Biomedical subjects

T Tsuruo

Publications and source records attributed to T Tsuruo.

At least 145 records · Page 8Linked to original sources

PubMed1997

P-glycoprotein function involves conformational transitions detectable by differential immunoreactivity.

The MDR1 P-glycoprotein (Pgp), a member of the ATP-binding cassette family of transporters, is a transmembrane ATPase efflux pump for various lipophilic compounds, including many anti-cancer drugs. mAb UIC2, reactive with the extracellular moiety of Pgp, inhibits Pgp-mediated efflux. UIC2 reactivity with Pgp was increased by the addition of several Pgp-transported compounds or ATP-depleting agents, and by mutational inactivation of both nucleotide-binding domains (NBDs) of Pgp. UIC2 binding to Pgp mutated in both NBDs was unaffected in the presence of Pgp transport substrates or in ATP-depleted cells, whereas the reactivities of the wild-type Pgp and Pgps mutated in a single NBD were increased by these treatments to the level of the double mutant. These results indicate the existence of different Pgp conformations associated with different stages of transport-associated ATP hydrolysis and suggest trapping in a transient conformation as a mechanism for antibody-mediated inhibition of Pgp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Requirement of the caspase-3/CPP32 protease cascade for apoptotic death following cytokine deprivation in hematopoietic cells.

Hematopoietic cytokines transduce cell survival signals, which are distinct from the signals necessary for the stimulation of DNA synthesis. Recently, the Ras and phosphatidylinositol 3-kinase pathways have been shown to play important roles in preventing apoptosis in various cell types, e.g. hematopoietic cells and neuronal cells. Withdrawal of cytokine(s), in turn, results in rapid inactivation of these survival pathways and eventually leads to cell death accompanied by the hallmarks of apoptosis. However, the mechanism of cell death caused by cytokine deprivation has not been fully elucidated. In this study, we demonstrate that caspase-3/CPP32, a member of the caspase/interleukin-1beta-converting enzyme family, is activated upon interleukin (IL)-3 deprivation in IL-3-dependent cells as well as IL-2 deprivation in IL-2-dependent cells. In addition, poly(ADP-ribose) polymerase, a cellular substrate for the caspase family proteases, was degraded into apoptotic fragments in both cell lines after cytokine removal. Furthermore, inhibition of a caspase family protease by synthetic peptides suppressed apoptotic death. These results indicate that the activation of a caspase-like protease(s) is required for the progression of apoptosis following cytokine deprivation. However, readdition of IL-3 did not restore the proliferative potential of the cells that survived in the presence of the peptide inhibitor after IL-3 depletion. Therefore, cellular commitment to apoptosis appears to precede the activation of a caspase-like protease(s).

Animals↗

PubMed1997

c-Myc plays a role in cellular susceptibility to death receptor-mediated and chemotherapy-induced apoptosis in human monocytic leukemia U937 cells.

Human monocytic leukemia U937 cells readily undergo apoptosis when they are treated with TNF-alpha, anti-Fas antibody and anticancer drugs such as etoposide and Ara-C. To study the mechanism of apoptosis, we developed a novel apoptosis-resistant variant, UC, from U937 cells. The UC cells showed resistance to apoptosis induced by TNF-alpha, anti-Fas antibody, etoposide and Ara-C. Somatic cell hybridization between U937 and UC showed that apoptosis-resistance to TNF-alpha in UC was genetically recessive and resistance to etoposide was dominant, suggesting that UC has at least two different mutations functionally involved in apoptosis. Mechanistic analysis revealed that UC cells expressed reduced amounts of c-Myc. Transfection of the c-myc gene into UC cells restored the sensitivity of the cells to undergo apoptosis induced by TNF-alpha and anti-Fas, which attributes apoptosis-resistance in this circumstance to the reduced expression of c-Myc. On the other hand, c-myc transfection into UC cells could not restore their sensitivity to etoposide- and Ara-C-induced apoptosis, arguing against the role of c-myc in chemotherapy-induced apoptosis. However, treating the parental U937 cells with antisense oligonucleotides designed to reduce c-Myc expression rendered the cells resistant to etoposide-induced as well as to TNF-alpha-induced apoptosis. These results indicate that the reduced expression of c-Myc in UC is strongly associated with the resistance to etoposide-induced apoptosis. Our finding that c-myc transfection into UC could not restore the sensitivity to etoposide-induced apoptosis, suggests UC could have a second mutation that confers resistance to etoposide-induced apoptosis in a genetically dominant manner. Taken together, our present results indicate that c-Myc plays a role in cellular susceptibility to death receptor-mediated and chemotherapy-induced apoptosis.

