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Biomedical subjects

Takashi Tsuruo

Publications and source records attributed to Takashi Tsuruo.

108 records · Page 6Linked to original sources
PubMed2002

Involvement of Hsp90 in signaling and stability of 3-phosphoinositide-dependent kinase-1.

Serine/threonine kinase Akt is thought to mediate many biological actions toward anti-apoptotic responses. Screening of drugs that could interfere with the Akt signaling pathway revealed that Hsp90 inhibitors (e.g. geldanamycin, radicicol, and its analogues) induced Akt dephosphorylation, which resulted in Akt inactivation and apoptosis of the cells. Hsp90 inhibitors did not directly affect Akt kinase activity in vitro. Thus, we examined the effects of Hsp90 inhibitors on upstream Akt kinases, phosphatidylinositide-3-OH kinase (PI3K) and 3-phosphoinositide-dependent protein kinase-1 (PDK1). Hsp90 inhibitors had no effect on PI3K protein expression. In contrast, treatment of the cells with Hsp90 inhibitors decreased the amount of PDK1 without directly inhibiting PDK1 kinase activity. We found that the kinase domain of PDK1 was essential for complex formation with Hsp90 and that Hsp90 inhibitors suppressed PDK1 binding to Hsp90. PDK1 degradation mechanisms revealed that inhibition of PDK1 binding to Hsp90 caused proteasome-dependent degradation of PDK1. Treatment of proteasome inhibitors increased the amount of detergent-insoluble PDK1 in Hsp90 inhibitor-treated cells. Therefore, the association of PDK1 with Hsp90 regulates its stability, solubility, and signaling. Because Akt binding to Hsp90 is also involved in the maintenance of Akt kinase activity, Hsp90 plays an important role in PDK1-Akt survival signaling pathway.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2002

Evaluation of MS-209, a novel multidrug-resistance-reversing agent, in tumour-bearing mice by technetium-99m-MIBI imaging.

MS-209 is a newly synthesised multidrug-resistance (MDR)-reversing agent with few side-effects. In this study, we evaluated the effect of MS-209 on P-glycoprotein (Pgp)-positive tumours in mice by means of technetium-99m methoxyisobutylisonitrile (MIBI) imaging. Mice received Pgp-negative KB-3-1 or Pgp-positive KB-C1 cell xenografts. KB-3-1-bearing mice were administered 0 or 100 mg/kg of MS-209 (groups S0 and S100, respectively), and KB-C1-bearing mice 0, 50, 100 or 200 mg/kg (groups R0, R50, R100 and R200, respectively), 30 min before imaging studies. Dynamic 99mTc-MIBI images were acquired for 30 min, followed by biodistribution studies. Washout of 99mTc-MIBI from the tumours was faster in group R0 than in group S0 on visual analysis, and the washout half-time estimated by region of interest analysis was shorter in group R0 than in group S0. Biodistribution studies revealed that 99mTc-MIBI accumulation in tumours (expressed as %ID/g) was also lower in group R0 than in group S0. MS-209 delayed the 99mTc-MIBI washout from KB-C1 tumours. Washout half-time was longer in groups R50, R100 and R200 than in group R0. A higher %ID/g was observed in groups R100 and R200 than in group R0. In KB-3-1 tumours, MS-209 had no effect on the washout half-time or the %ID/g. This study demonstrated that MS-209 increases the 99mTc-MIBI accumulation in Pgp-positive tumours. The MDR-reversing effect of MS-209 could be effectively evaluated with 99mTc-MIBI visually and non-invasively in vivo. 99mTc-MIBI imaging with MS-209 prior to chemotherapy should contribute significantly to the treatment strategy in patients with multidrug-resistant tumours.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Decreased synthesis of matrix metalloproteinase-7 and adhesion to the extracellular matrix proteins of human colon cancer cells treated with troglitazone.

