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Biomedical subjects

M Clynes

Publications and source records attributed to M Clynes.

At least 19 recordsLinked to original sources
PubMed2006

A phase I clinical and pharmacokinetic study of the multi-drug resistance protein-1 (MRP-1) inhibitor sulindac, in combination with epirubicin in patients with advanced cancer.

PURPOSE: Multi-drug resistance mediated by ATP-binding cassette trans-membrane protein pumps is an important cause of cancer treatment failure. Sulindac has been shown to be a competitive substrate for the clinically important resistance protein, multi-drug resistance protein-1 (MRP-1), and thus might enhance the anti-cancer activity of substrate chemotherapeutic agents, e.g. anthracyclines. METHODS: We conducted a dose-escalating, single arm, prospective, open label, non-randomised phase I trial of epirubicin (75 mg/m(2)) in combination with escalating oral doses of sulindac (0-800 mg) in patients with advanced cancer to identify an appropriate dose of sulindac to use in future resistance studies. Anthracycline and sulindac pharmacokinetics were studied in cycles 1 and 3. RESULTS: Seventeen patients (8 breast, 3 lung, 2 bowel, 1 melanoma, 1 renal, 1 ovarian and 1 of unknown primary origin, 16/17 having had prior chemotherapy) were enrolled. Eight patients received a full six cycles of treatment; 14 patients received three or more cycles. Dose-limiting toxicity was observed in two patients at 800 mg sulindac (1 renal impairment, 1 fatal haemoptysis in a patient with advanced lung cancer), and sulindac 600 mg was deemed to be the maximum tolerated dose. Sulindac had no effect on epirubicin pharmacokinetics. Among 15 patients with evaluable tumour, two partial responses were seen (malignant melanoma and breast cancer). Four others had prolonged stable disease. CONCLUSION: Epirubicin 75 mg/m(2) and sulindac 600 mg are the recommended doses for phase II studies for these agents in combination.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Molecular markers of multiple drug resistance in breast cancer.

Breast cancer is a significant health problem in terms of both morbidity and mortality, with approximately 12% of women directly affected by this disease. Chemotherapy, given to patients with earlier stage disease, has a good survival impact and may contribute to cure. The failure of chemotherapeutic drugs to eradicate cancer cells in more advanced disease states may be due to intrinsic or acquired drug resistance, including multiple drug resistance. The drug resistance observed in breast cancer patients is likely to be multifactorial, involving mechanisms such as altered expression and/or activity of drug efflux pumps, nuclear DNA-binding enzymes, metabolizing and conjugating enzymes, and mismatch repair deficiency. More extensive transcriptomic and proteomic analyses of breast tumour and normal biopsies, followed by functional genomic studies in relevant cell line models, should increase our understanding of this phenomenon and lead to therapies being individualized for identifiable subgroups of breast cancer patients.

Antineoplastic Agents↗
PubMed2006

Biomarkers and multiple drug resistance in breast cancer.

Breast cancer, the most common form of cancer among women in North America and almost all of Europe, is a significant health problem in terms of both morbidity and mortality. It is estimated that each year this disease is diagnosed in over one million people worldwide and is the cause of more than 400,000 deaths. Although chemotherapy forms part of a successful treatment regime in many cases, as few as 50% patients may benefit from this, as a result of intrinsic or acquired multiple drug resistance (MDR). Through the use of in vitro cell culture models, a number of mechanisms of MDR have been identified; many, if not all, of which may contribute to breast cancer resistance in the clinical setting. This phenomenon is complicated by the likely multi-factorial nature of clinical resistance combined with the fact that, although apparently studied extensively in breast cancer, reported analyses have been performed using a range of analytical techniques; many on small sub-groups of patients, with different clinicopathological characteristics and receiving a range of therapeutic approaches. Larger defined studies, using standardised genomic and proteomics profiling approaches followed by functional genomics studies, are necessary in order to definitively establish the degree of complexity contributing to drug resistance and to identify novel therapeutic approaches - possibly involving chemotherapy, drug resistance modulators, and novel targeted therapies - to combat this disease.

Antineoplastic Agents↗
PubMed2004

A new superinvasive in vitro phenotype induced by selection of human breast carcinoma cells with the chemotherapeutic drugs paclitaxel and doxorubicin.