Antibodies↗

PubMed1997

Suppression of experimental lung colonization of mouse colon adenocarcinoma 26 in vivo by an anti-idiotype monoclonal antibody recognizing a platelet surface molecule.

The interaction between platelets and tumor cells is important in the formation of pulmonary metastasis. We previously established the 8F11 monoclonal antibody (mAb) by immunizing rats with the NL-17 cell line, a highly metastatic variant of mouse colon adenocarcinoma 26. 8F11 could inhibit the platelet aggregation in vitro and suppress the pulmonary metastasis in vivo by NL-17 cells. 8F11 recognized the Mr 44,000 sialoglycoprotein (gp44) on NL-17 cells, and the affinity-purified gp44 alone could induce platelet aggregation. Therefore, 8F11 might inhibit gp44-induced platelet aggregation by masking the epitope of gp44 that interacted with unknown molecule(s) on the platelet surface. To identify the platelet antigen that interacted with gp44, we generated anti-idiotype mAbs by immunizing rats with 8F11. Two of the established mAbs, AIP1 and AIP4, recognized not only 8F11 but also the Mr 160,000 platelet surface protein. AIP4 mAb could also inhibit the NL-17 cell-induced platelet aggregation in a dose-dependent manner. Furthermore, pretreatment of mice with AIP4 mAb suppressed the pulmonary metastasis of NL-17 cells in vivo. These results suggest that the Mr 160,000 platelet antigen participates in the NL-17 cell-induced platelet aggregation and colonization of NL-17 cells in the lung by interacting with the gp44 of NL-17 cells.

Adenocarcinoma↗

PubMed1997

Structure-activity relationship of newly synthesized quinoline derivatives for reversal of multidrug resistance in cancer.

The effect of 24 newly synthesized quinoline derivatives on tumor cell multidrug resistance (MDR) was examined in vitro. At low concentrations, these compounds enhanced the accumulation of [3H]vincristine in K562/ADM cells and reversed tumor cell MDR. The results of the structure-activity relationship analysis indicate that in highly active compounds the two aryl rings in the hydrophobic moiety deviate from a common plane, so they are capable of interacting with hydrogen bond donors of P-170 glycoprotein (P-gp) via pi-hydrogen-pi interactions. Other major structural features which influence the MDR-reversing activities of these compounds are a quinoline nitrogen atom and a basic nitrogen atom in piperazine. Furthermore, in highly active compounds, the distance between the hydrophobic moiety and the basic nitrogen atom (an atom connected to 2-hydroxypropoxyquinoline) must be at least 5 A. Several compounds were found to reverse vincristine resistance in K562/ADM cells in vitro, and compound 16 (MS-209) was selected for clinical studies.

Animals↗

PubMed1997

Overcoming of multidrug resistance by VA-033, a novel derivative of apovincaminic acid ester.

