|
1. |
The urokinase plasminogen activator receptor (uPAR) as a target for the diagnosis and therapy of cancer |
|
Anti-Cancer Drugs,
Volume 12,
Issue 5,
2001,
Page 387-400
Andrew Mazar,
Preview
|
PDF (194KB)
|
|
摘要:
The identification and characterization of validated molecular targets for cancer drug and diagnostic development is rapidly changing the way that promising new anti-cancer compounds are developed and evaluated. A significant body ofin vitroandin vivodata has established the urokinase plasminogen activator (uPA) system as a promising target for cancer drug development. The uPA system has been demonstrated to have pleiotropic activities in the development of tumors, and in tumor progression and angiogenesis. There are multiple ways to target this system, the most straightforward being the development of small molecule active site inhibitors of the serine protease, uPA. However, compounds of this type have not entered into clinical trials, and issues related to selectivity and specificity of this class of inhibitors have yet to be satisfactorily resolved. Recent evidence suggests that in addition to uPA, its specific cell surface receptor (uPAR) may also be a suitable target for the design and development of cancer therapeutic and diagnostic agents. uPAR is central to several pathways implicated in tumor progression and angiogenesis. The binding of the uPA zymogen (scuPA) to uPAR appears to be a pre-requisite for efficient cell-surface activation of scuPA to the active two-chain form (tcuPA) by plasmin, and simple ligand occupancy of uPAR by scuPA initiates various signaling pathways leading to alterations in cell motility and adhesion. One therapeutic rationale that is currently being investigated is the simple displacement of scuPA or tcuPA from suPAR, which may effectively inhibit both the proteolytic and signal-transducing cascades. In addition, other approaches to the modulation of the activity of this system that may also be useful include blocking the interaction of uPAR with integrins and extracellular matrix proteins as well as strategies to down-regulate the expression of uPA and uPAR in target cells. This review will summarize these approaches, and also describe the targeting of uPAR for diagnosis and imaging.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
|
2. |
Quinone isomers of the WS-5995 antibiotics: synthetic antitumor agents that inhibit macromolecule synthesis, block nucleoside transport, induce DNA fragmentation, and decrease the growth and viability of L1210 leukemic cells more effectively than ellagic acid and genisteinin vitro |
|
Anti-Cancer Drugs,
Volume 12,
Issue 5,
2001,
Page 401-417
Elisabeth Perchellet,
Bonnie Sperfslage,
Ghassan Qabaja,
Graham Jones,
Jean-Pierre Perchellet,
Preview
|
PDF (286KB)
|
|
摘要:
Antibiotic WS-5995A (code name J4) and two of its synthetic analogs,o-quinone J1 and modelp-quinone J7, which show some structural similarity with both ellagic acid (EA) and genistein (GEN), were compared for their antileukemic activity in L1210 cellsin vitro. Overall, J4 is more cytostatic and cytotoxic than J1 and J7, suggesting that methyl and methoxy substitutions, ap-quinone moiety, and a hydrogen bonding phenolic group may enhance the antitumor potential of these naphthoquinone lactones, which are all more potent than EA and GEN. For instance, the lead compound J4 inhibits tumor cell proliferation and viability at day 4 (IC50: 0.24-0.65 μM) more effectively than EA (IC50: 5-6 μM) and GEN (IC50: 7 μM). Since J4 does not increase but rather decreases the mitotic index of L1210 cells at 24 h, it is not an antitubulin drug but might arrest early stages of cell cycle progression like EA and GEN. A 1.5- to 3-h pretreatment with J4 is sufficient to inhibit the rates of DNA, RNA and protein syntheses (IC50: 2.0-2.5 μM) determined over 30- to 60-min periods of pulse-labeling in L1210 cellsin vitro, whereas EA (IC50: 20-130 μM) and GEN (IC50: 40-115 μM) are less effective against macromolecule synthesis. In contrast to 156 μM EA, which is inactive, a 15-min pretreatment with 10-25 μM J4 has the advantage of also inhibiting the cellular transport of both purine and pyrimidine nucleosides over a 30 s periodin vitro, an effect which can be mimicked by 156 μM GEN. Hence, the WS-5995 analogs and GEN may prevent the incorporation of [3H]adenosine and [3H]thymidine into DNA because they rapidly block the uptake of these nucleosides by the tumor cells. After 24 h, the concentration-dependent induction of DNA cleavage by J4 peaks at 10 μM and declines at 25 μM, whereas EA and GEN are ineffective at 10 μM but maximally stimulate DNA cleavage at 62.5 μM. Like EA and GEN, the mechanism by which J4 induces DNA fragmentation is inhibited by actinomycin D, cycloheximide, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone,N-tosyl-L-phenylalanine chloromethyl ketone and ZnSO4, suggesting that J4 triggers apoptosis by caspase and endonuclease activation. Because they are more potent than EA and GEN, and affect both nucleoside transport and DNA cleavage, the WS-5995 antitumor antibiotics might be valuable in polychemotherapy to potentiate the action of antimetabolites and sensitize multidrug-resistant tumor cells.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
|
3. |
