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

To evaluate the expression of multidrug resistance (MDR) on normal and leukemia cells, we examined P-glycoprotein (P-gp) by a newly devised flow cytometric method, utilizing a biotinylated monoclonal antibody (mAb) against P-gp (MRK16), a streptavidin-RED670 conjugate (SA-RED670) and appropriate emission filters. The combination of biotinylated MRK16 (b-MRK16) and SA-RED670 resulted in higher sensitivity as compared with standard methods such as the use of streptavidin-phycoerythrin (SA-PE) conjugate. The sensitivity was examined in K562, K562/ADR, NOMO-1, NOMO-1/ADR and HL60 cells, and compared with the data obtained from reverse transcription polymerase chain reaction (RT-PCR) of mdr-1 gene. P-gp positivity on flow cytometry was 10.4%, 99.9%, 1.4%, 90.4% and 0%, respectively. Mdr-1 mRNA was well expressed in K562/ADR and NOMO-1/ADR cells, but not in NOMO-1 and HL60 cells. In K562 cells, mdr-1 was found after 40 cycles of PCR, but not 25 cycles. These data are well correlated with those from the flow cytometry. We then studied the P-gp expression on normal peripheral blood cells and acute leukemia cells. P-gp was little expressed on peripheral lymphocytes, monocytes and granulocytes. It was also little expressed on blast cells from 5 patients with acute promyelocytic leukemia (AML) and 5 acute lymphocytic leukemia (ALL) expressed P-gp at diagnosis, ranging from 8.5% to 34.5% (16.9 +/- 11.8%) and from 2.3% to 45.6% (24.0 +/- 17.8%), respectively. All 9 relapsed or refractory cases expressed P-gp, ranging from 21.1% to 99.8% (52.2 +/- 29.9%). Significant differences were found in APL, CD34-positive and relapse and refractory cases (P = 0.0006, 0.0007 and 0.0088, respectively). These results indicate that this flow cytometric analysis is useful for the evaluation of clinical MDR status and can identify a group of patients with resistant leukemia.
 ...
PMID:New flow cytometric method for detection of minimally expressed multidrug resistance P-glycoprotein on normal and acute leukemia cells using biotinylated MRK16 and streptavidin-RED670 conjugate. 762 26

The very rapid development of techniques based on use of the polymerase chain reaction (PCR) for characterizing molecular lesions in leukaemia and lymphoma mow offers the opportunity for monitoring residual disease at a sensitivity of one malignant cell in 10(5) or 10(6) normal cells. Maximal specificity is achieved when the DNA sequences amplified are truly leukaemia-specific (i.e. BCR/ABL in CML, PML/RAR-alfa in APL, AML1/ETO in t(8; 21) AML and CBFB/MYH1 in inv(16) AML). A good level of sensitivity may also be achieved by using immunoglobin heavy chain (IGH) and T-cell receptor (TCR) gene rearrangements if a clonospecific probe can be generated. For clinical purposes the crucial issues are the following: can PCR techniques be used for confirmation of diagnosis and evaluation of extent of disease? Can PCR data obtained be developed to quantitate the PCR product and thereby increase its predictive value? These and other issues are still a matter of debate and several studies are presently in progress to address these points.
 ...
PMID:Minimal residual disease detection in human leukemias: biologic and clinical significance. 765 31

According to French and European experience, hyperleukocytosis occurs during ATRA differentiation therapy in about 70% of de novo and 25% of relapsed APL cases. The most frequently suggested cause for this side-effect is an ATRA-induced proliferation of APL cells. However, no definite explanation for such a proliferative effect has been clearly established. Another mechanism directly related to the differentiation of marrow leukemic cells could be a change in their microrheology, allowing their release from the bone marrow and their transfer toward peripheral blood (PB) and tissues. Using a single cell aspiration assay into a glass restrictive channel, we measured APL cell viscosity values in five de novo APL patients. A deformability index (DI) was defined as the ratio of mean normal neutrophil viscosity x 100/mean APL cell viscosity. Results were the following: (1) at diagnosis, two patients had high marrow DI (96 and 250%) and three patients had low marrow DI (16, 17, and 40%); (2) when PB and marrow APL cells were simultaneously tested, PB APL cells display higher DI than marrow APL-cells; (3) the two patients with high initial marrow DI experienced an ATRA-induced hyperleukocytosis after only 1 day of treatment; (4) in the three patients with low initial marrow DI, the DI was increasing during ATRA therapy and hyperleukocytosis seemed to occur when a large amount of maturing APL cells reached a viscosity value similar to that of mature neutrophils. These results suggest that an asynchronism between rheological and morphological maturation in each APL cell might explain the occurrence of hyperleukocytosis in some patients during ATRA differentiation therapy.
Leukemia 1995 Sep
PMID:Changes in microrheology of acute promyelocytic leukemia cells during all-trans retinoic acid (ATRA) differentiation therapy: a mechanism for ATRA-induced hyperleukocytosis? 765 14