We have studied the effects of a novel derivative of apovincaminic acid ester, VA-033, on the resistance of tumors to chemotherapeutic agents. VA-033 increased the sensitivity of drug-resistant cell lines (P388/VCR, P388/ADM, AD10, and K562/ADM) to adriamycin or vincristine. The potency of VA-033 was stronger than verapamil. The drug lengthened the survival time of the P388/VCR-implanted mice treated with vincristine. VA-033 increased the intracellular accumulation of vincristine in the tumor cells, and the photolabeling of P-glycoprotein by [3H]azidopine was inhibited by VA-033. VA-033 showed a slight inhibitory effect on the L-type Ca2+ current in the ventricular myocytes, and had less effect on the cardiovascular parameters such as blood pressure, contractile force and atrio-ventricular conduction time than verapamil when administered systemically in the dog. These results suggest that VA-033 may become a beneficial compound as a modifier to the neoplastic cell resistant to multidrugs.

Animals↗

PubMed1997

Stimulation of interleukin-11 production from osteoblast-like cells by transforming growth factor-beta and tumor cell factors.

Bone is one of the most common sites of metastasis in melanoma and breast cancer cells. Human melanoma (A375M) and human breast cancer (MDA-MB-231) cells form osteolytic bone metastasis in vivo when these tumor cells are injected into the left ventricles of BALB/c nude mice. These tumor cells promote bone resorption in the in vitro neonatal murine calvaria organ culture system by indirectly stimulating the production of a bone resorption-inducing factor (or factors) from human osteoblast-like cells. This secreted factor was identified as interleukin-11 (IL-11). Although many cytokines and hormones were associated with IL-11 production from osteoblasts, transforming growth factor-beta (TGF-beta) was found to be involved in the promotion of IL-11 production from osteoblasts, because the addition of a neutralizing anti-TGF-beta antibody decreased the production of IL-11. However, these tumor cells did not produce TGF-beta by themselves. We found that they enhanced IL-11 production by activating latent TGF-beta produced from osteoblast-like cells. Our results indicate that metastatic tumor cells induce osteolysis by activating TGF-beta, which leads IL-11 production from osteoblasts to promote bone resorption.

Animals↗

PubMed1997

Aggregation of Thy-1 glycoprotein induces thymocyte apoptosis through activation of CPP32-like proteases.

Mouse thymocytes are known to undergo apoptosis by ligating some unique anti-Thy-1 monoclonal antibodies (mAbs), G7 and KT16. However, the precise mechanisms of Thy-1-mediated apoptosis are as yet unclear. We investigated Thy-1-mediated apoptosis using our previously generated anti-Thy-1 mAb, MCS-34, which was similar to G7 because both antibodies recognized both Thy-1.1 and Thy-1.2 and bound Thy-1A epitope. Unlike G7, MCS-34 alone could not induce apoptosis in thymocytes; however, it could induce apoptosis when it was cross-linked with second antibodies. Thus, MCS-34 could not aggregate by itself, but G7 could. In the course of investigating the apoptosis-related molecules that were involved in the thymocyte apoptosis induced by cross-linking of MCS-34 or by G7 ligation, we found that CPP 32-like proteases were activated during the apoptosis. Furthermore, the expression of bcl-2 and bcl-XL proteins was decreased in these apoptosis processes. Whereas the ligation of MCS-34 alone could not generate apoptosis signals that led to the activation of CPP32-like proteases and the decrease in bcl-2 and bcl-XL expression, the aggregation of Thy-1 glycoprotein might be crucial to signal thymocyte apoptosis. These results indicate that MCS-34 is a useful anti-Thy-1 mAb for analyzing the Thy-1-mediated signals since MCS-34 can control the level of apoptosis by using second antibodies.

Animals↗

PubMed1997

Combined therapy of multidrug-resistant human lung cancer with anti-P-glycoprotein antibody and monocyte chemoattractant protein-1 gene transduction: the possibility of immunological overcoming of multidrug resistance.