Doxorubicin- and paclitaxel-selected variants of an in vitro invasive clonal population of the human breast cancer cell line, MDA-MB-435S, were established by pulse selection, and exhibited a novel 'superinvasive' phenotype. This phenotype is characterised by an ability to relocate to another surface following invasion through matrigel and membrane pores, by decreased adhesion to extracellular matrix proteins and by increased motility. This may represent an in vitro model of a step in the metastatic process occurring subsequent to invasion. The paclitaxel-resistant variants, MDA-MB-435S-F/Taxol-10p and MDA-MB-435S-F/Taxol-10p4p were resistant to paclitaxel, vincristine and docetaxel, but not to doxorubicin, carboplatin, etoposide or 5-fluorouracil. The doxorubicin-selected variants MDA-MB-435S-F/Adr-10p and MDA-MB-435S-F/Adr-10p10p, in contrast, exhibited only small increases in resistance to doxorubicin, although they were slightly resistant to VP-16 and docetaxel, and exhibited increased sensitivity to paclitaxel, carboplatin and 5-fluorouracil.

Adult↗
PubMed2004

Expression in murine teratocarcinoma F9 cells of transcription factors involved in pancreas development.

BACKGROUND: Although it has been established that formation and functional differentiation of the pancreas from embryonic endoderm is associated with activation/inactivation of many genes controlled by specific sets of transcription factors, the role and activation sequence of individual transcription factors has not yet been fully elucidated. This study sought to differentiate a murine teratocarcinoma cell line, F9, to endodermal-like cells and, subsequently; to investigate the effects of regulated expression of transcription factors in pancreas development. METHODS: Following differentiation using retinoic acid and db cAMP (RAC), resulting F9 cells (F9-RAC) were transfected with cDNAs for PDX-1, ngn3, beta 2/NeuroD (beta 2), and Nkx2.2, singly or in combination. Expression of these transcription factors was investigated using RT-PCR and immunofluorescence techniques. RT-PCR analysis was used to assess the subsequent effects of expression of these factors on endogenous genes related to pancreas development. RESULTS: Regulated differentiation of F9 cells generated endodermal-like cell types. Following transfection, PDX-1, ngn3, beta 2, and Nkx2.2 were expressed in F9-RAC cells, with their proteins localized mainly in cellular nuclei. Expression of these factors apparently did not affect the endogenous expression of preproinsulin, PDX-1, beta 2, Isl1, Pax4, Pax6, Sonic hedgehog, and Indian hedgehog. CONCLUSION: This study describes the successful transient expression of transcription factors related to pancreas development, following directed differentiation of F9 cells to endoderm-like cells, and shows that treatment of F9 cells with a combination of RAC causes up-regulation of genes relevant to pancreatic development. The lack of further effect of regulated transcription factor expression on these genes may suggest that parietal endoderm- like cells derived from F9 cells is not the optimal lineage from which to develop beta cells. It may be useful to include F9-derived visceral endoderm in future studies.

Animals↗
PubMed2004

Mechanisms associated with loss of glucose responsiveness in beta cells.

BACKGROUND: Cell replacement therapies have been proposed as possible alternatives to the current treatments for controlling blood glucose in insulin-dependent diabetes. Beta cells, however, often lose their glucose-stimulated insulin secretion (GSIS) when maintained for prolonged periods in culture. For beta cell lines to be considered as a suitable source of transplantable tissue, it is essential that their GSIS is maintained. This study aimed to investigate cellular events involved in this loss of GSIS, to enable future optimization and enhancement of this response. METHODS: GSIS was investigated in low and high-passage murine insulinoma MIN-6 cells (using in vitro static procedures) and assessing levels of secreted (pro)insulin by enzyme-linked immunosorbent assays. Expression of relevant islet gene transcripts, including insulin, glucagon, somatostatin, and pancreatic polypeptide, was investigated by RT-PCR analysis. RESULTS: At low-passage, MIN-6 cells produced an approximately four- to fivefold increase in (pro)insulin secretion in response to 26.7 mmol/L glucose compared to 3.3 mmol/L glucose; at high passage, this response was lost. Expression of glucagon and somatostatin mRNAs were down-regulated with increased passage, while levels of insulin and pancreatic polypeptide mRNAs were apparently unchanged. CONCLUSION: The maintenance of insulin mRNA levels in high-passage MIN-6 cells with down-regulation of glucagon (stimulates insulin secretion) and somatostatin (inhibits insulin secretion) gene transcript levels suggests that these cells have not lost their ability to maintain insulin production, but that the loss of glucose responsiveness may be due to a general effect on regulated secretion. Further studies investigating the regulated secretory pathway in these cells may further explain the mechanistic changes occurring with passaging of beta cells.

