BACKGROUND: Lymphocytes from patients affected by B-cell chronic lymphocytic leukemia (B-CLL) have frequently been shown to be positive for the multidrug resistance (MDR) phenotype. However, this phenotype does not seem to be responsible for the resistance to alkylating agents usually employed in the management of CLL. METHODS: Lymphocytes from 42 patients were evaluated by flow cytometry for P-170 expression and by spectrophotometry for glutathione-S-transferase (GST) activity. RESULTS: Our findings show that GST is not related to any clinical parameter but is increased in treated patients. Conversely, 85% of patients were positive for P-170 and this was related to the percentage of CD5/CD19-positive lymphocytes. CD5/CD19-negative patients were also negative for P-170. MDR was not related to any clinical parameter evaluated nor to GST activity in lymphocytes. CONCLUSIONS: MDR is constitutively expressed in B-cell chronic lymphocytic leukemia and seems to be related to a CD5/CD19 B-CLL phenotype. The increase of GST activity in treated patients is statistically significant (p < 0.005).

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Biological effects of PEMF (pulsing electromagnetic field): an attempt to modify cell resistance to anticancer agents.

Pulsing Electromagnetic Field (PEMF) effects lead to a modification of the multidrug resistance (MDR) of cells in vitro and in vivo. The murine leukemic doxorubicin-resistant cell line, P388/Dx, subjected to PEMF irradiation in vitro, showed a significant difference in thymidine incorporation when the concentration of doxorubicin reached a level of 1 microgram/mL, which corresponds to the inhibition dose 50 (ID50). The human lymphoblastic leukemia vinblastine-resistant cell line, CEM/VLB100, also showed a significant modification under the same experimental conditions at the in vitro ID50 corresponding to a vinblastine concentration of 100 ng/mL. BDF1 mice transplanted with P388/Dx cells also had an increase in their life span when doxorubicin was injected intraperitoneally in fractionated doses, while being subjected to PEMF irradiation.

Animals↗

PubMedDate not supplied

c-Jun and GST-pi expression in human plasma cells.

Bone marrow samples from 33 patients affected by MM and MGUS, and 8 patients not affected by lymphoproliferative diseases were studied for expression of c-Jun (a component of the transcription factor AP-1) and glutathione-S-transferase pi (GST-pi) using immunocytochemical methods. A high and frequent expression of these two proteins was found both in MM and MGUS patients (31/33 patients positive for c-Jun and 29/33 patients positive for GST-pi) and in controls not affected by monoclonal gammopathy (7/8 patients positive for both c-Jun and GST-pi). No statistically significant correlation was found between c-Jun- and GST-pi-positive plasma cells. The expression of these two proteins was not related to clinical or laboratory data. Our results seem to confirm a possible role of the transcriptional complex AP-1 in activating GST-pi promoter in human plasma cells.

Aged↗

PubMedDate not supplied

c-Ha-ras transfection and expression of MDR-related genes in MCF-10A human breast cell line.

BACKGROUND: We studied the relationship between ras transfection and the drug resistance phenotype in the MCF-10A cell line (a non-transformed immortalized human breast epithelial cell line). MATERIALS AND METHODS: Parental (MCF-10A) and c-Ha-ras transfected (MCF-10A H) cell lines were tested for resistance to Doxorubicin, Maphosphamide and Cisplatinum, by evaluating the inhibition of [3H]-thymidine incorporation. Cells were also examined for the expression of different resistance mechanisms by immunocytochemical and RT-PCR methods. RESULTS: ras-transfected cells were much more resistant to Cis-platinum than parental ones. GST-pi the GST isoenzyme frequently involved in human cancers) increased only in transfected cells. No expression of any other resistance mechanisms (MDR, MRP, LRP) was found by immunocytochemistry either in parental or in transfected cells; nevertheless, the more sensitive RT-PCR tests detected mrp products in parental and in transfected cells: gene expression levels were low and equivalent in both cell lines. CONCLUSIONS: ras transfection can induce resistance to Cis-platinum by increasing GST-pi expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

[Treatment of multidrug resistance in oncology and hematology].