We determined whether transduction of the monocyte chemoattractant protein-1 (MCP-1) gene into MDR human lung cancer cells affected their tumorigenicity and sensitivity to antibody-dependent cellular cytotoxicity (ADCC) reaction mediated by the anti-P-glycoprotein (P-gp) monoclonal antibody MRK16. The human MCP-1 gene inserted into an expression vector (BCMGSNeo) was transfected into MDR human small-cell lung cancer (H69/VP) cells. Monocyte chemotactic activity was found in culture supernatants collected from MCP-1-transfected H69/VP cells, but not in supernatants of parent and mock-transfected cells. In an in vitro experiment, recombinant MCP-1 did not affect monocyte-mediated ADCC against H69/VP cells when added to the monocyte culture in either the activation or the effector phase at sufficient concentrations to attract and activate monocytes. Tumorigenicity and growth rates of MCP-1-producing H69/VP cells in nude mice were similar to those of parental cells and mock-transfected cells. However, systemic treatment with MRK16 was more effective in inhibiting the formation of tumors by MCP-1-gene-transfected cells than by mock-transfected cells. Systemic treatment with MRK16 also inhibited the growth of a mixture (1:1) of MCP-1-producing cells and mock-transfected cells. These results suggest that combination therapy with MRK16 and MCP-1 gene transduction may be a useful immunological strategy to inhibit the growth of human MDR cancer cells expressing P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Apoxin I, a novel apoptosis-inducing factor with L-amino acid oxidase activity purified from Western diamondback rattlesnake venom.

Venom of the western diamondback rattlesnake (Crotalus atrox) induces apoptosis in human umbilical vein endothelial cells, which could result in hemorrhage in tissues bitten by the snake. To identify the hemorrhagic factor, we purified a novel protein, apoxin I, from rattlesnake venom. Apoxin I induced apoptosis in human umbilical vein endothelial, human promyelocytic leukemia HL-60, human ovarian carcinoma A2780, and mouse endothelial KN-3 cells. Amino acid sequence analysis of the apoxin I showed close similarity to L-amino acid oxidase from the Malayan pit viper (Calloselasma rhodostoma). The purified apoxin I oxidized L-leucine but not D-leucine to produce H2O2. The apoxin I-induced apoptosis was inhibited by catalase, a H2O2 scavenger. These results indicate that the H2O2 produced by L-amino acid oxidation by apoxin I is involved in the apoxin I-induced apoptosis and in hemorrhage caused by rattlesnake venom.

Amino Acid Oxidoreductases↗

PubMed1997

Regression of established tumors expressing P-glycoprotein by combinations of adriamycin, cyclosporin derivatives, and MRK-16 antibodies.

BACKGROUND: Overexpression of P-glycoprotein, a transmembrane protein capable of transporting a broad spectrum of anticancer drugs out of cells, likely contributes to tumor drug resistance. Strategies for overcoming this resistance include the use of specific compounds, such as cyclosporin derivatives, that modulate P-glycoprotein function and antibodies that bind to the protein, thereby altering its activity. PURPOSE: We examined the antitumor activity of combination treatment with the anti-P-glycoprotein monoclonal antibody MRK-16, a cyclosporin derivative (either cyclosporin A [CsA] or PSC 833), and the anticancer drug Adriamycin (ADM) against human colorectal carcinoma cells in vitro and established xenografts of these cells in vivo. METHODS: The human colorectal carcinoma cell line HCT-15 and its ADM-resistant subline HCT-15/ADM2-2 were used in this study. Cellular staining with a tetrazolium dye was used to assess the antitumor (i.e., antiproliferative) effects of treatment in vitro. Caliper measurement of tumor volumes was used to assess the antitumor effects of treatment in vivo. Cell surface binding of MRK-16 was measured by means of an immunofluorescence assay. Differences in the patterns of tumor cell growth in vitro and tumor growth rates in vivo were evaluated by means of repeated measure analysis of variance. Synergy in the combined effects of treatment was evaluated by means of the fractional product method. RESULTS: HCT-15 cells were found to express P-glycoprotein intrinsically; HCT-15/ADM2-2 cells expressed approximately five times more P-glycoprotein than the parental cells. HCT-15/ADM2-2 cells were also found to be about eight times more resistant to ADM in vitro than the parental cells. Incubation of both cell types in vitro with either MRK-16 and ADM or one of the cyclosporin derivatives and ADM inhibited cell growth minimally; however, ternary treatment with MRK-16, one of the cyclosporin derivatives, and ADM dramatically reduced the growth of both cell types. An analysis of treatment effects indicated that synergistic effects were obtained with ternary treatment. When athymic mice bearing established tumors (either HCT-15 or HCT-15/ADM2-2) were treated similarly with various combinations of the tested agents, the most pronounced antitumor effects were observed with ternary treatment. In some mice bearing HCT-15/ADM2-2 xenografts, ternary treatment led to complete tumor regression. Finally, CsA and PSC 833 were both shown to enhance MRK-16 binding to HCT-15 cells and HCT-15/ADM2-2 cells in vitro. CONCLUSION: Combination treatment with a cyclosporin derivative and an anti-P-glycoprotein antibody can be effective in circumventing P-glycoprotein-mediated drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Phosphatidylserine externalization is a downstream event of interleukin-1 beta-converting enzyme family protease activation during apoptosis.