Animals↗
PubMed2004

Synthesis of (2E)-2-methyl-3-(4-([4-(quinolin-2-ylmethoxy)phenyl]sulfanyl)phenyl)prop-2-enoic acid (VUFB 20609) and 2-methyl-3-(4-([4-(quinolin-2-ylmethoxy)phenyl]sulfanyl)phenyl)propanoic acid (VUFB 20584) as potential antileukotrienic agents.

The syntheses of (2E)-2-methyl-3-(4-([4-(quinolin-2-ylmethoxy)phenyl]sulfanyl)phenyl) prop-2-enoic acid (VUFB 20609) and racemic 2-methyl-3-(4-([4-(quinolin-2-ylmethoxy) phenyl]sulfanyl)phenyl)propanoic acid (VUFB 20584) as new potential antileukotrienic drugs are described. Due to a low reactivity of the 4-substituted aryl bromides (coupling of the 4-substituted aryl bromides do not provide an activating functional group with 4-methoxybenzene-1-thiol), special conditions, in particular specific heterogeneous copper catalysts, were used. Catalytic hydrogenation of the conjugated double bond on Pd/C in the presence of the sulfanyl group is discussed. In-vitro cytotoxicity testing was performed using a microplate colorimetric acid phosphatase assay. Antiplatelet activity was evaluated using an in-vitro test in human platelet-rich plasma. Some substances inhibited arachidonic acid-induced platelet aggregation.

Arachidonic Acid↗
PubMed2003

Prognostic importance of survivin in breast cancer.

Survivin is a member of the inhibitor of apoptosis (IAP) family, and is also involved in the regulation of cell division. Survivin is widely expressed in foetal tissues and in human cancers, but generally not in normal adult tissue. This study examined the expression of surviving protein in a series of 293 cases of invasive primary breast carcinoma. Survivin immunoreactivity was assessed using two different polyclonal antibodies, and evaluated semiquantitatively according to the percentage of cells demonstrating distinct nuclear and/or diffuse cytoplasmic staining. Overall, 60% of tumours were positive for survivin: 31% demonstrated nuclear staining only, 13% cytoplasmic only, and 16% of tumour cells demonstrated both nuclear and cytoplasmic staining. Statistical analysis revealed that survivin expression was independent of patient's age, tumour size, histological grade, nodal status, and oestrogen receptor status. In multivariate analysis, nuclear survivin expression was a significant independent prognostic indicator of favourable outcome both in relapse-free and overall survival (P<0.001 and P=0.01, respectively). In conclusion, our results show that survivin is frequently overexpressed in primary breast cancer. Nuclear expression is most common and is an independent prognostic indicator of good prognosis.

Adult↗
PubMed2003

Survivin: role in normal cells and in pathological conditions.

Survivin, an inhibitor of apoptosis (IAP) containing one baculovirus IAP repeat (BIR) domain, has been reported to be capable of regulating both cellular proliferation and apoptotic cell death. Survivin splice variants, survivin-DeltaEx3 and survivin-2B, have apparently retained and lost anti-apoptotic potential, respectively. As survivin was first discovered due to its high homology with effector cell protease receptor (EPR-1), a protein involved in blood coagulation, it has been suggested (but not proven) that EPR-1 may act as a natural anti-sense to survivin in cells. Survivin homologs have been found in non-human species. Survivin expression has been described during embryonic development and in adult cancerous tissues, with greatly reduced expression in adult normal differentiated tissues, particularly if their proliferation index is low. Survivin has been defined as a universal tumor antigen and as the fourth most significant transcriptosome expressed in human tumors. Although survivin is usually located in the cell cytoplasmic region and associated with poor prognosis in cancer, nuclear localisation, indicative of favorable prognosis, has also been reported. Survivin expression has also been reported in a number of proliferating normal adult tissues. Extensive research has been conducted, aimed at increasing our understanding of survivin, by determining its sub-cellular structure and location, mechanism(s) of action and control of expression. While much important information on this molecule has been accumulated, there are still many areas of controversy or limited information. Further research may enable exploitation of survivin overexpression in cancer compared to normal tissues, making survivin a potentially attractive target for cancer therapeutics.