Initial results of ATRA in newly diagnosed APL showed that this drug was associated with a high complete remission (CR) rate but also (i) to a risk of hyperleukocytosis and of ATRA syndrome, (ii) to rapid relapse unless ATRA was followed by intensive chemotherapy. These findings prompted our group to design an approach combining ATRA and intensive chemotherapy in newly diagnosed APL, where chemotherapy could prevent relapses and also, in cases with increasing leukocyte counts, could prevent the ATRA syndrome. In a pilot study, this approach gave a high CR rate (96%) and (with now prolonged follow-up) a significant reduction in the incidence of relapse, as compared to a historical control treated with chemotherapy alone. The superiority of the combination of ATRA and chemotherapy over chemotherapy alone (especially for the incidence of relapse) was subsequently confirmed in a randomized European trial (APL 91 trial). We are now testing in a new European trial (APL 93 trial) whether chemotherapy should be administered with ATRA, or should follow ATRA during induction treatment, and whether maintenance therapy with intermittent ATRA, low-dose chemotherapy, or both can further reduce the risk of relapse.
Leukemia 1994
PMID:Results of APL 91 European trial combining ATRA and chemotherapy: presentation of APL 1993 trial. 780 29

The current treatment of acute promyelocytic leukemia (APL, also called AML3 subtype) is focused on differentiating agents such as the vitamin A derivative all-trans retinoic acid (ATRA). This agent is a novel and very promising therapy for this disease characterized cytogenetically by a translocation t(15;17)(q21;q22) involving the alpha retinoic acid receptor on chromosome 17 and the PML gene on chromosome 15. Clinical trials have demonstrated that ATRA followed by or combined with conventional chemotherapy may be more beneficial than chemotherapy for inducing complete remission. Unfortunately, ATRA as a single agent, does not appear able to maintain patients in remission (median 5 months), and when relapse occurs resistance to a second induction of ATRA therapy is observed in almost all cases. Recently our laboratory investigated whether specific features of the AML3 cells at relapse could explain the in vivo resistance observed. We have demonstrated that AML3 patients' cells (from four patients) at relapse show high levels of CRABP, a cytosolic retinoic acid binding protein and this protein was not detected prior to ATRA therapy. Relapse-AML3 cells (n = 12) showed reduced differentiation induction when compared with 'virgin'-AML3 cells. Results from this study suggest that CRABP could modulate ATRA cellular concentrations reaching the nucleus. This induced ATRA hypercatabolytic state should be monitored during consolidation therapy and at relapse by evaluating CRABP and RA metabolite levels, in order to detect ATRA resistance in patients with AML3.
Leukemia 1994
PMID:In vitro all-trans retinoic acid (ATRA) sensitivity and cellular retinoic acid binding protein (CRABP) levels in relapse leukemic cells after remission induction by ATRA in acute promyelocytic leukemia. 781 31

All-trans retinoic acid (ATRA) has been demonstrated to be an efficient alternative to chemotherapy in the treatment of acute promyelocytic leukemia (APL or AML3). Complete remission is obtained by inducing granulocytic differentiation of the leukemic cells. To date, the exact mechanism through which ATRA exerts its differentiating effect is not known. The present investigation was initiated to characterize ATRA intracellular concentrations achieved in human myeloid leukemic cells in relation to their different sensitivity to ATRA differentiating effect. During the first 24 h of incubation, a significant decrease of ATRA in the culture medium and a marked increase in the intracellular concentrations were observed. Maximal uptake by the leukemic cells was reached within minutes, with levels between 20 and 260 pmol/10(6) cells (median = 100). Interestingly, a correlation between ATRA-induced differentiation and the intracellular ATRA concentration achieved was observed. In fact, patients with intracellular levels below 60 pmol/10(6) cells defined slow uptakers, never exceeded 40% differentiated cells at day 3. On the other hand, cells with 2-4-fold higher concentration (100-250 pmol/10(6) cells) achieved 100% differentiated cells at day 3. This report suggests that intracellular ATRA concentration is a key pharmacological parameter that should be taken into account to gain further insights into ATRA sensitivity in APL patients.
Leukemia 1995 Jan
PMID:Differential uptake of all-trans retinoic acid by acute promyelocytic leukemic cells: evidence for its role in retinoic acid efficacy. 784 8