Phosphatidylserine (PS), a class of acidic phospholipids, normally localizes on the internal surface of cellular plasma membranes. The internal PS is externalized when cells undergo apoptosis; however, the mechanism for this is largely unknown. To study the mechanism of PS externalization during development of apoptosis, we examined the correlation between the activation of interleukin-1 beta-converting enzyme (ICE) family protease and PS externalization in human monocytic leukemia U937 cells and in their apoptosis-resistant variants, UK711 and UK110, after treatment with etoposide and anti-Fas antibody. We found that PS externalization accompanied the development of apoptosis and the activation of ICE family proteases in these cell lines. Furthermore, inhibitors of ICE family proteases, Z-Asp and Z-VAD, prevented apoptosis and PS externalization in etoposide-treated U937 cells. These results indicate that PS externalization is a downstream event of ICE family protease activation during apoptosis development. Because ICE family proteases play a crucial role in apoptosis, PS externalization could be a rational and useful marker for the development of apoptosis.

Apoptosis↗

PubMed1997

Actin cleavage by CPP-32/apopain during the development of apoptosis.

Interleukin-1beta-converting enzyme (ICE)/ced-3 family proteases play key roles in apoptosis. However, cellular substrates for ICE family proteases involved in apoptosis are not well understood. We previously showed that actin is cleaved in vitro by an ICE family protease, distinct from ICE itself, which is activated during VP-16-induced apoptosis. In this report, we demonstrate that the actin-cleaving ICE-family protease in the apoptotic cell extract is the activated CPP-32/apopain. CPP-32 effectively cleaves actin protein to 15 kDa and 31 kDa fragments. Studies with an antibody raised against Gly-Gln-Val-Ile-Thr peptide, the N-terminal sequence of the cleaved 15 kDa actin fragment, showed that actin is also cleaved in vivo during the development of apoptosis. Moreover, Benzyloxycarbonyl-Glu-Val-Asp-CH2OC(O)-2,6,-dichlorobenzene (Z-EVD-CH2-DCB), a selective inhibitor of CPP-32(-like) protease, efficiently inhibited the cleavage of actin and the apoptosis of VP-16-treated U937 cells. Our present results indicate that actin is the substrate of CPP-32/apopain(-like) protease both in vitro and in vivo and suggest the role of actin in the control of cell growth and apoptosis.

Actins↗

PubMed1997

Isolation of murine and human homologues of the fission-yeast dis3+ gene encoding a mitotic-control protein and its overexpression in cancer cells with progressive phenotype.