PURPOSE: In the present study, we investigated the effect of troglitazone, a selective ligand and agonist of PPAR-gamma, on the metastatic potential of human colon cancer cells. METHODS: High- and low-PPAR-gamma expression clones of the colon cancer cell line, HT29, namely clones 21 and 3 respectively, were used. We investigated the effect of troglitazone on the proliferation, on the adhesion to extracellular matrix proteins and on the synthesis of matrix metalloproteinases (MMPs) of colon cancer cells. RESULTS: Troglitazone inhibited the proliferation of both subclones, in a dose-dependent manner, and the inhibitory effect correlated with the level of PPAR-gamma expression. Troglitazone strongly inhibited the production of MMP-7, an enzyme associated with invasiveness of cancer cells, by both subclones. In addition, troglitazone caused a strong decrease in the adhesion of clone 21 to extracellular matrix (ECM) proteins, laminin and type IV collagen. This effect was independent of beta1-integrins expression CONCLUSION: In addition to inhibition of cancer cell growth, troglitazone had an inhibitory effect on two important events associated with the metastatic potential of cancer cells, production of MMPs and adhesion to ECM proteins. Consequently, troglitazone is a promising agent for the treatment and prevention of colon cancer metastasis.

Antineoplastic Agents↗
PubMed2002

Group IID heparin-binding secretory phospholipase A(2) is expressed in human colon carcinoma cells and human mast cells and up-regulated in mouse inflammatory tissues.

Group IID secretory phospholipase A(2) (sPLA(2)-IID), a heparin-binding sPLA(2) that is closely related to sPLA(2)-IIA, augments stimulus-induced cellular arachidonate release in a manner similar to sPLA(2)-IIA. Here we identified the residues of sPLA(2)-IID that are responsible for heparanoid binding, are and therefore essential for cellular function. Mutating four cationic residues in the C-terminal portion of sPLA(2)-IID resulted in abolition of its ability to associate with cell surface heparan sulfate and to enhance stimulus-induced delayed arachidonate release, cyclooxygenase-2 induction, and prostaglandin generation in 293 cell transfectants. As compared with several other group II subfamily sPLA(2)s, which were equally active on A23187- and IL-1-primed cellular membranes, sPLA(2)-IID showed apparent preference for A23187-primed membranes. Several human colon carcinoma cell lines expressed sPLA(2)-IID and sPLA(2)-X constitutively, the former of which was negatively regulated by IL-1. sPLA(2)-IID, but not other sPLA(2) isozymes, was expressed in human cord blood-derived mast cells. The expression of sPLA(2)-IID was significantly altered in several tissues of mice with experimental inflammation. These results indicate that sPLA(2)-IID may be involved in inflammation in cell- and tissue-specific manners under particular conditions.

Animals↗
PubMed2002

Transluminal gene transfer into brain capillary endothelial cells in vivo with HVJ-liposomes.

Bioactive proteins or peptides cannot be effectively delivered into brain capillary endothelial cells (BCECs) or brain parenchyma. In this study, we selectively transferred Escherichia coli beta-galactosidase gene (beta-gal) as a model gene into BCECs by using the hemagglutination virus of Japan (HVJ)-liposomes. HVJ-liposomes encapsulating a beta-gal plasmid were used to transfect MBEC4 cells in vitro, and were administrated via the internal carotid artery to rat in vivo. Success of the procedure was confirmed by the detection of 116 kDa beta-gal protein in transfected MBEC4 cells and in brain capillaries isolated from transfected rats, by Western blot analysis and histological staining. The enzymatic activities of beta-galactosidase were 5- to 10-fold and 20-fold higher than when beta-gal-containing liposomes without fusogenic activity (uncoated liposomes) or plasmid alone were employed in vitro and in vivo, respectively. Thus, HVJ-liposomes were demonstrated to be a useful vector to transfer a foreign gene into the brain capillary endothelium in vivo via the transluminal route.

Animals↗
PubMed2002

Prediction of sensitivity to STI571 among chronic myeloid leukemia patients by genome-wide cDNA microarray analysis.

One of the most critical issues to be solved in regard to cancer chemotherapy is the establishment of ways to predict the efficacy of anti-cancer drugs for individual patients. To develop a prediction system based on expression of specific genes, we analyzed expression profiles of mononuclear cells from 18 chronic myeloid leukemia (CML) patients who were treated with the tyrosine kinase inhibitor STI571. cDNA microarrays representing 23 040 genes identified 79 genes that were expressed differentially between responders and non-responders to STI571. On the basis of the expression patterns of 15 or 30 of these genes among the patients, we developed a "Prediction Score" system that could clearly separate the responder group from the non-responder group. Verification of this system using four additional ("test") cases succeeded in predicting the response of each of those four patients to the drug. These results provide the first evidence that gene-expression profiles can predict sensitivity of CML cells to STI571, and may eventually lead to the achievement of "personalized therapy" for this disease.