Amino Acid Sequence↗
PubMed2002

Methods for generation of monoclonal antibodies to the very small drug hapten, 5-benzimidazolecarboxylic acid.

Drug-specific monoclonal antibodies (MAbs) were produced against the very small drug hapten (162.15 Da), 5-benzimidazolecarboxylic acid, an analogue of 2-(4-Thiazolyl)benzimidazole (TBZ) but lacking the thiol group. TBZ is widely used as a broad-spectrum anthelmintic in various animal species and humans and also as a food preservative and agricultural fungicide. The anti-5-benzimidazolecarboxylic acid antibodies produced have potential use for extraction and/or detection of protein-bound residue forms of TBZ. Three in vivo immunisation regimes (with combinations of two related small drug haptens and two different adjuvants/carrier molecules) and an in vitro immunisation procedure using a combination of three related unconjugated small drug haptens were investigated. Specificity for the hapten immunogen/s was initially determined using two different ELISA procedures. BIACORE analysis, in conjunction with drug binding inhibition studies, was used to confirm the specificity of a small number of selected clones. In vivo immunisation with a drug molecule conjugated to a lipopeptide/T-cell epitope, which acts both as a carrier molecule and an adjuvant was the most useful of the methods tested for the production of specific MAbs to a typically very small hapten with low immunogenic properties.

Animals↗
PubMed2002

Structure-activity relationship of indomethacin analogues for MRP-1, COX-1 and COX-2 inhibition. identification of novel chemotherapeutic drug resistance modulators.

We report the screening of analogues of indomethacin to investigate the structure-activity relationship (SAR) of indomethacin-mediated multidrug resistance associated protein-1 (MRP-1) inhibition. By examining the activities of compounds with minor variations of the parent structure, we were able to separate MRP-1, glutathione-S-transferase (GST), cyclooxygenase (COX)-1 and COX-2 inhibitory activities. Combination cytotoxicity assays were utilised to identify agents which possess synergistic potential in MRP-1-expressing cell lines. MRP-1 Inside Out Vesicles (IOVs) were utilised to demonstrate the ability of the indomethacin analogues to inhibit the pump directly. Most of the indomethacin analogues active as MRP-1 inhibitors were poor GST inhibitors when compared with the GST-inhibitory activity of indomethacin. Two of the MRP-1 inhibitory analogues were found to have no COX-1 inhibitory activity and low COX-2 inhibitory activity, suggesting potentially reduced clinical toxicity. One MRP-1 inhibitory indomethacin analogue was also found to have low COX-1 inhibitory activity, but significant COX-2 inhibitory activity, making this analogue again interesting in terms of low potential toxicity, but with the possibility of direct inhibitory effects on tumour growth.

Cyclooxygenase 1↗
PubMed2001

Selection with melphalan or paclitaxel (Taxol) yields variants with different patterns of multidrug resistance, integrin expression and in vitro invasiveness.

A melphalan-resistant variant (Roswell Park Memorial Institute (RPMI)-2650Ml) and a paclitaxel-resistant variant (RPMI-2650Tx) of the drug-sensitive human nasal carcinoma cell line, RPMI-2650, were established. The multidrug resistance (MDR) phenotype in the RPMI-2650Tx appeared to be P-glycoprotein (PgP)-mediated. Overexpression of multidrug resistant protein (MRP) family members was observed in the RPMI-2650Ml cells, which were also much more invasive in vitro than the parental cell line or the paclitaxel-resistant variant. Increased expression of alpha(2), alpha(5), alpha(6), beta(1) and beta(4) integrin subunits, decreased expression of alpha(4) integrin subunit, stronger adhesion to collagen type IV, laminin, fibronectin and matrigel, increased expression of MMP-2 and MMP-9 and significant motility compared with the parental cells were observed, along with a high invasiveness in the RPMI-2650Ml cells. Decreased expression of the alpha(2) integrin subunit, decreased attachment to collagen type IV, absence of cytokeratin 18 expression, no detectable expression of gelatin-degrading proteases and poor motility may be associated with the non-invasiveness of the RPMI-2650Tx variant. These results suggest that melphalan exposure can result in not only a MDR phenotype, but could also make cancer cells more invasive, whereas paclitaxel exposure resulted in MDR without increasing the in vitro invasiveness in the RPMI-2650 cells.