BACKGROUND: Drug resistance, which often occurs also during chemotherapy, is yet a great obstacle to the success of the human malignancies treatments. Among many possible mechanisms of drug resistance (biological, biochemical, kinetic or pharmacological), both typical and atypical multidrug-resistance (MDR) have been extensively studied. Multidrug resistance is the phenomenon whereby the development of resistance to one drug is accompanied by the simultaneous development of resistance to a variety of structurally unrelated drugs. Typical MDR seems to depend on the expression of an 170 KD protein, the P-170 or P-glycoprotein, that acts as an energy-dependent pump removing possible toxic agents, including antiblastic drugs, from the cell. High levels of the mdr1 expression have been found in normal adrenal gland, kidney, colon, jejunum and liver, whereas low levels were detected in skin, muscle, brain, nervous system and bone marrow, where CD34+ stem cells are P-170 positive. Moreover, heat shock proteins or oncogene transfection, cell differentiation or proliferation could modulate the P-glycoprotein expression: low protein levels were described in resting B lymphocytes and monoblast cells, whereas plasma cells and monocytes express higher P-170 levels. On the contrary, more differentiated myeloid cells show a low MDR1 expression. METHODS: Since normal kidney and haematopoietic cells physiologically express P-170 protein, 20 renal cell carcinomas at the surgery and many hematological patients were evaluated in this study, including acute leukemias, chronic myeloid, chronic lymphocytic leukemias and multiple myeloma. Moreover we evaluated the MDR expression in 23 non small cell lung cancers. The MDR1 gene expression was showed by RT-PCR assays, whereas the P-170 protein was detected by immunological and cytofluorometric reactions employing the C-219 and JSB1 monoclonal antibodies. RESULTS AND CONCLUSIONS: Of the 32 acute leukemia patients, 15 (47%) resulted P-170 positive; 14 out of the 15 positive, but 12 out of the 17 negative cases were resistant to the chemotherapy, with an higher positivity in monoblastic types; on the contrary, all lymphoblastic leukemias resulted P-170 negative and only 2 of 13 patients resulted drug resistant. A very high MDR expression was showed in chronic disorders: in the lymphocytic ones, only samples CD5/CD19 negative (3 of 42) resulted P-170 negative, confirming the basal MDR phenotype expression. In these cases, nevertheless, the protein expression was not related to the treatment response. Also in the multiple myeloma patients, no relations between clinic parameters and P-170 expression were found; however a significant relationship between treatment response and P170 expression was found. In kidney and lung cancer samples examined, a low percentage of positive samples was detected without any relationship to the evaluated clinical parameters.

Drug Resistance, Multiple↗

PubMedDate not supplied

Multidrug resistance related genes and p53 expression in human non small cell lung cancer.

BACKGROUND: Many genes (mdr1, mrp, DNA topoisomerases II) are known to be involved in the resistance to unrelated drugs (the MDR phenomenon), but the mechanisms of their activation have to be further investigated. MATERIALS AND METHODS: Because several authors showed that p53 mutated gene was able to induce mdr1 overexpression, we evaluated in 51 non small cell lung cancer samples, already tested for p53 mutations, the expression of mdr1, mrp, DNA topoisomerase II alpha and beta mRNAs by qualitative RT-PCR assays. RESULTS: Mutations of p53 were found in 56% of cases. Mdr1 expression was detected in 27%, mrp in 100%, topoisomerase alpha in 82% and beta in 94% of the samples. CONCLUSIONS: It was not possible to detect any relationship between the expression of the MDR-related genes and tumor histological type, stage or lymph node involvement. Nevertheless, a close association between p53 alterations and either mdr1 gene (p = 0.001) or DNA topoisomerase II alpha (p = 0.003) expression was found.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

[The evaluation by performance indicators of the impact of organizational changes on the activities of a hospital presidium of Lombardy].

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Diagnosis-Related Groups↗