Adult↗
PubMed2002

Estrone and 17beta-estradiol reverse breast cancer resistance protein-mediated multidrug resistance.

Breast cancer resistance protein (BCRP), an adenosine triphosphate-binding cassette transporter, confers resistance to a series of anticancer reagents, including mitoxantrone, SN-38 and topotecan. In the present study, we found that estrone and 17beta-estradiol potentiated the cytotoxicity of mitoxantrone, SN-38 and topotecan in BCRP-transduced K562 cells (K562 / BCRP). These estrogens showed only a marginal effect, or none, in parental K562 cells. Estrone and 17beta-estradiol increased the cellular accumulation of topotecan in K562 / BCRP cells, but not in K562 cells, suggesting that these estrogens inhibit the BCRP-mediated drug efflux and overcome drug resistance.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2002

Enhancement of L-cystine transport activity and its relation to xCT gene induction at the blood-brain barrier by diethyl maleate treatment.

The purpose of the present study was to elucidate the mechanism of enhancement of L-cystine uptake at the blood-brain barrier (BBB). The uptake of [(14)C]L-cystine and [(3)H]L-glutamic acid (L-Glu) was determined using a mouse brain endothelial cell line (MBEC4) as an in vitro BBB model. The mRNA levels of L-cystine/L-Glu exchanger, system x(c)(-), which consists of xCT and 4F2hc, were determined by quantitative real-time reverse transcription-polymerase chain reaction analysis. The [(14)C]L-cystine uptake by MBEC4 cells appeared to be mediated via an Na(+)-independent saturable process. The corresponding Michaelis-Menten constant (K(m)) was 63.7 microM. In the presence of L-Glu, there was competitive inhibition with an inhibition constant (K(i)) of 83.5 microM. [(3)H]L-Glu uptake in the absence of Na(+) was saturable with a K(m) of 48.1 microM, and it exhibited competitive inhibition with a K(i) of 24.9 microM in the presence of L-cystine. The mutual inhibition between L-cystine and L-Glu and the type of inhibition suggest that system x(c)(-) operates in MBEC4 cells. The xCT and 4F2hc mRNAs were expressed in MBEC4 cells and, following diethyl maleate (DEM) treatment, the xCT mRNA level and L-cystine uptake in MBEC4 cells were enhanced in parallel with an increase in DEM concentration (up to 500 microM). Concomitantly, the glutathione concentration in MBEC4 cells was increased. In conclusion, system x(c)(-)-mediated L-cystine uptake takes place in MBEC4 cells. L-Cystine transport via system x(c)(-) at the BBB is likely to be induced under oxidative stress conditions following DEM treatment due to enhanced transcription of the xCT gene.

Algorithms↗
PubMed2002

Involvement of FKHR-dependent TRADD expression in chemotherapeutic drug-induced apoptosis.

Chemotherapeutic drugs exhibit their cytotoxic effect by inducing apoptosis in tumor cells. Because the serine/threonine kinase Akt is involved in apoptosis suppression, we investigated the relationship between Akt activity and drug sensitivity. We discovered that certain chemotherapeutic drugs induced apoptosis with caspase activation only when Akt was inactivated after drug treatment, while inactivation of Akt was not observed when tumor cells showed resistance to the drug-induced caspase activation. So, turn-off of the Akt-mediated survival signal is correlated with the sensitivity of the cells to chemotherapy. With a cDNA microarray, we revealed that tumor necrosis factor receptor-associated death domain (tradd) gene expression was elevated in response to Akt inactivation. Reportedly, Forkhead family transcription factors are phosphorylated by Akt, which results in their nuclear exit and inactivation. Analysis of the tradd promoter revealed that it contains at least one potential Forkhead family transcription factor-responsive element, and we confirmed that this element was involved in chemotherapeutic drug-induced TRADD expression. Overexpression of mutant TRADD proteins to block its apoptosis-inducing capability attenuated chemotherapeutic drug-induced apoptosis. Thus, chemotherapeutic drugs exhibited their cytotoxic effects in part by down-regulating Akt signaling following TRADD expression. These results indicate that Akt kinase activity after drug treatment is a hallmark of sensitivity of the cells to chemotherapeutic drugs.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2002

Contribution of P-glycoprotein to efflux of ramosetron, a 5-HT3 receptor antagonist, across the blood-brain barrier.

