[Prognosis factors in imatinib mesilate therapy in patients with a chronic phase of Ph-positive chronic myeloid leukemia: data from a multicenter non-randomized trial in Russia].

AIM: To reveal prognostically significant factors affecting efficacy of glivek therapy in untreated (duration of the disease < or = 6 months) and pretreated (duration of the disease > 6 months) patients with chronic myeloid leukemia (CML) in a chronic phase. MATERIAL AND METHODS: A total of 338 patients (64 untreated and 274 pretreated) with a chronic-phase CML on glivek therapy entered the trial. RESULTS: Five-year survival on glivek was high (89, 98 and 88% in untreated and pretreated patients, respectively). Incidence of transformation in the acceleration phase and blast crisis was low both in untreated and pretreated patients (1.6 and 11%, respectively) and correlated with the rate of a complete cytogenetic response (CCR). Untreated patients had no factors affecting treatment efficacy negatively, CCR probability was 96%. Blastemia, thrombocytosis and splenomegaly reduced CCR probability significantly in pretreated patients. Slow reduction of the tumor mass, late achievement of a complete hematological response and a cytogenetic response decreased probability of CCR. CONCLUSION: Glivek is a drug of choice for patients with chronic-phase CML. High probability of CCR both in untreated and pretreated patients lowers the risk of the disease transformation into the phase of acceleration/blast crisis and raises overall survival in both groups.

[The influence of mesenchymal stem cell transplantation time on myocardial reparation in rat experimental heart failure].

Mesenchymal stem cells (MSCs) have an ability to migrate in the organism to injured tissue to exert influence on inflammation and reparation in these regions. The aim of this study was to determine the optimal time of MSCs transplantation for myocardial reparation in rat experimental heart failure. The experiments were carried out on inbred line Wistar-Kyoto rats. Myocardial experimental infarction (EI) was induced by ligation of the left descending coronary artery. MSCs were isolated from bone marrow, cultivated in vitro and injected into the tail vein on the day of experimental infarction operation. It was shown that the time of MSCs transplantation exerted an essential influence on angiogenesis in a damaged myocardium, on ventricular dilatation and morphological structure of the scar. The best time for MSCs transplantation was determined within two days before EI, and seven days after EI. As a result, the overload of the border zone of infarct region decreased, and no features of infarction relapse were shown in the border zone.

[The effect of the bone marrow fibroblasts from patients with malignant diseases of the blood system on the colony-forming capacity of granulomonocytic precursor cells]. / Vliianie fibroblastov kostnogo mozga bol'nykh zlokachestvennymi zabolevaniiami sistemy krovi na kolonieobrazuiushchuiu sposobnost' granulomonotsitarnykh kletok-predshestvennikov.

The inhibiting activity of bone marrow fibroblasts and their ability to sustain survival of granulocytic cell precursors have been studied in patients with chronic myelocytic leukemia, chronic lymphoproliferative disorders, acute leukemia, myelodysplastic syndrome. Fibroblast conditioned medium inhibits proliferation of granulomonocytic precursors stimulated by leucocyte feeder layer or leucocyte conditioned medium. The effect depends both on the presence of monocytes and the specificity of the disease. The inhibitory effect is related with long-ranged factors. Bone marrow fibroblasts are able to sustain survival of hemopoietic precursors via humoral and cell-cell mechanisms. The regulatory role of bone marrow fibroblasts in hemopoietic disorders is discussed.

[The sensitivity to growth factors of NIH 3T3 cells transformed by the v-myc oncogene]. / Chuvstvitel'nost' k faktoram rosta kletok NIH 3T3, transformirovannykh onkogenom v-myc.

Transformation of NIH 3T3 cells, induced by v-myc oncogene, activates a proliferative potential of the cells cultivated in the serum-free medium, and reduces the ratio of 3H-Tdr incorporation into the cells grown in the presence of 10% fetal serum in comparison to those grown in the serum-free medium. The v-myc transformed cells (NIH 3T3-v-myc) as well as the untransformed ones are very responsive to insulin. On the other hand, the epidermal growth factor, able to stimulate proliferation of NIH 3T3 cells, exert no effects on the NIH 3T3-v-myc cells. The NIH 3T3-v-myc cells cultivated in the medium, containing 2.5% human plasma enriched with thrombocytes, have the same proliferative characteristics as cells grown in the thrombocyte-free plasma. It is concluded that transformation of NIH 3T3 cells induced by v-myc oncogene may reduce a requirement for thrombocyte-released growth factors and EGF but not for insulin.