Antigens, CD↗
PubMed2001

A new monoclonal antibody, P2A8(6), that specifically recognizes a novel epitope on the multidrug resistance-associated protein 1 (MRP1), but not on MRP2 nor MRP3.

Multidrug resistance (MDR) is a major problem in the chemotherapeutic treatment of cancer. Overexpression of the multidrug resistance-associated protein 1 (MRP1), is associated with MDR in certain tumors. A number of MRP1-specific MAbs, which facilitate both clinical and experimental investigations of this protein, are available. To add to this panel of existing antibodies, we have now generated an additional MRP1-specific monoclonal antibody (MAb), P2A8(6), which detects a unique heat stable epitope on the MRP1 molecule. Female Wistar rats were immunized via footpad injections with a combination of two short synthetic peptides corresponding to amino acids 235-246 (peptide A) and 246-260 (peptide B) of the MRP1 protein. Immune reactive B cells were then isolated from the popliteal lymph nodes for fusion with SP2/O-Ag14 myeloma cells. Resultant hybridoma supernatants were screened for MRP1-specific antibody production. Antibody P2A8(6) was characterized by Western blotting and immunocytochemistry on paired multidrug resistant (MRP1 overexpressing) and sensitive parental cell lines. The antibody detects a protein of 190 kDa in MRP1-expressing cell lines but not in MRP2- or MRP3-transfected cell lines. P2A8(6) stains drug-selected and MRP1-transfected cell lines homogeneously by immunocytochemistry and recognizes MRP1 by immunohistochemistry on formalin-fixed paraffin wax-embedded tissue sections. Peptide inhibition studies confirm that P2A8(6) reacts with peptide B (amino acids 246-260), therefore recognizing a different epitope from that of all currently available MRP1 MAbs. This new MAb, chosen for its specificity to the MRP1 protein, may be a useful addition to the currently available range of MRP1-specific MAbs.

Animals↗
PubMed2001

Bromodeoxyuridine increases keratin 19 protein expression at a posttranscriptional level in two human lung tumor cell lines.

Keratins form the largest subfamily of intermediate filament proteins and show strict lineage- and differentiation-associated expression in epithelial cells. Little is known about the mechanisms that control keratin protein synthesis in these cells. We have examined the effect of the differentiation-modulating agent, 5'-bromo-2'-deoxyuridine (BrdU), on keratin 19 (K19) expression in two human lung carcinoma cell lines, DLKP and A549. Treatment of both cell lines with 10 microM BrdU for 7 d induced the expression of K19 protein in keratin-negative DLKP cells, and significantly increased K19 protein expression in A549 cells. K19 messenger ribonucleic acids (mRNAs) were detected by Northern blot and reverse transcriptase-polymerase chain reaction analyses in both cell lines, but no increase in K19 mRNA levels was detected in either cell line, even with treatment with BrdU for up to 21 d. This suggests that K19 protein synthesis is normally blocked at a posttranscriptional level in DLKP cells, and BrdU can somehow reverse this block, resulting in the induction of K19 protein synthesis. Treatment of HL60, a leukemic cell line, with BrdU, resulted in noninduction of K19 protein synthesis, and no K19 mRNA transcripts were detected before and after BrdU treatment, possibly suggesting that BrdU is acting in an epithelial-specific manner to reverse a block in K19 protein synthesis in DLKP keratin-negative lung cancer cells. Therefore, DLKP (and A549) may be useful cellular models to investigate if this represents a regulatory step in early lung development or a mechanism whereby tumor cells possess the ability to down-regulate the expression of a more-differentiated phenotype.

Blotting, Northern↗
PubMed2001

Bromodeoxyuridine induces integrin expression at transcriptional (alpha2 subunit) and post-transcriptional (beta1 subunit) levels, and alters the adhesive properties of two human lung tumour cell lines.

