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 have examined the effect of FK506 on the Adriamycin sensitivity of the multidrug resistant human chronic myelocytic leukemia cell line (K562/ADM). In K562/ADM cells, 1.0 microgram/ml FK506 reversed the resistance of Adriamycin, and increased the IC50 value for Adriamycin up to 17 fold. However, IC50 value for the parent cells (K562) increased only 1.5 fold. By cell cycle analysis, the accumulation in late S-G2M phase was confirmed on K562/ADM cells, treated with 1.0 microgram/ml FK506 and low-dose of Adriamycin. Cyclosporin A (CsA) could also restored the Adriamycin sensitivity in the K562/ADM cells, as previously reported. 1.0 microgram/ml FK506 as well as CsA significantly increased radioactive Adriamycin accumulation in K562/ADM cells and blocked [3H]azidopien photoaffinity labeling of P-glycoprotein. These results suggest that 1.0 microgram/ml FK506 could reverse the Adriamycin resistance in a MDR human leukemia cells through the interaction with P-glycoprotein.
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PMID:FK506 reverses adriamycin resistance in a multidrug-resistant human leukemia cell line. 128 34

SDZ 280-446 is a semi-synthetic derivative of a natural cyclic peptolide. Its ability to sensitise in vitro tumour cells whose resistance is due to P-glycoprotein-mediated anticancer-drug efflux was shown using four different pairs of parental drug-sensitive (Par-) and multidrug-resistant (MDR-) cell lines, from three different species (mouse, human, Chinese hamster) representing four different cell lineages (monocytic leukaemia, nasopharyngeal epithelial carcinoma, colon epithelial carcinoma, ovary fibroblastoid carcinoma), and using four different drug classes (colchicine, vincristine, daunomycin/doxorubicin and etoposide). By measuring its capacity to restore normal drug sensitivity of MDR-cells in culture in vitro, it appeared that SDZ 280-446 belongs to the same class of very potent chemosensitisers as the cyclosporin derivative SDZ PSC 833: both are about one order of magnitude more active than cyclosporin A (CsA), which is itself about one order of magnitude more active than other known chemosensitisers (including verapamil, quinidine and amiodarone which have already entered clinical trials in MDR reversal). Low concentrations of SDZ 280-446 could also restore cellular daunomycin retention in MDR-P388 cells to the levels found in the Par-P388 cells. SDZ 280-446 was also effective as a chemosensitiser when given orally in vivo. In a syngeneic mouse model, combined therapy with vinca alkaloids given i.p. and SDZ 280-446 given per os for 5 consecutive days significantly prolonged the survival of MDR-P388 tumour-bearing mice, when compared with mice receiving vinca alkaloids alone. Another protocol, using three cycles of i.p. doxorubicin at 4 day intervals, could also not increase MDR-P388 tumour-bearing mouse survival unless the mice received SDZ 280-446 orally 4 h before each doxorubicin injection. Though only very few combined therapy treatment protocols have been tested so far, clear increases in survival time of MDR-tumour-bearing mice were regularly obtained, leaving hope for major improvement of the therapy using other dosing schedules.
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PMID:SDZ 280-446, a novel semi-synthetic cyclopeptolide: in vitro and in vivo circumvention of the P-glycoprotein-mediated tumour cell multidrug resistance. 134 65

The hyperthermia as well as radiation responses of multidrug resistant (CEM/VLB100 with classical MDR and CEM/VM-1 with atypical MDR), methotrexate resistant (CEM/MTX) subclones of CCRF-CEM T-lineage ALL cell line were compared with those of a drug sensitive (CEM-1-3) subclone from the same parent cell line. Also analyzed were the hyperthermia as well as radiation responses of multidrug resistant (HL60/AR) and drug sensitive subclones of the HL60 AML cell line. Notably, the drug resistant subclones of CEM and HL60 were as sensitive to hyperthermia as were the drug sensitive subclones. Importantly, no thermotolerant plateau was observed in the hyperthermia survival curves of the drug resistant subclones, indicating that drug/multidrug resistance is not associated with a greater likelihood of thermal tolerance development during hyperthermia. Similarly, the drug resistant CEM and HL60 subclones were not more radiation resistant than the drug sensitive subclones. Thus, the classical or atypical forms of multidrug resistance or methotrexate resistance of the analyzed leukemic cell lines were not associated with radiation resistance. Furthermore, the radiation survival curves of the drug resistant subclones lacked a distinct initial shoulder and their n values were not greater than those of the drug sensitive subclones, suggesting that multidrug resistance is not associated with an increased ability to repair or accumulate sublethal radiation damage. Our findings provide evidence that there is no apparent association between drug/multidrug resistance and heat or radiation sensitivity of CEM T-lineage ALL or HL60 AML leukemia cells. The results of this study indicate that acquired resistance to methotrexate, vinblastine, vincristine, etoposide, actinomycin-D, adriamycin, or daunomycin, or pleiotropic multidrug resistance do not necessarily confer radiation resistance for human leukemic cells.
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PMID:Radiation and heat sensitivity of human T-lineage acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) clones displaying multiple drug resistance (MDR). 157 9

