Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We succeeded in establishing a human myelogenous leukemia model in severe combined immunodeficient (SCID) mice by transplanting 2 x 10(7) ML-2 cells intraperitoneally (i.p.) with cyclophosphamide (CTX) pretreatment. Two months after transplantation, 9 of 10 mice developed leukemia and leukemia cells were detected in the peripheral blood (PB) and bone marrow (BM). The main findings at autopsy were peritoneal and pleural effusions and large tumor masses involving the peritoneal organs. However, successful transplantation required injection of a large number of cells. We therefore established a new cell line, ML-2S, from the PB of a mouse with ML-2 leukemia. Although only 2 x 10(6) ML-2S cells were inoculated, ML-2S induced the same pattern of leukemic dissemination reminiscent of the parent ML-2 cells. Compared to ML-2, progression of ML-2S was slow, suggesting that ML-2S is suitable as a leukemia model to study treatment. Furthermore, we confirmed that ML-2S cells are of human origin using isoenzyme analysis and also that ML-2S and ML-2 cells have the same phenotypic character by cell surface marker analysis.
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PMID:Establishment of an in vivo human myeloid leukemia model in the SCID mouse. 1021 30

An interim report evaluating the feasibility of myeloablative therapy followed by peripheral blood stem cell (PBSC) autotransplant in patients aged >60 years is presented. In the last 2 years 19 patients >60 years old with several oncological conditions, mostly hematological, underwent PBSC autotransplant either as salvage therapy following relapse or resistance to conventional treatment, or as consolidating therapy as a part of a well defined protocol. There were 13 males and six females; the mean age was 66.9 years (range 61-76 years); nine patients had resistant or relapsed lymphoma, six myeloma, two acute leukemia, one Waldenstrom's disease and one lung cancer. Myeloablative schemes included BEAM exclusively for lymphomas, busulfan and melphalan (Bu-MPH) mainly for myeloma, busulfan and cyclophosphamide (Bu-CTX) for lymphomas and leukemia and VP-16 and CTX for lung cancer. Mobilization of CD34+ cells was achieved in all patients with the combination of high-dose CTX and G-CSF with collections between 2.83 to 19.04 x 10(6)/kg (mean 7.1). All patients engrafted with a median time for recovery of PMN (>0.5 x 10(3)/microl) of 10 days (range 8-12 days) and for PLT (>20 x 10(3)/microl) of 12 days (range 10-17 days). Major responses were obtained in 15 of 16 patients evaluable for response and eight patients entered CR; overall eight patients are in CR, five are alive with disease, five are dead from disease progression and one is dead because of congestive heart failure 7 months following PBSC autotransplant. No early deaths following the procedure occurred; major side-effects were grade I-II mucositis (58%), fever with documented sepsis (10%), pneumonia (5%), cardiac, renal and liver toxicity (5%). Cardiac function was evaluated before and after myeloablative therapy by VEF in all patients; no significant modifications were necessary. In conclusion, our experience demonstrates that myeloablative therapies in older selected patients can be feasible; the feasibility of introducing PBSC autotransplantation following myeloablative therapy as a front-line treatment in patients aged >60 years, needs accurate guide lines for selection of appropriate patients.
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PMID:Analysis of feasibility of myeloablative therapy and autologous peripheral stem cell (PBSC) transplantation in the elderly: an interim report. 1041 15

Cancer cells may frequently develop cross-resistance to structurally dissimilar chemotherapeutic agents. However, the molecular mechanisms for sensitivity and resistance of tumor cells towards chemotherapy are still partially understood. Antineoplasic drugs have been shown to induce apoptosis in chemosensitive leukemias and solid tumors. In this work, cross-resistance among vincristine (VCR), doxorubicin (DOX) and other antineoplasic agents commonly used in the treatment of leukemia such as etoposide (VP-16), methotrexate (MTX), cyclophosphamide (CTX), dexamethasone (DEX), cytarabine (Ara-C) and L-asparaginase on vincristine resistant (LBR-V160), doxorubicin resistant (LBR-D160) and sensitive (LBR-) murine leukemic T cell lines, was determined. The effect of antineoplasic agents was assayed by tritiated thymidine incorporation. Our results showed that VCR exhibited cross-resistance with DOX, VP-16, DEX and MTX, while DOX demonstrated cross-resistance with VCR, VP-16 and MTX. Ara-C failed to present cross-resistance with any cell line. Apoptosis induced by the above drugs on the same cell lines was analyzed by acridine orange and ethidium bromide staining, DNA hypoploidy (flow cytometry) and oligonucleosomal fragmentation of nuclear DNA showing that therapeutic concentrations of these chemotherapeutic agents induced apoptosis in the LBR- cell line. Our results demonstrated that, except for DEX, none of the drugs presenting cross-resistance were able to induce cell death on LBR-V 160 or LBR-D 160 cell lines.
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PMID:Correlation between decreased apoptosis and multidrug resistance (MDR) in murine leukemic T cell lines. 1169 8

