Home About us Contact
|
Home About us Contact | ||
|
|
||
Resistant Variants (resistant + variants)
Selected AbstractsABCG2 overexpression in colon cancer cells resistant to SN38 and in irinotecan-treated metastasesINTERNATIONAL JOURNAL OF CANCER, Issue 6 2004Laurent Candeil Abstract Overcoming drug resistance has become an important issue in cancer chemotherapy. Among all known mechanisms that confer resistance, active efflux of chemotherapeutic agents by proteins from the ATP-binding cassette family has been extensively reported. The aim of the present study was to determine the involvement of ABCG2 in resistance to SN38 (the active metabolite of irinotecan) in colorectal cancer. By progressive exposure to increasing concentrations of SN38, we isolated 2 resistant clones from the human colon carcinoma cell line HCT116. These clones were 6- and 53-fold more resistant to SN38 than the HCT116-derived sensitive clone. Topoisomerase I expression was unchanged in our resistant variants. The highest resistance level correlated with an ABCG2 amplification. This overexpression was associated with a marked decrease in the intracellular accumulation of SN38. The inhibition of ABCG2 function by Ko143 demonstrated that enhanced drug efflux from resistant cells was mediated by the activity of ABCG2 protein and confirmed that ABCG2 is directly involved in acquired resistance to SN38. Furthermore, we show, for the first time in clinical samples, that the ABCG2 mRNA content in hepatic metastases is higher after an irinotecan-based chemotherapy than in irinotecan-naive metastases. In conclusion, this study supports the potential involvement of ABCG2 in the development of irinotecan resistance in vivo. © 2004 Wiley-Liss, Inc. [source] Favorable outcome of ex-vivo purging of monocytes after the reintroduction of treatment after interruption in patients infected with multidrug resistant HIV-1,JOURNAL OF MEDICAL VIROLOGY, Issue 11 2007Hamid Hasson Abstract In multidrug resistant patients treatment interruptions allow the selection of archived wild-type drug-susceptible viruses that compete for the less fit drug-resistant strains. However, the selection of viruses with increased replicative capacity is often followed by a loss of CD4+ T cells. In addition, drug resistant variants later re-emerge limiting the overall clinical benefit of treatment interruption. Blood monocytes are a key component of the HIV reservoir and can be partially removed by a system for purging of myeloid cells (MYP). This study tested the safety and efficacy of MYP on multidrug resistant patients who underwent treatment interruption. Twelve patients were randomized to receive or not six cycles of MYP during treatment interruption. An optimized antiretroviral regimen was reintroduced after the reappearance of a drug susceptible genotype. Following therapy reintroduction, a long lasting increase in CD4+ T cell counts was observed only in the treatment interruption,+,MYP patients but not in the control patients. Five/six treatment interruption,+,MYP patients never experienced virological rebound during a median follow up period of 98 weeks. In contrast, 4/6 patients who did not receive MYP never reached complete viral suppression and had a virological rebound after a median of 16.5 weeks after treatment reintroduction. The difference between the two groups in the time to virological rebound was statistically significant (P,=,0.021). A consistent decrease of HIV DNA load in CD14+ purified cells was observed only in treatment interruption,+,MYP patients. These data suggest that MYP can improve the immunological and virological response to treatment interruption. J. Med. Virol. 79:1640,1649, 2007. © 2007 Wiley-Liss, Inc. [source] Alterations in Mitochondrial and Apoptosis-regulating Gene Expression in Photodynamic Therapy-resistant Variants of HT29 Colon Carcinoma Cells,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 2 2005Xiao Yun Shen ABSTRACT Photodynamic therapy (PDT) is a novel cancer therapy inducing irreversible photodamage to tumor tissue via photosensitizer-mediated oxidative cytotoxicity. The cellular and molecular responses associated with PDT are only partially understood. We have reported previously the generation of several photosensitizer-specific PDT-resistant cell variants of HT29 human colon adenocarcinoma cells by selecting cells from sequential PDT treatment using different photosensitizers. In this report, we describe the use of messenger RNA (mRNA) differential display to identify genes that were differentially expressed in the parental HT29 cells compared with their resistant variants. In comparison with parental HT29 cells, mRNA expression was increased in the PDT-resistant cell variants for BNIP3, estrogen receptor-binding fragmentassociated gene 9, Myh-1c, cytoplasmic dynein light chain 1, small membrane protein I and differential dependent protein. In contrast, expression in the PDT-resistant variants was downregulated for NNX3, human HepG2 3,region Mbol complementary DNA, glutamate dehydrogenase, hepatomaderived growth factor and the mitochondrial genes coding for 16S ribosomal RNA (rRNA) and nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 4. The reduction for mitochondrial 16S rRNA in the PDT-resistant variants was confirmed by Northern blotting, and the elevated expression of the proapoptotic BNIP3 in the PDT-resistant variants was confirmed by Northern and Western blotting analysis. We also examined the expression of some additional apoptosis-regulating genes using Western blotting. We show an increased expression of Bcl-2 and heat shock protein 27 and a downregulation of Bax in the PDT-resistant variants. In addition, the mutant p53 levels in the parental HT29 cells were reduced substantially in the PDT-resistant variants. We suggest that the altered expression in several mitochondria1 and apoptosisregulating genes contributes to PDT resistance. [source] Activity against drug resistant-tuberculosis strains of plants used in Mexican traditional medicine to treat tuberculosis and other respiratory diseasesPHYTOTHERAPY RESEARCH, Issue 1 2008María del Rayo Camacho-Corona Abstract Tuberculosis (TB) kills about 3 million people per year worldwide. Furthermore, TB is an infectious disease associated with HIV patients, and there is a rise in multidrug-resistant TB (MDR-TB) cases around the world. There is a need for new anti-TB agents. The study evaluated the antimycobacterial activity of nine plants used in Mexican traditional medicine to treat tuberculosis and other respiratory diseases. Nasturtium officinale showed the best activity (MIC = 100 µg/mL) against the sensitive Mycobacterium tuberculosis. The following plants were active also but at 200 µg/mL: Citrus sinensis, Citrus aurantifolia, Foeniculum vulgare, Larrea tridentata, Musa acuminata and Olea europaea. Contrary to the above data, activity against drug-resistant variants of M. tuberculosis was more evident, e.g. N. officinale was the most potent (MIC , 100 µg/mL) against the four mono-resistant variants tested; F. vulgare and O. europaea were active against all the resistant variants (MICs , 100 µg/mL). The most susceptible variant was the isoniazid resistant, being inhibited by C. aurantifolia, C. sinensis and O. europaea (MIC = 25 µg/mL). These data point to the importance of biological testing of extracts against drug-resistant M. tuberculosis isolates, and the bioguided assay of these extracts for the identification of lead compounds against MDR-TB isolates. Copyright © 2007 John Wiley & Sons, Ltd. [source] | |||||||||||||