In-situ rat and mouse brain perfusion data indicated that the brain distribution of ramosetron (R-ramosetron), a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, was extremely low compared with that expected from its lipophilicity. We hypothesized the involvement of an efflux system(s) and investigated the contribution of P-glycoprotein to efflux transport of ramosetron across the blood-brain barrier by means of an in-vitro uptake study in cell lines that over-express P-glycoprotein. We examined the contributions of mdr1a, mdr1b and MDR1 P-glycoprotein by using LV500 cells, MBEC4 cells and LLC-GA5-COL300 cells, which over-express mdr1a P-glycoprotein, mdr1b P-glycoprotein and MDR1 P-glycoprotein, respectively. The uptake of [14C]ramosetron by LV500 cells and LLC-GA5-COL300 cells was significantly lower than that by the respective parental cells. Next, we studied the effects of P-glycoprotein inhibitors, verapamil and ciclosporin, on uptake of [14C]ramosetron by these cell lines. The uptake of [14C]ramosetron by LV500 cells and LLC-GA5-COL300 cells was significantly increased in the presence of verapamil or ciclosporin, while verapamil did not affect the uptake of [14C]ramosetron by MBEC4 cells. These results indicate that the efflux of [14C]ramosetron is partly mediated by mdr1a P-glycoprotein, but not by mdr1b P-glycoprotein, and that there is a difference in substrate specificity between mdr1a P-glycoprotein and mdr1b P-glycoprotein. Further, [14C]ramosetron was confirmed to be effluxed by human MDR1 P-glycoprotein. We conclude that the limited distribution of ramosetron to the brain is due, at least in part, to efflux mediated by the P-glycoprotein at the blood-brain barrier.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2002

Clonal endothelial cells produce humoral factors that inhibit osteoclast-like cell formation in vitro.

Angiogenesis and bone remodeling are closely associated, and vascular endothelial cells may have potential roles for osteoclastic bone resorption. We examined whether clonal endothelial cells established from bone, aorta and brain of Balb/c mice influenced osteoclast-like cell formation in vitro. As low as 1% conditioned media of those endothelial cells inhibited osteoclast-like cell formation in bone marrow cultures induced by 1,25-dihydroxyvitamin D3, and did so in spleen cell cultures in the presence of soluble receptor activator of nuclear factor-kappaB ligand (RANKL), M-CSF and prostaglandin E2. The level of osteoprotegerin (OPG), a decoy receptor for RANKL, secreted by endothelial cells was not high enough to inhibit osteoclastogenesis. These observations suggest that endothelial cells derived from various tissues secrete factor(s) that inhibits precursors to differentiate into osteoclasts even in the presence of optimal stimulators for osteoclastogenesis. Hence, endothelial cells in bone may inhibit recruitment of fresh osteoclasts, and those in tissues other than bone may be involved in prohibiting ectopic osteoclastogenesis.

Animals↗
PubMed2002

MS-209, a quinoline-type reversal agent, potentiates antitumor efficacy of docetaxel in multidrug-resistant solid tumor xenograft models.

The existence of multidrug-resistant (MDR) cells in cancer is a major obstacle to effective cancer chemotherapy. Expression of P-glycoprotein (P-gp) in cancer cells causes resistance against paclitaxel and docetaxel, as well as against vincristine and doxorubicin (ADM). MS-209 is a novel MDR-reversal agent currently under clinical evaluation, which is shown to be active against ADM and vincristine resistance in MDR cancer cells in vitro and in vivo. In this paper, we report the combined effect of MS-209 with docetaxel in various MDR cancer cell lines that express P-gp. MS-209 at 3 microM effectively overcame docetaxel resistance in MDR cancer cells, and this concentration was achieved in blood plasma for > 7 h without serious toxicity. To study the effect of MS-209 in a clinically relevant model, we compared the antitumor efficacy of docetaxel alone with that of docetaxel combined with MS-209 at equitoxic doses in established solid tumor xenograft models. Treatment with docetaxel alone at the maximal tolerated dose (MTD) showed an apparent antitumor activity to an intrinsically resistant HCT-15 tumor xenograft, and MS-209 additionally potentiated the antitumor activity of docetaxel. Against a MCF-7/ADM tumor xenograft expressing larger amounts of P-gp, docetaxel alone at the MTD showed no antitumor activity, whereas the MTD of docetaxel combined with MS-209 greatly reduced MCF-7/ADM tumor growth. These results indicate that MS-209 could be a clinically useful drug to modulate MDR in docetaxel therapy.