[Effect of UV-irradiated donor blood on the colony-forming ability of human bone marrow cells in culture]. / Vliianie UF-obluchennoi donorskoi krovi na kolonieobrazuiushchuiu sposobnost' kletok kostnogo mozga cheolveka v kul'ture.

A possible mechanism of the hemopoiesis stimulation by UV and solar radiation was studied. The UV irradiation of leucocyte-enriched donor serum results in increasing the colony formation activity of the serum. The addition of such a serum but depleted of leucocytes to human bone marrow cells in semisolid agar culture stimulates its colony formation by 1.5-3 times. A serum depleted of leucocytes before the irradiation has not this property. It is supposed that cell surface glycoproteins, desorbing into the serum under UV irradiation, induce the colony formation activity of UV-irradiated blood.

[Mesenchymal stem cell transplantation for myocardial reparation of rat experimental heart failure]. / Terapiia éksterimental'nogo infarkta miokarda u krys s pomoshch'iu transplantatsii singennykh mezenkhimnykh stvolovykh kletok.

Mesenchymal stem cells (MSC) are resident pluripotent cells of bone marrow stroma. MSC have the ability to differentiate into osteoblasts, chondroblasts and adipocytes, neurons, glia and also into cardiomyocytes. The problem of MSC use in cell therapy of various diseases and in myocardial infarction therapy is widely discussed at present. The experiments were carried out on the inbred line Wistar--Kyoto rats. Myocardial experimental infarction (EI) was induced by left descending coronary artery ligation. MSC were isolated from bone marrow, cultivated in vitro and injected into the tail vein on the day of experimental infarction operation. It was shown that the structure of injured myocardium in experimental group significantly differed from that in control group. MSC transplantation led to inflammatory process acceleration and to increased angiogenesis in the damaged myocardium; also, live cardiomyocyte layers were detected in the scar. As a result, ventricular dilatation and overload of the border zone of infarct region decreased, no features of infarction relapse were shown in the border zone.

[The effect of the murine stromal cell line MS-5 on the proliferation and apoptosis of human erythromyeloid leukemic cell line K562]. / Vliianie myshinoi stromal'noi linii MS-5 na proliferatsiiu i apoptoz éritroleikemicheskoi linii k562.

Effects of stromal environment on human leukemic cell apoptosis and proliferation have been investigated. The MS-5 cell line (kindly provided by Dr.Itoh) capable of supporting human hemopoietic cells and the K562 human erythromyeloid leukemic cell line were used. The total increment of cultured leukemic cells was lower than in control due to their co-cultivation with stromal cells, 96% of cells remaining viable. Colony formation by K562 cells appeared to be significantly lower, too (7.2 vs. 22 colonies per 10(3) cells). Inhibition by stromal cells was reproduced when stromal and leukemic cells were separated by a 0.5% agar layer as well as when leukemic cells were cultured on an agar layer which contained a 50% condition medium. Morphological signs of apoptosis in 78.75 +/- 7.64% of leukemic cells, as a result of serum deprivation, were in evidence after 72 hr. while only 14.33 +/- 3.69% of cells co-cultured with MS-5 died. Only 4% of adherent cells showed morphological signs of programmed death. Since protein bcl-2 was not detected in K562 cells it may be suggested that apoptosis of leukemic cells co-cultured with stromal ones does not use the bcl-2 gene pathway. Stromal cell-mediated inhibition of proliferation may be effected through humoral mechanisms.

[Effect of ionizing radiation on functional activity of macrophagesi]. / Vliianie ioniziruiushchei radiatsii na funktsional'nuiu aktivnost' makrofagov.

It was shown that in vitro irradiation (8 Gy) of murine peritoneal macrophages suppressed their spontaneous cytotoxity and induced growth-stimulating activity. Exposure to 4 Gy induced mRNA proximal factors--TGF-beta and TNF-alpha and boosted growth-stimulating activity. These effects should be considered when evaluating efficacy of radiotherapy for tumors.

[Effect of stromal cells of the bone marrow on hematopoiesis in culture]. / Vliianie stromal'nykh kletok kostnogo mozga na gemopoez v kul'ture.

