). Multivariate regression analysis identified significantly better disease-free survival after the first 6 months in matched URD versus Auto in younger patients, in those in CR2 with CR1 >1year, WBC <50 x 10(9)/L, performance status > or =90%, and in those who have undergone transplantation since 1995. These comparative data suggest that both matched URD and Auto transplantation can yield extended survival. Although URD transplantation offers substantially better protection against leukemic relapse, improvements in allotransplantation safety and refinements in patient selection are required to better aid treatment decision making for the best overall survival.

Adolescent↗
PubMed1991

Unusually long survival after autografting in second partial remission of translocation t(4;11) acute infant leukemia.

About 70% of children with acute lymphoblastic leukemia may be cured by conventional chemotherapy. The prognosis is considerably worse in infant leukemia with a translocation t(4;11). We report an infant with a diagnosis of cytochemically undifferentiated acute hybrid leukemia (pre pre B-ALL coexpressing one myelomonocytic marker) and t(4;11). Initial clinical presentation and the course of the disease were typical for t(4;11) acute leukemia. After an early hematologic relapse intensive chemotherapy resulted only in a second partial remission 7 months after initial diagnosis. Subsequent bone marrow transplantation with 16 mg/kg busulfan and 200 mg/kg cyclophosphamide followed by the infusion of autologous purged bone marrow resulted in a continuous second remission which has lasted 46 months so far.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

MHC allograft immunogenicity--its role in bone marrow transplantation and its constant downregulation.

Since 1972 our laboratory has performed a large variety of studies in the rat and mouse models. These have shown that it is possible to achieve MHC fully allogeneic hematopoietic chimerism with complete restitution of immunological reactivity but lasting immunotolerance of donor type cells following transplantation of lymphocyte-purged bone marrow into lethally irradiated recipients. The clinical application of this obvious immunobiological potential is, however, still in its infancy. This is largely due to the belief that graft-versus-host reactions and host-versus-graft reactions balance each other out--a view that cannot be upheld. A decisive element in the network of immunoregulation following BMT is the immunogenic strength of the BM. In this context the following bits of information are given: (1) Bone marrow that has been completely purged of lymphocytes loses its allograft immunogenicity to a great extent and may even allow induction of tolerance, whereas unpurged BM is strongly immunogenic. (2) This reduction of alloimmunogenicity is only partially determined by lymphocytes and other MHC class II-expressing cells. (3) By incubating bone marrow with our new cytotoxic monoclonal antibody K31, directed against an epitope located an all human lymphocytes and defined cells of the monocytic lineage, both the alloimmunogenicity and the accessory cell potential of the bone marrow can be greatly reduced. (4) Recent analyses with macrophage cell clones rather than heterogeneous mixtures of BM cells indicate that oncogene transfections may allow us to completely down-regulate their alloimmunogenicity, in spite of unaltered high MHC expression, by genetically downregulating Il-1. In conclusion, it is suggested that MHC allogeneic BMT will become feasible in the human, as it is well-established in preclinical models.

Animals↗