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)

Kinetics of transport of the acridine derivative 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) were examined in P388 murine leukemia cells and in P388/ADR, a subline selected for adriamycin resistance and cross-resistant to a variety of drugs including m-AMSA. Compared with the drug-responsive parent cell line, P388/ADR cells showed impaired accumulation of m-AMSA and an enhanced rate of drug exodus. Competition studies demonstrated structural specificity of the outward transport process. There was a low degree of intracellular m-AMSA binding, and steady-state drug levels were reached in less than 1 min. These results suggest that m-AMSA will be a useful probe for studying transport systems associated with anthracycline resistance.
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PMID:m-AMSA as a probe for transport phenomena associated with anthracycline resistance. 658 5

Idarubicin (IDR) is a new analog of Daunorubicin (DNR) selected for clinical trials because of its outstanding activity in experimental leukemias of mice and in several experimental models when compared to DNR and Doxorubicin. This Phase I trial was designed to determine the maximal tolerated dose in adult patients with acute leukemia refractory to prior treatment, using intravenously (I.V.) daily treatments for 5 consecutive days. Eleven patients were entered in this study. The initial dose of IDR was 4 mg/m2/d X 5 I.V. The highest dose given was 8 mg/m2/d X 5 I.V. Dose limiting toxicity were gastrointestinal side effects at the 8 mg/m2/d X 5 level (mucositis-diarrhea). Antileukemic activity has been detected in acute non-lymphoblastic leukemia not pretreated with anthracyclines. For Phase II adult leukemia studies using this schedule, it is recommended that the IDR dose should be 7 mg/m2/d.
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PMID:Phase I trial of Idarubicin (4-demethoxydaunorubicin) in adult acute leukemia. 659 42

The effects of perhexiline maleate on growth and drug sensitivity were studied in the P388 murine leukemia cell line and in an anthracycline-resistant subline (P388/ADR). At noninhibitory concentrations, perhexiline maleate markedly increased the sensitivity of P388/ADR cells to doxorubicin but did not have such an effect on anthracycline-sensitive cells. The effects of perhexiline maleate on P388/ADR cells were reversible. Perhexiline maleate also increased the accumulation of another anthracycline, daunorubicin, in P388/ADR cells but did not increase its accumulation in the anthracycline-sensitive cells. Perhexiline maleate did not affect the sensitivity of either cell line to methotrexate or to 6-mercaptopurine. However, its effects on the sensitivity and on drug accumulation of vinblastine, a drug to which P388/ADR cells are cross-resistant, were similar to those observed for the anthracyclines. Although perhexiline maleate has been reported to be a calcium antagonist in other systems, our data do not suggest that this mechanism is involved in its enhancement of the sensitivity of P388/ADR cells to doxorubicin. We suggest instead that this effect might be associated with alterations of cell lipid metabolism induced by perhexiline maleate.
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PMID:Reversal of acquired resistance to doxorubicin in P388 murine leukemia cells by perhexiline maleate. 669 32

An anthracycline-resistant subline of P388 murine leukemia cells, P388/ADR, has been shown to have an altered total lipid content and composition when compared to the parent line. When specific lipids of the cell lines are compared, it is found that P388/ADR cells contain approximately 3.6 times the amount of triglycerides as P388 cells. Although no differences are noted in the amounts of unesterified cholesterol or total phospholipids in the two cell lines, they do differ in specific phospholipid patterns. P388/ADR cells contain relatively less phosphatidylcholine and more sphingomyelin than drug-sensitive cells. No differences are observed in the content of phosphatidylethanolamine and cardiolipin. The difference in phosphatidylcholine/sphingomyelin ratio (5.57 for ADR-sensitive cells and 3.28 for ADR-resistant cells) may account for the previously observed difference in plasma membrane lipid structural order between these cell lines. Measurements of the relative activity of phosphocholine transferase in the two lines, using the rate of incorporation of 3H-choline into phosphatidylcholine, indicate that lower phosphocholine transferase activity in P388/ADR cells may account for the observed changes in cellular lipid and phospholipid composition.
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PMID:Differences in lipid composition of doxorubicin-sensitive and -resistant P388 cells. 671 19

E-N-L-trimethyl lysine (TML) decreases the toxicity of Vincristin, Cyclophosphamide and Doxorubicin (Adriamycin) when administered simultaneously to healthy mice. Simultaneous treatment of L1210 ascites leukemia bearing mice with 100 mg/kg TML and 2, 2.5, 3.2, 3.5, 4 mg/kg Vincristin or 10-15; 20 mg/kg Doxorubicin increases significantly the survival of the animals when compared with untreated and Vincristin or Doxorubicin treated mice. Repeated impulse treatment of S-180 subcutaneous sarcoma with 100 mg/kg TML and 50-100 mg/kg Cyclophosphamide results in a significantly higher surviving time and surviving rate than Cyclophosphamide treatment alone.
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PMID:Combined effect of cytostatic drugs and E-N-L-trimethyl lysine in healthy and transplantable tumor bearing mice. 681 49