Integrins are a family of transmembrane glycoproteins that participate in a wide range of cellular events including proliferation, apoptosis and differentiation. Little is known about the mechanisms that control integrin subunit expression in epithelial cells, especially during lung cell differentiation. We have examined the effect of the differentiation-modulating agent, 5-bromo-2'-deoxyuridine (BrdU), on integrin expression in 2 human lung carcinoma cell lines, DLKP and A549. Treatment of both DLKP and A549 with 10 microM BrdU for 7 days resulted in increased expression of alpha2 and beta1 integrin subunit protein expression. Northern blot and RT-PCR analyses revealed progressively increasing levels of the alpha2 mRNA transcripts following BrdU treatment up to 21 days in both cell lines. However, no increase in beta1 integrin mRNA levels was observed in either cell, suggesting post-transcriptional regulation by BrdU. Treatment of HL-60, a leukaemic cell line, with BrdU up to 21 days resulted in no change in alpha2 or beta1 integrin subunit levels at either protein or mRNA levels suggesting that the change seen in the lung cell lines may be epithelial cell lineage-specific. BrdU has also been found to alter the adhesive properties of A549 and DLKP cells. Treated cells were found to adhere significantly faster to collagen type IV and laminin compared to untreated cells. The results presented here suggest that DLKP (and A549) may be useful cellular models to investigate the role of the alpha2beta1 integrin in lung epithelial cell differentiation.

Antigens, CD↗
PubMed2000

Altered cell cycle response of drug-resistant lung carcinoma cells to doxorubicin.

The effect of doxorubicin treatment on cell cycle parameters in asynchronous populations of multidrug-resistant human lung carcinoma cell lines was investigated. A sensitive (DLKP-SQ) and three resistant (DLKP-SQ A250 10p#7, DLKP-A2B and DLKP-A5F) variants of a human lung carcinoma cell line DLKP were exposed to equitoxic concentrations of doxorubicin. The latter three were 8-fold, 30-fold and 300-fold resistant to doxorubicin, respectively. Irreversible G2/M arrest in sensitive (DLKP-SQ) cells was observed 24 h after initiation of doxorubicin treatment. In resistant variants, G2/M arrest occurred at 12-16 h with a subsequent bypass of the G2/M arrest to re-emerge and accumulate in G1. This transient G2/M arrest and subsequent progression into G1 indicated an inefficient checkpoint for monitoring DNA damage induced by doxorubicin treatment. Caffeine treatment could bypass the G2/M block in DLKP-SQ cells. Doxorubicin treatment did not alter cyclin B or cdc2 protein levels, the ability of cdc2 to form complexes with cyclin B or the levels of cyclin B bound to cdc2. The G2/M arrest seen in sensitive cells was associated with an increase in inhibitory phosphorylation of Tyr15 on cdc2. In contrast, tyrosine 15 phosphorylation did not change in resistant variants after drug treatment and a general increase in cdc2 kinase activity was seen. Cdc25C levels were not altered following drug treatment.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Altered expression of mRNAs for apoptosis-modulating proteins in a low level multidrug resistant variant of a human lung carcinoma cell line that also expresses mdr1 mRNA.

An in vitro model that might be relevant to cancer cell chemoresistance in vivo was generated by exposing the human lung carcinoma clonal cell line DLKP-SQ to 10 sequential pulses of pharmacologically attainable doses of doxorubicin. The resistant variant, DLKP-SQ/10p, was found to be cross-resistant to doxorubicin (10x), vincristine (43x), etoposide (3x), sodium arsenate (3x), paclitaxel (38x) [which could imply overexpression of P-glycoprotein (P-gp) and possibly increased multidrug resistance-associated protein activity] and 5-fluorouracil (4x), but slightly sensitized to carboplatin. Analysis of mRNA levels in the resistant variant revealed overexpression of mdr1 mRNA without significant alteration in mrp, Topo. IIalpha, GSTpi, dhfr or thymidylate synthase mRNA levels. Overexpression of the anti-apoptotic bcl-xL transcript and the pro-apoptotic bax mRNA was also detected but no alterations in bcl-2 or bag-1 mRNA levels were observed. Resistance to a P-gp-associated drug, doxorubicin, could be reversed with P-gp circumventing agents such as cyclosporin A and verapamil, but these substances had no effect on resistance to 5-fluorouracil. Overexpression of the pro-apoptotic bcl-xS gene in the DLKP-SQ/10p line partially reversed resistance not only to P-gp-associated drugs but also to 5-fluorouracil, indicating that the ratio of bcl family members may be important in determining sensitivity to chemotherapeutic drug-induced apoptosis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