Animals↗
PubMed2002

[Globalization of anti-cancer therapies].

Based on short reviews of lung, gastric, colorectal, prostate, breast and ovarian cancer, there remain significant differences between Japan and the West in the therapeutic regimen for most cancers. Some of the differences are due to differences in stage of disease at diagnosis or historical factors affecting availability of products. In both Japan and the West, there are initiatives to prepare treatment guidelines based on published data. For Japan this initiative is limited by the lack of Japanese clinical trial data or even safety data. When guidelines are prepared from international data, many of the products have limited indications in Japan and therefore not reimbursed. Availability of the most appropriate therapies to Japanese patients will depend on a facilitation of clinical trials in both primary and additional indications. However, the experience in other countries is that, even where data and registration approval are available, guidelines are hard to agree and are not uniformly accepted by prescribers. The ICH E5 guideline on the use of bridging studies to interpolate Western data to Japanese regulatory dossiers provides an opportunity to accelerate availability of new medicines to Japanese prescribers and patients. The use of bridging studies has so far been limited for anti-cancer therapies. Where relevant pharmacodynamic endpoints can be measured, (e.g. aromatase inhibition) there can increase confidence in bridging. The newer types of agent which act to stabilise disease rather than tumour shrinkage present a special problem. In some cases surrogate markers can be valuable but in each case they need to be validated. As globalization continues, an alternative approach is to include a significant cohort of Japanese patients in Japanese patients but this depends on sufficient similarity in the patient population and background therapy. The most significant limitation to either large outcome studies in Japan or for Japanese centers to join international trials has been the environment for conduct of clinical trials. There have been some recent improvements and further progress is expected so that Japanese doctors can play a full role in the evaluation of new therapies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

[Post launch studies].

Evidence Based Medicine (EBM) is a growing concept in Japan as it is elsewhere. Central to improving the use of EBM is generation of data through well conducted controlled clinical studies. There are many problems associated with conduct of clinical studies after launch in Japan, and many initiatives are ongoing to improve the situation. Development of Clinical Research Coordinators (CRO) and central Data Management centers are key to improving the quality of clinical research in Japan. Currently Japan has an undeveloped legal system with regard to post-launch trials and off-label use of registered drugs. There is no reimbursement for off-label and various restrictions imposed on the recipients of the Ministry of Health, Labour and Welfare's (MHLW) funds. Maybe the biggest problem is the high cost of post-marketing studies sponsored by pharmaceutical manufacturers. A high quality system to support post launch clinical studies need a solid financial base. There is a need for a suitable review system for investigator initiated multi-centre studies, as the current IRB system is not sufficient. There are also challenges regarding the differences, perceived or real, in treatment practice and available registrations in Japan and in the West, causing problems in choosing suitable comparators and study designs. At the present time it is not clear whether investigator initiated trials will be acceptable for registration purposes in Japan. The agreed first priority is to build a suitable and strong infrastructure within the academic community to support researchers to investigate important questions with or without pharmaceutical company support. Despite all these issues, several groundbreaking projects are under way throughout Japan, in many different areas and by different collaborative groups, some with government support. In fact, researcher-initiated clinical trials achieved a rapid growth in Japan in the past year.

Clinical Trials as Topic↗
PubMed2002

C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance.