MDR gene expression in murine leukemia L 1210 cells was investigated during treatment in vivo with 0.5 mg doxorubicin/kg body weight (BW). Drug resistance (measured by an in vitro short-term test and immunohistochemistry) increased with the number of treatments and the maximum resistance reached after 8 treatments was similar with that of an established multidrug- resistant cell line (20 treatments, 2 mg/kg BW). Southern-blot and DNA dot-blot analyses show that development of MDR is associated with MDR-gene amplification and correlates with the degree of drug resistance and P-glycoprotein-expression. After cessation of doxorubicin treatment, resistance decreased continuously and disappeared after 20 passages. This decrease in resistance is accompanied by a loss of MDR gene amplification and P-glycoprotein expression. Furthermore, P-glycoprotein expression was analyzed in the first hours after treatment with doxorubicin in vivo (0.5 mg/kg BW). Expression was markedly increased and peaked at about 24 hours after treatment. In contrast, only slightly increased resistance and no MDR gene amplification could be detected.
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PMID:Time course of MDR gene amplification during in vivo selection for doxorubicin-resistance and during reversal in murine leukemia L 1210. 167 79

Recently, detection of the minimal residual disease (MRD) has become possible by polymerase chain reaction (PCR) using leukemia specific DNA or mRNA sequences originated from t(9; 22), t(1; 19) and t(14; 18) translocations, T cell receptor or immunoglobulin CDRIII. This method made possible to detect one leukemic cell out of 10(4)-10(5) cells, and the presence of MDR became clear during complete remission after chemotherapy or bone marrow transplantation. This suggests the usefulness of this method in the treatment of leukemia.
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PMID:[Minimal residual disease in leukemia]. 188 77

We studied blood and bone marrow cells from 42 patients with Ph-chromosome positive chronic myeloid leukemia (CML) and 20 normal subjects for amplification of the multidrug resistance gene (MDR-1) by Southern blotting and for overexpression of P-glycoprotein (P-170) by immunocytochemistry on intact cells with the monoclonal antibody C219. No P-170 could be detected in normal bone marrow or buffy coat. Overexpression of P-170 without amplification of MDR-1 was found in four of 11 patients with chronic phase CML at diagnosis, seven of 16 patients treated with busulfan or hydroxyurea in chronic phase and four of 15 patients in blast crisis. The P-170 overexpression involved only cells of the granulocyte lineage and varied from weak to strong in individual patients. It did not correlate with duration of or response to treatment during chronic phase. In transformation P-170 expression was seen in differentiated cells of the granulocyte lineage but not in blast cells, although three patients had been treated intensively with lipophilic and other cytotoxic drugs to which they had become resistant. We conclude that resistance to busulfan and hydroxyurea in chronic phase and resistance of blast cells to other cytotoxic drugs in transformation are not mediated primarily through the MDR-1/P-170 pathway.
Leukemia 1990 Oct
PMID:The role of the MDR-1/P-170 mechanism in the development of multidrug resistance in chronic myeloid leukemia. 197 71

We investigated whether two representative 1,4-dihydropyridine derivatives, NK-250 and NK-252, could potentiate the antitumor activity of multiple anticancer agents including vincristine (VCR), vinblastine, vindesine and actinomycin D in drug-resistant tumor cells and their parental drug-sensitive tumor cells. NK-250 and NK-252 at 5-10 microM almost completely reversed VCR resistance in cultured VCR-resistant P388/VCR cells derived from the mouse drug-sensitive P388/S leukemia cell line and also potentiated the cytocidal activity of VCR in drug-sensitive P388/S cells. NK-250 and NK-252 at 1-10 microM inhibited the photoaffinity labeling by [3H]azidopine of the cell-surface 170,000-molecular-weight P-glycoprotein. In chemotherapeutic experiments with leukemia-bearing mice, NK-250 or NK-252 was orally administered in combination with different drugs of the MDR phenotype administered intraperitoneally. The antitumor activity of the various combinations was found to be augmented in mice bearing P388/S- and P388/VCR-leukemia. Among the combinations examined, the combination of NK-250 and VCR was the most effective. These two 1,4-dihydropyridines, NK-250 and NK-252, are unique compounds because they were effective not only in circumventing the drug resistance, but also in potentiating the action of antitumor drugs against drug-sensitive tumors.
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PMID:Reversal by two dihydropyridine compounds of resistance to multiple anticancer agents in mouse P388 leukemia in vivo and in vitro. 197 28

