Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A multidrug-resistant Chinese hamster cell line, LZ-8, was subcultured in increasing levels of doxorubicin (DOX) until capable of growth in 100 micrograms/mL DOX. This new derivative, designated LZ-100, is the most DOX-resistant line in the LZ series, based on a comparison of Ki-1 values from cell survival studies. This increased level of drug resistance in LZ-100 cells did not result from (i) higher levels of P-glycoprotein (P-gp) in the plasma membrane compared with LZ-8 cells, since this protein constitutes approximately 20% of the total plasma membrane protein in both cell lines, or (ii) more efficient drug pumping by the same amount of P-gp, since efflux of rhodamine 123 and DOX was comparable in the two cell lines. However, an altered drug distribution was observed in LZ-100 cells compared with wild-type V79 cells; in LZ-100 cells DOX was largely excluded from the nucleus and was sequestered in vesicles in the cytoplasm. The number of vesicles per cell seen after DOX exposure corresponded with the level of drug resistance achieved by the LZ cell lines studied. DOX concentration-response experiments revealed that vesicle formation exhibited a biphasic relationship, with an initial rapid increase followed by a plateau where no further increase was observed. Time-course studies in LZ-100 cells revealed that the maximum number of DOX-containing vesicles per cell occurred 3-4 hr following initiation of DOX treatment. Radiation exposure (10 Gy) immediately preceding DOX treatment decreased the number of vesicles formed in LZ-100 cells by more than one-half and altered the subcellular distribution of DOX from an almost exclusively cytoplasmic to a homogeneous nuclear/cytoplasmic distribution. This redistribution was not a result of radiation inhibition of P-gp efflux. The inhibitory effect of radiation on vesicle formation increased with increasing radiation dose up to 10 Gy. Drug-containing vesicles were also observed in LZ-100 cells following exposure to mitoxantrone or daunorubicin (to which LZ-100 cells are also resistant), but fewer vesicles were observed than with DOX. These studies demonstrate that the drug sequestration phenomenon (i) occurs in cells exhibiting widely different levels of drug resistance, (ii) correlates with the level of drug resistance in LZ cell lines, (iii) occurs rapidly following exposure to DOX, mitoxantrone, or daunorubicin, and (iv) can be inhibited by irradiation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sequestration of doxorubicin in vesicles in a multidrug-resistant cell line (LZ-100). 791 6

The virus-associated T cell leukaemias/lymphomas are characterized by a poor prognosis primarily because of the rapid emergence of drug resistance which may lead to failure of subsequent chemotherapy. We report here a case of Epstein-Barr virus-associated T cell lymphoma which relapsed soon after chemotherapy and radiotherapy. The neoplastic cells of the relapsed tumour expressed high levels of multi-drug resistance gene (mdr1)-related P-glycoprotein and glutathione-S-transferase-pi, both of which were absent in the pre-chemotherapy tumour tissues. Empirical treatment with oral 13-cis-retinoic acid (RA) was then given with subsequent complete disappearance of the tumour. The therapeutic effect of RA appears to act through an apoptotic process. In accordance with our previous report of a successful salvage of a refractory Ki-1 large cell lymphoma. RA appears to be a potentially useful drug for some specific type T-cell lymphomas.
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PMID:Retinoic acid-induced apoptosis and regression of a refractory Epstein-Barr virus-containing T cell lymphoma expressing multidrug-resistance phenotypes. 791 55