The authors studied the effect of medullary fibroblasts on granulomonocytopoiesis in a semi-solid agar gel. Seventy-three untreated patients with the blood system diseases and 18 hematologically healthy subjects were entered into the study. The medium conditioned with fibroblasts and fibroblasts themselves are capable of stimulating granulomonocytopoiesis. In addition, fibroblasts can exert an inhibitory effect on granulomonocytopoiesis, with the degree of this effect being dependent on the agar layer thickness. Patients with chronic lympholeukemia and acute lymphoblastic leukemia showed a decrease in the stimulating activity of fibroblasts, whereas in patients with chronic myeloleukemia, that activity was elevated. In patients with neutropenic conditions, the stimulating activity of fibroblasts depended on a factor that produced neutropenia. The role of the alterations in question in the pathogenesis of the blood system diseases and other possible influences of fibroblasts on myelopoiesis are discussed.

[Effectiveness of dose-intensive polychemotherapy with autologous hemopoietic cell transplantation for high-grade non-Hodgkin lymphoma]. / Effektivnost' intensifikatsii polikhimioterapii, vkliuchaia autologichnuiu transplantatsiiu gemopoéticheskikh kletok, u bol'nykh nekhodzhkinskimi limfomami vysokoi stepeni zlokachestvennosti.

The study included 29 patients with high-grade non-Hodgkin's lymphoma. Nine patients (group 1) received 6-8 cycles of CHOP, another 20-6 cycles of CHOP and Dexa-BEAM followed by autologous hemopoietic cell transplantation with CBV or BEAM conditioning regimen (bone marrow or peripheral stem cells) (group 2). The groups were comparable as far as gender and age are concerned. Overall 5-year survival was in 24.1 and 71.4%, respectively. Double CHOP-Dexa-BEAM plus autologous hemopoietic cell transplantation proved superior to standard CHOP-therapy.

[The MDR gene and cellular sensitivity to various effects]. / Gen mdr i chuvstvitel'nost' kletok k razlichnym vozdeistviiam.

mdr-Transfected K-562 cells revealed a relatively high resistance to cytotoxic monokines and ionizing radiation as compared to parental cells. Taken together with what is known about the resistance of mdr-expressing cells to multiple cytotoxic drugs, our results point to malignant cells having universal mechanisms of chemo-, bio- and radioresistance.

[Use of dexamethasone in treatment of high- and low-grade non-Hodgkin's lymphoma]. / Primenenie deksametazona pri nekhodzhinskikh limfomakh vysokoi i nizkoi stepeni zlokachestvennosti.

Since it exerts a stronger antitumor action than predinisolone, dexamethasone was used for therapy of patients with non-Hodgkin's lymphoma refractory to CHOP. All patients (66), resistant to CHOP, suffered bone marrow involvement. Dexamethasone pulsed therapy was given to 45 patients, with 21 COP-BLAM or ASHAP, MAD, Dexa-BEAM treated in control. Median response duration in high- and low-grade non-Hodgkin's lymphoma groups was 2 and 12 months, respectively.

[The use of fludarabine phosphate (Fludara) to treat chronic B-cell lymphocytic leukemia and non-Hodgkin's lymphoma resistant to standard chemotherapy]. / Fludarabina fosfat (Fludara) v lechenii reziztentnykh k standartnoi khimioterapii bol'nykh B-kletochnym khronicheskim limfoleikozom i nekhodzhkinskimi limfomami.

Following monochemotherapy with fludarabin phosphate (fludara), complete (18%), and partial remission (27%) with stabilization (45%) was recorded in patients with B-cell chronic lymphocytic leukemia, most of whom were resistant to alkylating cytostatic drugs and their combinations containing anthracyclines. Long-term remission was registered in patients with low and moderate grade non-Hodgkin's lymphoma, resistant to standard cytostatic treatment, due to the therapeutic synergism of fludara and cytosinarabinoside (FAVAMP).

[The clinical significance of MDR-1 gene expression in the hemopoietic cells of patients with acute leukemias in different phases of the disease]. / Klinicheskoe znachenie ékspressii gena MDR-1 v gemopoéticheskikh kletkakh bol'nykh ostrymy leikozami v raznykh fazakh zabolevaniia.