To investigate genes involved in metastasis, we used a differential display method to compare the levels of gene expression in three cell lines derived from murine colon-adenocarcinoma 26 that show different metastatic potentials. The results, and subsequent Northern analyses, confirmed that one gene was expressed most strongly in NL17, the cell line with the highest experimentally metastatic potential to the lung; strongly in NL22, the line with moderately metastatic potential; and very weakly in NL4, which has no metastatic potential in recipient mice. Using this fragment as a probe, we isolated the murine cDNA as well as its human homologue and determined their DNA sequences. The cDNA sequences from both species contained open reading frames of 2874 nucleotides, encoding peptides of 958 amino acids with calculated molecular weights of approximately 109,000; the murine and human nucleotide sequences were 90% identical. The deduced amino acid sequences of these cDNAs revealed significant homology (45% identity) to the dis3+ gene product of Schizosaccharomyces pombe, a protein thought to be essential for mitotic control in the yeast. We therefore termed the murine and human genes hmc (homologue to the mitotic-control gene) and HMC, respectively. In 7 of 13 patients with colorectal cancers and liver metastases, expression of HMC was increased up to 38-fold in primary tumors and metastatic foci as compared to adjacent normal colorectal mucosa. An increase in expression of HMC, its novel product likely to belong to a structurally distinct family of mitotic-control proteins, may be associated with malignant phenotypes of some colorectal cancers.

Adenocarcinoma↗

PubMed1997

c-Jun NH2-terminal kinase-mediated activation of interleukin-1beta converting enzyme/CED-3-like protease during anticancer drug-induced apoptosis.

Upon treatment with various anticancer drugs, myeloid leukemia U937 cells undergo apoptosis. In this study, we found that either etoposide (VP-16) or camptothecin (CPT) activated c-Jun N-terminal kinase 1/stress-activated protein kinase (JNK1/SAPK), transient c-jun expression, and ICE (interleukin-1beta converting enzyme)/CED-3-like proteases in U937 cells. Phorbol ester-resistant U937 variant, UT16 cells, displayed a decreased susceptibility to apoptosis induced by these drugs. The drugs did not cause JNK1 activation, c-jun expression, nor activation of ICE/CED-3-like proteases in UT16 cells. As reported previously, benzyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene (Z-Asp), a preferential inhibitor of ICE/CED-3-like proteases, blocked the apoptosis of U937 cells. Interestingly, however, Z-Asp did not inhibit JNK1 activation in either VP-16- or CPT-treated U937 cells. The JNK1 antisense oligonucleotides diminished protein expression of JNK1 and inhibited drug-induced apoptosis of U937 cells, whereas sense control oligonucleotides did not. Consistent with this observation, the antisense oligonucleotide-treated cells did not respond to VP-16 or CPT with Z-Asp-sensitive proteases. These results indicate that JNK1 triggers the DNA damaging drug-induced apoptosis of U937 cells by activating Z-Asp-sensitive ICE/CED-3-like proteases.

Antineoplastic Agents↗

PubMed1997

In vivo detection of multidrug-resistant (MDR1) phenotype by technetium-99m sestamibi scan in untreated breast cancer patients.

Technetium-99m sestamibi is a transport substrate recognised by the multidrug-resistant P-glycoprotein (Pgp). To test whether 99mTc-sestamibi efflux is enhanced in breast carcinomas overexpressing Pgp, we determined the efflux rates of 99mTc-sestamibi and Pgp levels in tumours from 30 patients with untreated breast carcinoma. Patients were intravenously injected with 740 MBq of 99mTc-sestamibi and underwent a 15-min dynamic study followed by the acquisition of static planar images at 0.5, 1, 2 and 4 h. Tumour specimens were obtained from each patient 24 h after 99mTc-sestamibi scan and Pgp levels were determined using 125I-MRK16 monoclonal antibody and in vitro quantitative autoradiography. All breast carcinomas showed high uptake of 99mTc-sestamibi and data from region of interest analysis on sequential images were fitted with a monoexponential function. The efflux rates of 99mTc-sestamibi, calculated from decay-corrected time-activity curves, ranged between 0.00121 and 0.01690 min-1 and were directly correlated with Pgp levels measured in the same tumours (r=0.62; P<0.001). Ten out of 30 breast carcinomas (33%) contained 5 times more Pgp than benign breast lesions and showed a mean concentration of 5.73+/- 1.63 pmol/g of tumour (group A). The remaining 20 breast carcinomas had a mean Pgp concentration of 1.29+/-0.64 pmol/g (group B), equivalent to that found in benign breast lesions. 99mTc-sestamibi efflux from tumours of group A was 2.7 times higher than that observed in tumours of group B (0.00686+/-0.00390 min-1 vs 0.00250+/-0.00090 min-1, P<0.001). The in vivo functional test with 99mTc-sestamibi showed a sensitivity and a specificity of 80% and 95%, respectively. In conclusion, the efflux rate of 99mTc-sestamibi may be used for the in vivo identification of the multidrug resistant (MDR1) phenotype in untreated breast cancer patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Overexpression of thioredoxin does not confer resistance to cisplatin in transfected human ovarian and colon cancer cell lines.