Seventeen patients and their family donors HLA 2 - 3 antigen mismatched of 2 - 3 loci were enrolled in the study of haploidentical transplants from February 1999 to March 2001. Among patients with leukemia, most patients were classified as high risk. Eleven patients with ALL were all in more than second remission but one was in relapse. Patients with AML were one in CR1, one in CR2 while 4 patients with CML were two in CP and two in AP. The male-to-female ratio was 14:3 and the median age was 15 (range from 8 to 35). Conditioning regimens included Ara-C 3.0 g/m(2), 2 times per day x 3 d, on day 7, 6 and 5 pre-transplantation, CTX 45 mg/(kg per d) x 2 d on day 5 and 4 pretransplantation. TBI with 1000 cGy by 2 fractions on day 2 and 1 pretransplantation. The fresh and unmanipulated marrow was infused on day 0. Donors were received G-CSF (Lenograstim) at 3 - 4 microg/(kg per d) x 7 d. The BM cells were collected on eighth day. In GVHD prophylaxis, CSA, MTX, ATG (Antithymocyte globulin, Rabbit Fresenius S) and MMF (mycophenolate mofetic) were used in different periods. The dose of CSA was 1.5 mg/(kg per d) on day 7 to 1 pretransplantation, then 3 mg/(kg per d) from day 1 pretransplantation. MTX was 15 mg/m(2) on day 1 and 10 mg/m(2) on day 3, 6 and 11 posttransplantation. ATG was administered day 4 to 1 pretransplantation at 5 mg/(kg per d) and MMF dose was 1.0 g/d from day 7 posttransplantation. All patients established successful engraftment after initial transplantation. The median days of neutrophil exceeding 0.5 x 10(9)/L and platelet exceeding 20 x 10(9)/L were 18 (range 13 - 23) and 20 (range 16 - 32) days, respectively. Patients were monitored up to day 100 for the sign of aGVHD. The established grades II to IV aGVHD occurred in 5 out of 17 patients (29.4%). Eleven patients were surviving at a median follow-up of 13 months (range 3 - 27 months). Six out of the 17 patients died those 3 of them died of severe aGVHD, 2 of infection and 1 of leukemia relapse. Severe regimen-related toxicities were not experienced in all patients. The median follow-up period was 13 (range 3 - 27) months. Eleven patients were alive in disease-free situation with a Karnofsky performance status of 100%. This could be caused by the low overall incidence of aGVHD as a result of BM primed with G-CSF. The four-agent of immunosuppressive combined prophylaxis against GVHD in different periods may be highly effective.
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PMID:[Successful engraftment of T-cell undepleted haploidentical transplants by donor primed with G-CSF and additional use of ATG and MMF for recipients]. 1251 19

To establish a mouse model bearing transplantable human chronic myeloid leukemia for hematopoietic stem cell transplantation to treat leukemia, 4 - 5-week-old female BALB/c nude mice were given cyclophosphamide 2 mg/mouse at day -2, -1, and then the human chronic myeloid leukemia K562 cells were engrafted into the mice at day 0 by injection via tail vein or peritoneal cavity. PB and BM cells were collected, the CD45, CD13, and CD33 antigens were delected by using FCM, the bcr/abl fusion gene mRNA was examined by RT-PCR. The results showed that transplantable leukemic mice could be yielded from 4 - 5-week-old nude mice either by injection through tail vein or peritoneal cavity when the total number of inoculated tumor cells was more than 2 x 10(5) per mouse, whether being pretreated with 2 mg CTX/mouse or not. The transplanted mice could survive 30 - 60 day with leukemia. In conclusion, the mouse model bearing leukemia can be established by inoculation 2 x 10(5) K562 cells into immunodeficient BALB/c nude mice.
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PMID:Establishment of a transplantable human myeloid BALB/c nude mouse model. 1612 41

Cardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has been reported to have anticancer activity. CTX III-induced K562 cell apoptosis was confirmed by DNA fragmentation (DNA ladder, sub-G1 formation) and phosphatidylserine (PS) externalization with an IC(50) value of 1.7 microg/ml at 48 h. A mechanistic analysis demonstrated that CTX III-induced apoptotic cell death was accompanied by up-regulation of both Bax and endonuclease G (Endo G), and downregulation of Bcl-X(L). CTX III had no effect on the levels of Bcl-2, Bid, XIAP survivin, and AIF proteins. CTX III treatment caused loss of the mitochondrial membrane potential (DeltaPsim), release of mitochondrial cytochrome c to the cytosol, and activation of both caspase-9 and -3. CTX III-induced apoptosis was significantly blocked by the broad-spectrum caspase inhibitor Z-VAD-FMK. However, CTX III did not generate reactive oxygen species (ROS) and antioxidants, including N-acetylcysteine and catalase, did not block CTX III-induced apoptosis in K562 cells. Modulation of Bax, Bcl-XL, and the Endo G proteins, release of mitochondrial cytochome c, and activation of caspase-3 and -9 all are involved in the CTX III-triggered apoptotic process in human leukemia K562 cells.
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PMID:Up-regulation of Bax and endonuclease G, and down-modulation of Bcl-XL involved in cardiotoxin III-induced apoptosis in K562 cells. 1695 23