1. APP is activated by adenosine kinase to its 5'-phosphate (APP-MP). 2. APP-MP inhibits PRPP synthetase, and depletes cellular PRPP and purine and pyrimidine nucleotides. 3. APP inhibits synthesis of DNA and RNA, and blocks cells in G1 phase of the cell cycle. 4. APP retains full activity against MDR cells. 5. APP is equally active against quiescent and proliferating CHO cells. 6. APP has only weak activity against L1210 leukemia in vivo, but has substantial activity against mammary carcinoma 16/c. 7. In vitro, APP has a relatively high ratio of solid tumor: leukemia activity.
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PMID:Biochemical pharmacology and antitumor properties of 4-amino-8-[beta-D-ribofuranosylamino]pyrimido-[5,4-d]pyrimidine. 256 Mar 25

The fact that cancer cell acquires multidrug resistance to carcinostatics at cancer treatment is a very important subject clinically. The mode of multidrug-resistance is complicated, but the gene associated with multidrug resistance (MDR 1) has been isolated. It has become evident that MDR 1 gene carries membrane glycoprotein (P-glycoprotein) which occurs in the cell acquired drug-resistance. Assessment has been made this time regarding the occurrence of P-glycoprotein in the tumorous cells and tissues by the use of monoclonal antibody (C 219) to P-glycoprotein. Occurrence of P-glycoprotein in malignant lymphoma exhibited positivity in 9 cases out of 36 immunohistologically. 170 KD P-glycoprotein was detected in 4 cases out of 10 at Western blotting analysis of the protein isolated from the nuclear cell in the peripheral blood in the patients with leukemia. Further, P-glycoprotein positive cases were all progressive cases clinically and showed resistance to treatment. From these results, it has been clarified that occurrence of P-glycoprotein in haematological tumors is related to multidrug resistance.
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PMID:[Expression of P-glycoprotein (multidrug-resistance gene product) in haematological tumors]. 257 82

We investigated the prognosis value of CD34 and P-170 expression in blast cells of adult patients affected by de novo acute myeloid leukemia (AML). CD34 antigen was analyzed by indirect immunofluorescence (IFI) and alkaline phosphatase-labeled streptavidin biotine (AP-LSAB) in 62 patients (median age: 51 years). P-170 expression was determined by AP-LSAB in 51 cases using JSB1 and C219 monoclonal antibodies. All patients were treated with conventional chemotherapy induction regimen. Follow-up was from 6 to 79 months. Complete remission (CR) rate was not statistically different between CD34+ and CD34- patients (67 vs. 84%, p = 0.2). The duration of CR and survival were not influenced by CD34 expression. Karyotype abnormalities were more frequent among MDR+ patients (65 vs. 21%, p < 0.01). CR rate was statistically lower in MDR+ patients as compared to MDR- patients (63 vs. 96%, p = 0.01). Median disease-free survival (DFS) was shorter for MDR+ patients but the difference was not significant (5 vs. 10 months, p = 0.09). Patients who were positive for both parameters CD34 and P-170, had a poor prognosis with a 50 vs. 100% CR rate for CD34/P-170 negative patients, (p = 0.002), a lower median DFS (3 vs. 12 months, p = 0.01) and overall survival (OS) (3 vs. 14.5 months, p = 0.01). Results of cytogenetic analysis did not influence CR rate but the relapse rate was higher, although not significant, for the patients with unfavorable karyotype (63 vs. 33%). The seven CD34+/MDR+ patients with poor prognosis karyotype had a statistically lower CR rate, median DFS and OS than the 7 CD34-/MDR- patients with normal or favorable karyotype (CR: 29% vs. 100%, p = 0.02), (DFS: 3 vs. > 12 months, p = 0.01), (OS: 4 vs. > 12 months, p = 0.02). Our data indicate that P-170 but not CD34 expression is predictive for a lower CR rate. The identification of a bad prognosis subgroup of CD34+/MDR+ AML patients (and especially those with poor prognosis karyotype) has to be confirmed on larger series using uniform methodology.
Leukemia 1994 Nov
PMID:P-glycoprotein (P-170) and CD34 expression in adult acute myeloid leukemia (AML). 752 90


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