Breast cancer resistance protein (BCRP) confers multidrug resistance to cancer cells against agents such as SN-38 (an active metabolite of irinotecan), mitoxantrone, and topotecan. Among 59 human tumor cell lines tested, 6 cell lines, A549, NCI-H460, KM-12, HT-29, OVCAR-5, and RPMI8226, showed high BCRP expression. BCRP cDNA was isolated from 11 cancer cell lines and three variant cDNAs [G34A substituting Met for Val-12 (V12M), C421A substituting Lys for Gln-141 (Q141K), and 944-949 deletion lacking Ala-315 and Thr-316 (delta315-6)] were identified. G34A and C421A variants were polymorphisms, and 944-949 deletion was a splicing variant. C421A BCRP-transfected PA317 cells showed markedly decreased protein expression and low-level drug resistance compared with wild-type BCRP-transfected cells when transfectants expressed similar levels of BCRP mRNA. G34A or 944-949-deleted BCRP-transfected PA317 cells showed similar or somewhat lower protein expression and drug resistance compared with wild-type BCRP-transfected cells. Of 124 healthy Japanese volunteers, 67 were wild-type, 48 were heterozygous, and 9 were homozygous for the C421A allele. These results suggest that some people possess the C421A polymorphic BCRP gene and express low amounts of Q141K BCRP. In addition to that, C376T polymorphism in exon 4 substituting stop codon for Gln-126 was found in 3 of the 124 general Japanese population. This C376T polymorphism may also have high impact because active BCRP protein will not be expressed from the C376T allele. Therefore, people with C376T and/or C421A polymorphisms may express low amounts of BCRP, and this low BCRP expression might result in hypersensitivity of normal cells to such anticancer drugs as irinotecan and mitoxantrone.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2002

Telomere shortening and growth inhibition of human cancer cells by novel synthetic telomerase inhibitors MST-312, MST-295, and MST-1991.

Epidemiological studies suggest potent anticancer effects of tea catechins. Previously, we have reported (I. Naasani et aL, Biochem. Biophys. Res. Commun., 249: 391-396, 1998) that epigallocatechin gallate (EGCG), a major tea catechin, strongly and directly inhibits telomerase, a ribonucleoprotein that maintains telomeres and has been implicated in tumorigenesis. Here, we describe newly synthesized compounds MST-312, MST-295, and MST-199, as more effective telomerase inhibitors than EGCG. Continuous treatment of human monoblastoid leukemia U937 cells with a nontoxic dose of each drug caused progressive telomere shortening and eventual reduction of growth rate accompanied by induction of the senescence-associated beta-galactosidase activity. Particularly, in the case of MST-312, the effective dose required for the telomere shortening was 1-2 microM, which was 15- to 20-fold lower than that of EGCG. These compounds may provide a novel chemotherapeutic strategy for the treatment of cancers.

Antineoplastic Agents↗
PubMed2000

In vivo veritas: Bcl-2 and Bcl-X(L)mediate tumor cell resistance to chemotherapy.

Apoptosis is cellular suicide, the functional opposite of mitosis. It may play an important role in tissue growth control and removal of damaged and premalignant cells. The fact that diverse chemotherapeutic agents induce apoptosis, while they engage different intracellular targets and cause DNA damage, raises a concern that tumors resistant to chemotherapy are unable to initiate the apoptotic process. The anti-apoptotic Bcl-2 family proteins, Bcl-2 and Bcl-X(L), play an important role in the regulation of apoptotic cell death. Bcl-2 and Bcl-X(L)have been reported to confer chemotherapy resistance in short-term survival assays in vitro. However, they failed to provide a long-term clonogenic survival advantage. Thus, the role of anti-apoptotic Bcl-2 and Bcl-X(L)on chemotherapy resistance in vivo remains unclear. In vivo, tumor cells receive survival signals from the extracellular microenvironment. Since the microenvironmental factors have been reported to modulate the expression and function of Bcl-2 family proteins, Bcl-2 and Bcl-X(L)might be associated with the chemotherapy resistance in vivo through the influence of these factors. Consistent with this hypothesis, several investigators have recently reported that the sensitivity to chemotherapy in in vitro clonogenic assays did not correlate with that in in vivo tumor models. The lack of microenvironmental factors might cause the discrepancy between in vitro clonogenic growth and in vivo tumor growth. These results suggest that Bcl-2 and Bcl-X(L)could contribute to chemotherapy resistance in vivo, along with already defined drug resistance mechanisms (i.e. P-glycoprotein, MRP). Therapies aimed at suppressing the expression and function of Bcl-2 and Bcl-X(L)or at intercepting microenvironmental factors might successfully overcome chemotherapy resistance. Copyright 2000 Harcourt Publishers Ltd.

Journal Article↗