All-trans-retinoic acid (ATRA) has been proven active against a range of malignancies in isolated tissue culture systems and in human clinical trials, but the duration of its effects has been transient. Recent evidence indicates that the basis for the limited duration of ATRA's activity, at least in one form of leukemia, is a pharmacological adaptation that results in reduced serum concentration after prolonged treatment. This finding suggests that an i.v. formulation of ATRA may significantly improve the potency and duration of ATRA's activity in leukemia and, potentially, other malignancies as well. Liposomal ATRA (L-ATRA) was developed to provide a formulation of this retinoic acid isomer that can be administered intravenously to provide potential pharmacological advantages over the oral formulation. When L-ATRA was administered to rats over a prolonged period, the blood levels of the drug did not change over time. In vitro studies of isolated liver microsomes revealed that catabolism of the drug was not altered in rats that were repeatedly administered the L-ATRA formulation. Whereas microsomes isolated from animals that were orally administered free ATRA the same number of times with the same doses showed a significant increase in metabolism of the drug. These results suggest that an i.v. formulation of ATRA such as L-ATRA could be extremely useful in inducing long-term remissions in patients with APL.
 ...
PMID:Liposome encapsulation circumvents the hepatic clearance mechanisms of all-trans-retinoic acid. 806 60

Annexin VIII is preferentially expressed in APL, but its level of expression in other subtypes of AML is much lower. Annexin VIII was originally found to be a vascular anticoagulant, but evidence obtained from our recent studies suggests that it does not play a role in hemorrhage diathesis in APL. The specific expression of annexin VIII in APL may relate to its possible role in hematopoietic cell differentiation. The expression of annexin VIII is developmentally regulated in APL-derived NB4 cells. It can be downregulated as a response to induction by ATRA, an agent which is also capable of inducing maturation of NB4 cells. Our current understanding is that annexin VIII is most likely involved in signal transduction and may have a role as a modulator of PKC. A change in cellular PKC activity is expected to have a significant impact on cell differentiation and proliferation. The biological function of annexin VIII is currently unknown, but its expression in APL and its possible role in differentiation and proliferation of the leukemia cells would provide an excellent model system to study and elucidate this intriguing question.
 ...
PMID:Expression of the annexin VIII gene in acute promyelocytic leukemia. 806 82

The apoptosis-associated DNA strand breaks were detected in situ, in individual leukemic cells in peripheral blood and bone marrow of over 110 patients with different types of leukemia (ALL, AML, CML in blastic crisis, APL), prior to and during routine chemotherapy. The DNA strand breaks were labeled with digoxigenin- or biotin-conjugated dUTP in the reaction catalyzed by exogenous terminal deoxynucleotidyl transferase, and the cells, counterstained for DNA, were analyzed by bivariate flow cytometry. The proportion of cells with DNA strand breaks prior to therapy, most likely reflecting spontaneous apoptosis, varied from 0.1 to 16%, but in the large majority of cases was below 3%. Administration of drugs of different classes, which included DNA topoisomerase I (Topotecan) and II (mitoxantrone, VP-16) inhibitors, antimetabolite (ara-C) or microtubule poison (Taxol), all triggered the appearance of cells with extensive DNA breakage, typical of apoptosis, to up to 80%. The peak of the response, measured as maximal percent of cells with DNA strand breaks, which varied between individual patients by as much as factor 10, was generally seen between 8 to 24 h after the initial administration of DNA topoisomerase inhibitors, and somewhat later (48-72 h) during the response to Taxol or ara-C. Thus, the data show that the response to treatment with a variety of drugs, in terms of induction of apoptosis, can be conveniently measured by the present method. The prognostic value of the apoptotic index, before, as well as during treatment, is being estimated for each type of leukemia, in the ongoing prospective studies.
 ...
PMID:Apoptotic cell death during treatment of leukemias. 807 83

Leukemia is well suited for monoclonal antibody therapy due to the accessible, differentiation antigens that characterize stages of maturation. In this paper, we describe the use of radio-labeled M195, a murine IgG2a, anti-CD33 monoclonal antibody, that can be used to effectively cytoreduce AML cells in relapsed patients when tumor burden is high; or to eliminate minimal residual disease and lengthen disease-free survival in patients with APL in remission. To decrease the likelihood of immunogenicity, a humanized IgG1 version of M195 was constructed that demonstrated a higher avidity and improved effector function than the parent murine antibody. Preliminary results of the first trial in AML using a humanized antibody showed specific bone marrow targeting without an immunogenic response.
 ...
PMID:Anti-CD33 monoclonal antibody M195 for the therapy of myeloid leukemia. 812 21


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>