Cell surface modification was studied in a subline of murine leukemia resistant to adriamycin (P388/ADR). Lectin-induced agglutination was used as a probe. Agglutination was studied using two plant lectins, wheat germ agglutinin (WGA) and Ricinus communis agglutinin-I (RCA-I). A 7-fold higher amount of WGA and 14-fold higher amount of RCA-I were required to bring about minimum agglutination of P388/S as compared to P388/ADR. The present studies clearly indicate a change in the plasma membrane of P388/ADR cells.
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PMID:Differential agglutination of P388 adriamycin-sensitive and P388 adriamycin-resistant leukemia cells. 684 44

Prolymphocytic leukemia (PL) is a clinically distinct leukemic disorder. Cytochemical and surface marker characteristics help to differentiate PL from other types of leukemia, including chronic lymphocytic leukemia (CLL). In contrast to patients with CLL, those with PL frequently require early therapeutic intervention. Standard treatment regimens for CLL as well as splenectomy and splenic irradiation have not been effective in the treatment of PL. Combination chemotherapy with cyclophosphamide, Doxorubicin, vincristine, and prednisone (CHOP) has produced impressive clinical responses in patients with PL. The treatment of a patient with PL is discussed and the literature is reviewed.
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PMID:Prolymphocytic leukemia: treatment with combination chemotherapy to include doxorubicin. 695 Aug

Calphostin C is a potent and specific inhibitor of protein kinase C (PKC). In this investigation we examined the effect of Calphostin C (without prior exposure to light) on daunorubicin (DNR) accumulation and sensitivity to DNR in multidrug-resistant (MDR) murine leukemia P388/ADR and human myeloid leukemia HL60/AR cells. P388/ADR cells overexpress P-glycoprotein, whereas HL60/AR cells lack any expression of P-glycoprotein (both at mRNA and protein levels). Calphostin C, in a concentration-dependent manner, increased the accumulation of DNR in P388/ADR cells and partially reversed (threefold) the DNR resistance in P388/ADR cells but had no effect on either of the parameters in HL60/AR cells. Calphostin C-induced increased accumulation of DNR in P388/ADR cells was due to increased uptake and decreased efflux of DNR. Furthermore, Calphostin C increased the uptake and decreased the efflux of rhodamine 123 (a substrate for P-gp) in P388/ADR cells but had no such effect in P388 cells. In addition, Calphostin C without exposure to light did not inhibit PKC activity in any of the cell lines studied. Taken together, these data suggest that Calphostin C may reverse drug resistance via P-glycoprotein independently of its effect on PKC activity. Therefore, any data regarding the effect of Calphostin C on the reversal of MDR should be interpreted in the light of these findings.
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PMID:Effect of Calphostin C (PKC inhibitor) on daunorubicin resistance in P388/ADR and HL60/AR cells: reversal of drug resistance possibly via P-glycoprotein. 751 83

The development of drug resistance in cancer cells is a significant clinical problem for the successful cancer chemotherapy. Since the cytoskeleton, including microtubules, may be involved in modulating cellular signal transduction, morphological and structural changes, the microtubules assembly of multidrug resistant cells was examined using Confocal Laser Microscope MRC500 system (Bio Rad). In this study, multidrug resistant cells were established by the continuous exposure to ADR(adriamycin) starting with 20 nM up to 1 microM. The expression of MDR-1 (multidrug resistance) gene was detected in K562 leukemia cells and to more extent in the multidrug resistant K562/ADR cells, but not in HL-60 leukemia cells and multidrug resistant HL-60/ADR cells by RT-PCR method. The chronological features of microtubules assembly in the parent cell lines were lost on day 3, after incubation with 20nM of ADR. In accordance with development of drug resistance, the microtubules assembly appeared to be more dense and stronger than that of parent cells. During the development of drug resistant cells, the ADR-accumulation in the nucleus was decreased according to the increase of microtubules assembly. In the case of incubation with 0.5 microM colcemid, an inhibitor of microtubules polymerization, for 3 hours, the stainings of microtubules were lost their fine network and appeared to be diffuse and dot-like pattern. At the same time, both untreated HL-60/ADR and K562/ADR showed the decrease of ADR-accumulation, but the accumulations both colcemid treated resistant cells were increased the same level of their parent cells at the point of 120 min. These results suggested that the resistance to ADR in human leukemia cells correlated with microtubules assembly, and the microtubules assembly played an important role of drug resistance with or without MDR-1 gene overexpression.
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PMID:[Studies on the microtubules assembly of multidrug-resistant human leukemic cells]. 759 Jun 4

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.
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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


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