Disease relevance of TBC1D9

• Increased expression and amplification of mdr1 sequences were also found in multidrug-resistant sublines of human leukemia and ovarian carcinoma cells [1].
• The proportion of breast tumors expressing MDR1/gp170 in all of the studies was 41.2%, but there was substantial heterogeneity in the values across individual studies (P<.0001) [2].
• MDR1 gene expression and treatment outcome in acute myeloid leukemia [3].
• MDR1 RNA levels were also increased in some cancers at relapse after chemotherapy, including ALL, ANLL, breast cancer, neuroblastoma, pheochromocytoma, and nodular, poorly differentiated lymphoma [4].
• The levels of MDR1 mRNA were correlated with history of chemotherapeutic treatment for all tumors; for ovarian and small-cell lung carcinomas (SCLCs), these levels were also correlated with subsequent tumor response to chemotherapy [5].

Psychiatry related information on TBC1D9

• Recent data suggest that MDR-1 expression may affect HIV-1 infectivity by modulating the immune response and its cellular permissiveness [6].
• Psychological stress induces chemoresistance in breast cancer by upregulating mdr1 [7].

High impact information on TBC1D9

• Primitive cells bearing Y chromosomes that expressed c-kit, MDR1, and Sca-1 were also investigated [8].
• Of several peptides selected, one, termed RGP8.5, was linked to upregulation of expression of the gene ABCB1 (also known as MDR1, for multiple drug resistance) in HeLa cells [9].
• Tissue-specific expression of MDR1 and other members of the MDR gene family has been observed in normal cells, suggesting a role for P-glycoproteins in secretion [10].
• Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification [1].
• Multidrug resistance in human KB carcinoma cells selected in colchicine, vinblastine, or Adriamycin is associated with amplification of specific DNA sequences (the multidrug resistance locus, mdr1) [1].

Chemical compound and disease context of TBC1D9

• Reversal of multidrug resistance in human colon cancer cells expressing the human MDR1 gene by liposomes in combination with monoclonal antibody or verapamil [11].
• For comparison, we used MCF-7ADR human breast cancer cells, which overexpress MDR1 and have also lost the requirement for 17 beta-estradiol supplementation to form tumors in nude mice [12].
• Amplification and increased expression of the mdr1 gene associated with multidrug resistance in human tumors were found in multidrug-resistant sublines of human myelogenous leukemia K562 selected with vincristine (K562/VCR) or adriamycin (K562/ADM) [13].
• The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis [14].
• The resistance to rhodamine 123 and sensitivity to gossypol was also observed with cells transfected with the MDR1 gene, showing that the difference in toxicity is mainly due to the different response to the P-170 drug efflux pump [15].

Biological context of TBC1D9

• Recently, several SNPs have been identified in the MDR1 gene, some of which can affect P-glycoprotein expression and function [16].
• Genetic polymorphisms of the human MDR1 drug transporter [16].
• We find that in vivo expression of the MDR1-containing operon is regulated by metal ion availability [17].
• We have developed a preclinical model of MDR/CML uncomplicated by other mechanisms of drug resistance to evaluate the effects of MDR1 overexpression on cytodestructive and differentiation therapy and the ability of sensitizers to restore chemosensitivity in this disease [18].
• CONCLUSIONS: The data indicate that overexpression of the MDR1 gene alone confers a multidrug-resistant phenotype, but it does not directly result in either cross-resistance to antiestrogens or a loss of steroid hormone receptor expression [12].

Anatomical context of TBC1D9

• MDR1/gp170 expression was not associated with lymph node metastases, estrogen receptor status, tumor size, tumor grade, or tumor histology [2].
• MDR1 RNA levels were usually elevated in untreated, intrinsically drug-resistant tumors, including those derived from the colon, kidney, adrenal gland, liver, and pancreas, as well as in carcinoid tumors, chronic myelogenous leukemia in blast crisis, and cell lines of non-small cell carcinoma of the lung (NSCLC) with neuroendocrine properties [4].
• After VAD plus cyclosporin, no MDR-1-positive plasma cells were present in 6 of 8 patients tested [19].
• Immunofluorescence microscopy revealed that the majority of the Mdr1 was localized to the plasma membrane (although a significant amount was also found in the endoplasmic reticulum) [20].
• Results of MDR-1 vector modification trial indicate that granulocyte/macrophage colony-forming unit cells do not contribute to posttransplant hematopoietic recovery following intensive systemic therapy [21].

Associations of TBC1D9 with chemical compounds

• Verapamil and quinidine lowered the IC50 values of doxorubicin for MDR1-positive cell lines [22].
• Variability across the studies in the proportion of tumors expressing MDR1/gp170 was assessed by use of chi-squared tests of homogeneity, weighted means, and weighted linear regression [2].
• Such data suggest that, at least for two distinct human cell line (SKOV3 and DU145), estramustine does not induce the overexpression of the MDR1 gene [23].
• These findings together suggest an association between overexpression of the MDR1 gene and cross-resistance to progestin and antiestrogen therapies [12].
• Other study results indicate that both progestins and triphenylethylene antiestrogens may be substrates for P-glycoprotein, the product of the MDR1 gene [12].

Other interactions of TBC1D9

• AtrDp shows a particularly high degree of identity to the amino acid sequence of Afu Mdr1p, a previously characterized ABC transporter from the human pathogen A. fumigatus [24].
• This finding suggests that drug-resistance may involve synergy between energy-dependent drug efflux pumps CDR1p and MDR1p in some but not all isolates [25].

Analytical, diagnostic and therapeutic context of TBC1D9

• The human multidrug-resistance P-glycoprotein, encoded by the MDR1 gene, is also an ABC transporter, overexpression of which is one of the principal causes of resistance of human cancers to chemotherapy [26].
• Expression of mdr1 messenger RNA (mRNA) was investigated using RT-PCR, and P-glycoprotein (Pgp) expression was determined by immunoflow cytometry with the monoclonal antibodies MRK16 and C219 [27].
• METHODS: A sensitive assay based on the polymerase chain reaction (PCR) was used in a retrospective study to measure MDR1 mRNA in biopsy samples of 100 solid tumors, including 60 ovarian and 32 lung carcinomas [5].
• RESULTS: Slot-blot analysis and immunocytochemistry showed that two cell lines expressed high levels of MDR1 mRNA, one expressed an intermediate level, and all others were low expressors [22].
• The expression of MDR1 and GST-pi genes was assessed in the mRNA extracted from xenografts by Northern blot analysis [28].

References