Cardiotoxin III (CTX III) is a basic polypeptide of 60-amino acid residues isolated from Naja naja atra venom, exerts its anti-proliferative activity in human leukemia K562 cells. In the present study, the expression of mRNAs and proteins related to cell cycle and apoptosis in human leukemia K562 cells induced by CTX III was investigated by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. Flow cytometric analysis revealed that CTX III resulted in G2/M phase arrest in the cell cycle progression, which was associated with a marked decrease in the mRNA and protein expressions of cyclin A, cyclin B1, and Cdk 2, with no detectable changes in the levels of Cdk 1, cyclin D1, and cyclin E. Moreover, the increase in apoptosis was associated with the Bax gene and protein levels significantly increased as treatment durations of CTX III increased, while the Bcl-2 mRNA and protein levels exhibited no changes. We also observed that caspase-9 and caspase-3 genes remained unchanged up to 12 h with 2 microg/ml CTX III. These molecular alterations provide an insight into CTX III-caused growth inhibition, G2/M arrest, and apoptotic death of K562 cells.
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PMID:Effects of cardiotoxin III on expression of genes and proteins related to G2/M arrest and apoptosis in K562 cells. 1714 43

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor clinical outcome. Although front therapy induces a high rate of complete remission (CR), relapse is inevitable and new regimens are much needed for relapsed MCL. The proteasome inhibitor bortezomib (BTZ) induces apoptosis and sensitizes MCL cells to chemotherapy in relapsed MCL, but CR rates are low, with a short duration of response and severe toxicity. Here we evaluated whether BTZ is additive or synergistic with cyclophosphamide (CTX) and rituximab (RTX). Increasing doses of BTZ with a fixed dose of RTX and CTX (BRC regimen) resulted in markedly synergistic growth inhibition of MCL cells. BRC significantly enhanced apoptosis in MCL cell lines and primary tumor cells compared with single-agent treatment. Furthermore, western blotting analysis indicated that BRC induces apoptosis earlier via activation and cleavage of caspases-8, -9 and -3, and poly (ADP-ribose) polymerase, than single-agent treatment. The pan-caspase inhibitor completely blocked apoptosis induced by BRC. In vivo studies showed that BRC eradicated subcutaneous tumors in MCL-bearing SCID mice and significantly prolonged the long-term event-free survival in 70% of the mice. Hence, our study demonstrates that cytoreductive chemotherapy with both BTZ and anti-CD20 antibody may offer a better therapeutic modality for relapsed MCL.
Leukemia 2008 Jan
PMID:Bortezomib is synergistic with rituximab and cyclophosphamide in inducing apoptosis of mantle cell lymphoma cells in vitro and in vivo. 1789 87

Human thioredoxin reductase (TrxR) system is associated with cancer cell growth and anti-apoptosis process. Effects of 1,2-[bis(1,2-benzisoselenazolone-3(2H)-ketone)]ethane (BBSKE), a novel TrxR inhibitor, were investigated on human leukemia cell lines HL-60 and K562. BBSKE treatment induced cell growth inhibition and apoptosis in both cell lines. Apoptosis induced by BBSKE is through Bcl-2/Bax and caspase-3 pathways. Ehrlich's ascites carcinoma-bearing mice were used to investigate the anti-tumor effect of BBSKE in vivo. Tumor-bearing mice treated with BBSKE showed an increase of life span with a comparable effect to cyclophosphamide (CTX). These results suggest a potential usage of BBSKE as a therapeutic agent against non-solid tumors.
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PMID:A novel thioredoxin reductase inhibitor inhibits cell growth and induces apoptosis in HL-60 and K562 cells. 1819 8

We examined the anti-tumour activity of exosomes derived from dendritic cells (DCs) in combination with cyclophosphamide (CTX) and polyinosinic-polycytidylic acid sodium salt (poly I:C). DCs were pulsed with L1210 lymphocytic leukaemia cell antigen and lipopolysaccharide. The exosomes that the DCs secreted were purified. In vitro, the anti-tumour activity of exosomes was assessed by measuring their ability to induce spleen cell proliferation and the extent to which they induced spleen cells to kill L1210 cells. Poly I:C was able to induce DC maturation. DC-derived exosomes stimulated spleen cell proliferation and enhanced the cytotoxic effects of spleen cells in vitro. DC-derived exosomes, in combination with CTX and poly I:C, suppressed L1210 tumour growth in vivo and gave the greatest prolongation of survival time in tumour-bearing DBA2 mice. These findings suggest that this combination of a tumour vaccine, a conventional anti-cancer agent and a promoter of DC maturation might be a useful anti-cancer therapy.
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PMID:Anti-tumour effects of exosomes in combination with cyclophosphamide and polyinosinic-polycytidylic acid. 1909 45


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