PURPOSE: We have previously reported increased expression of thioredoxin (TRX) in cell lines with both acquired and intrinsic cisplatin (cDDP) resistance. We found that the expression levels of TRX correlate with cellular resistance to the drug. The purpose of this study was to elucidate whether TRX induces cDDP resistance in the absence of other intracellular changes. METHODS: We developed cell lines stably expressing high levels of TRX by transfection of human ovarian cancer A2780 and colon cancer HT-29, and examined their sensitivity to cDDP. RESULTS: The TRX transfectants expressed two- to threefold more TRX with corresponding activities than the parental cells or mock transfectants. TRX-transfected HT-29 cells expressed higher levels of TRX than cDDP-resistant variant cells. Both TRX-transfected A2780 and HT-29 cells showed no resistance to cDDP. Though TRX-transfected A2780 cells showed 1.8-fold increased resistance to H2O2, resistance to adriamycin and mitomycin C, which generate oxygen radicals, was not observed in the transfectants. CONCLUSIONS: These results suggest that TRX may be necessary but insufficient to induce resistance against cDDP as well as other chemotherapeutic drugs.

Antineoplastic Agents↗

PubMed1997

A novel quinoline derivative, MS-209, overcomes drug resistance of human lung cancer cells expressing the multidrug resistance-associated protein (MRP) gene.

PURPOSE AND METHODS: MS-209 is a newly synthesized quinoline compound used orally to overcome human P-glycoprotein (Pgp)-mediated multidrug resistance (MDR). The multidrug resistance-associated protein (MRP) gene is thought to play an important role in MDR in lung cancer. To investigate whether MS-209 could also overcome MRP-mediated MDR, we examined the effect of the compound using a cytotoxicity assay on MDR1 gene-negative drug-selected MDR and wildtype lung cancer cells with various levels of MRP gene expression. The effects of MS-209 were compared with those of verapamil (VER) and cyclosporin A (CsA). The level of MRP gene expression in the cells was evaluated semiquantitatively by RT-PCR. For vincristine (VCR), intracellular accumulation of [3H]-VCR was measured with or without MS-209. RESULTS: In MDR UMCC-1/VP small-cell lung carcinoma cell line, 5 microM of MS-209 and VER enhanced the cytotoxicity of etoposide, doxorubicin (DOX) and VCR more than twofold, and completely reversed the resistance to VCR. The mean reversing effects of MS-209 on DOX and VCR were significantly stronger than those of VER and CsA. In wildtype non-small-cell lung carcinoma cells, the effects of MS-209 were almost equal to those of VER and CsA. The effect of these three agents correlated with the level of MRP gene expression. The MS-209-induced increase in intracellular accumulation of VCR was proportional to the level of MRP gene expression in these cells. CONCLUSION: Our results indicate that MS-209 is a potentially useful drug that can overcome MRP-mediated intrinsic and acquired MDR in human lung cancer.

Antineoplastic Agents↗