AIM: Analysis of cytostatic therapy effects on expression of gene MDR-1 in hemopoietic cells of patients with acute leukemia (AL) in complete clinicohematological remission (CCHR). MATERIALS AND METHODS: The study included 48 AL patients. 27 of them were untreated, 25 were resistant to or had recurrent AL. 4 patients were followed up. Bone marrow mononuclear fraction was investigated. Expression of MDR-1 gene in the cells was evaluated at hybridization. RESULTS: High expression of MDR-1 gene occurred in leukemic blast cells either upon achievement of CCHR or at least 6 months after its onset. When using schemes of chemotherapy containing two potential inductors of gene MDR-1, expression of this gene was registered significantly more frequently than in using schemes based on one inducing drug (p < 0.05). Frequency of occurrence of enhanced expression of gene MDR-1 in leukemic blasts significantly correlated with frequency of CCHR (p < 0.05). Correlation between occurrence of the gene's expression in normal hemopoietic cells in CCHR and occurrence of early AL recurrences was not found. CONCLUSION: The findings may facilitate design of new AL treatment programs.

[Hyperexpression of the multiple drug resistance gene (MDR-1) in chronic myeloleukemia patients]. / Giperékspressiia gena mnozhestvennoi lekarstvennoi ustoichivosti (MDR-1) u bol'nykh khronicheskim mieloleikozom.

AIM: To elucidate prognostic value of MDR-1 gene expression in patients with chronic myeloid leukemia (CML). MATERIALS AND METHODS: The MDR-1 gene expression was studied by in situ hybridization in hemopoietic cells of 63 Ph-positive CML patients in different phases of the disease. The survival of the patients and duration of the chronic phase (CP) were evaluated using the Caplan-Meyer method. RESULTS: MDR-1-positive patients had a shorter survival (p < 0.01) and CP (p < 0.05) than negative ones. MDR-1 gene overexpression has no impact either on the survival or duration of AP and BP (p < 0.05). Moreover, the MDR-1 gene overexpression is not dependent either on the previous treatment or other prognostic markers. CONCLUSION: Overexpression of MDR-1 gene is an independent prognostic factor and an additional parameter to Sokal's scores.

[The effectiveness of interferon-alpha therapy in Ph-positive chronic myeloid leukemia]. / Effektivnost' interferon-alpha terapii u bol'nykh Ph-pozitivnym khronicheskim mieloleikozom.

Chronic myeloid leukemia (CML) is a hemopoietic condition caused by chromosomal translocation t(9;22)(q34;q11) or bcr-abl fusion gene. The predominant variants of bcr-abl oncogene rearrangement are b3a2 and b2a2. The present study evaluated the efficacy of interferon-a therapy of CML patients and molecular prognostic factors. Cytogenetic response and complete hematological remission were more frequent in CML b3a2 treatment with interferon-a. Moreover, after therapy, chronic phase lasted in that group (p = 0.026) much longer. Overall survival in the group was significantly longer, too (p = 0.046).

[Effectiveness of high-dose polychemotherapy and autologous hemopoietic cell transplantation in patients with low-grade non-Hodgkin lymphoma]. / Effektivnost' intensifikatsii polikhimioterapii i autologicheskoi transplantatsii gemopoéticheskikh kletok u bol'nykh nekhodzhkinskimi limfomami nizkoi stepeni zlokachestvennosti.

The study included 70 patients with high-grade malignant non-Hodgkin's lymphoma (Kiel) who received the following treatment: group 1(24)--6-8 cycles of CHOP; group 2 (relapse or tumor progression after standard chemotherapy--13)--6 cycles of CHOP and Dexa-BEAM, and group 3 (relapse or tumor progression after standard chemotherapy--8)--6 cycles of CHOP plus Dexa-BEAM plus autologous hemopoietic cell transplantation with CBV or BEAM conditioning regimen (bone marrow or peripheral stem cells). The groups were comparable as far as gender and age are concerned. Overall 5-year survival rates were 81, 20 and 48%, respectively. CHOP-Dexa-BEAM plus autologous hemopoietic cell transplantation proved superior to CHOP-Dexa-BEAM alone.

[Detection of chromosome translocation t(9;22) using RT-PCR]. / Vyiavlenie khromosomnoi translokatsii t(9;22) metodom RT-PTSR.

The investigation deals with a simplified modification or molecular-genetic detection of translocation t(9;22) using a combination of reverse transcription and polymerase chain reactions (RT-PCR). Unlike the available protocols, analysis is carried out using one enzyme--TET-Z polymerase--(instead of two) which has both revertase and DNA-polymerase activities. The present modification is highly sensitive, less time-consuming and cheaper. The method has proved useful for both diagnosing t(9;22) translocation and diagnosing and monitoring minimal residual disease remaining after marrow transplantation.