Active transepithelial transport of irinotecan (CPT-11) and its metabolites by human intestinal Caco-2 cells |
|
Anti-Cancer Drugs,
Volume 12,
Issue 5,
2001,
Page 419-432
Wataru Yamamoto,
Jaap Verweij,
Peter de Bruijn,
Maja de Jonge,
Hiroshi Takano,
Masahiko Nishiyama,
Minoru Kurihara,
Alex Sparreboom,
Preview
|
PDF (270KB)
|
|
摘要:
Irinotecan (CPT-11) is a camptothecin analog with low (about 10-20%) and variable oral bioavailability in animal models. Here, Caco-2 cells were used to evaluate the transepithelial transport of CPT-11 and its metabolites. Caco-2 cells demonstrated significant expression of P-glycoprotein (P-gp), multidrug resistance-associated protein and canalicular multispecific organic anion transporter. Both the lactone and carboxylate forms of CPT-11 and SN-38 were actively transported across the cell monolayers, mainly by the apical-localized P-gp pump. Cellular permeability of CPT-11 at a concentration of 17 μM converted from active to passive-diffusional transport between the 2 and 6 h exposure time points. Antiproliferative effects of CPT-11 were related to permeability of the lactone form, whereas for SN-38 efficacy was dependent on lactone accumulation. Exposure of CPT-11 with cyclosporin A significantly enhanced its efficacy, whereas this was not observed with verapamil and R101933. In contrast, SN-38 efficacy decreased in the presence of P-gp inhibitors due to active transport toward the basolateral side, thereby reducing drug accumulation. Hence, multiple-active transport systems could be demonstrated to be responsible for not only accumulation profiles but also cytotoxic efficacy of CPT-11 and SN-38 in the intestinal Caco-2 cells. It is suggested that CPT-11 might act in a time-dependent manner and that SN-38-mediated cytotoxicity relates to (dose-dependent) lactone kinetics. The results detailed in this report could contribute toward the development of a clinically useful oral formulation of CPT-11 with improved absorption characteristics and suggest that cyclosporin A is a suitable agent for further research of this concept.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
|
4. |
Antitumor bicyclic hexapeptide RA-VII modulates cyclin D1 protein level |
|
Anti-Cancer Drugs,
Volume 12,
Issue 5,
2001,
Page 433-439
Ken-ichi Wakita,
Megumi Minami,
Akella Venkateswarlu,
Vedula Sharma,
Mullangi Ramesh,
Kouichi Akahane,
Preview
|
PDF (144KB)
|
|
摘要:
A bicyclic hexapeptide, RA-VII orO-methyl deoxybouvardin, isolated fromRubia cordifolia, is known to inhibit protein biosynthesisin vitroandin vivo. We here demonstrate that the treatment of human colon cancer DLD-1 cells with RA-VII induces cell growth inhibition associated with a partial G1arrest and a rapid decrease (below 2 h) in the level of cyclin D1 protein. Since cycloheximide, another protein synthesis inhibitor, neither decreased the amount of cyclin D1 in the cells nor arrested cells in G1phase, it is unlikely that this RA-VII-induced reduction of cyclin D1 was fully dependent on its direct inhibitory effect of protein synthesis. Northern blot analysis revealed that RA-VII did not affect the level of cyclin D1 mRNA. Meanwhile, pre-treatment of cells with lactacystin, a proteasome inhibitor, abolished the RA-VII-induced decrease in cyclin D1. Moreover, RA-VII still decreased cyclin D1 protein in the presence of cycloheximide. These results indicate that the RA-VII-induced cyclin D1 decrease depends on cyclin D1 degradation via the ubiquitin-proteasome pathway and does not require additional protein synthesis. RA-VII might actively proceed the degradation process of cyclin D1 via the ubiquitin-proteasome pathway in DLD-1 cells.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
|
5. |
Altered DNA-cleavage activity of topoisomerase II from WEHI-3B leukemia cells with specific resistance to ciprofloxacin |
|
Anti-Cancer Drugs,
Volume 12,
Issue 5,
2001,
Page 441-451
Augusto Pessina,
Alessandro Raimondi,
Cristina Croera,
Mara Acchini,
Elisabetta Mineo,
Paola Foti,
Maria Neri,
Preview
|
PDF (251KB)
|
|
摘要:
In order to investigate the mechanisms of drug resistance arising in tumor cells, we investigated the capacity of fluoroquinolones to inhibit thein vitrogrowth of WEHI-3B monomyelocytic leukemia cells and then we established a variant of this line (currently maintained in the absence of drug). The line, named WEHI-3B/CPX, expresses a specific resistance to ciprofloxacin (CPX; resistance index=17.3±2.2), and does not show cross-resistance with other fluoroquinolones, camptothecin and topoisomerase II inhibitors such as doxorubicin, etoposide and teniposide. Although a little decrease in intracellular accumulation of CPX is observed in WEHI-3B/CPX cells, these cells do not express MDR or LRP markers, and the resistance is not circumvented by verapamil. Purified nuclear extracts from WEHI-3B and WEHI-3B/CPX cells were tested for topoisomerase I catalytic activity and checkingin vitrotopoisomerase I sensitivity to CPX and camptothecin inhibition, but no difference was observed. As the treatment with CPX showed that the resistant cell line suffers a significantly lower number of breaks in the DNA molecule we also addressed our investigations to the topoisomerase II-dependent DNA cleavage that, in the resistant clone, was found dramatically less susceptible to be enhanced by CPX both in pre-strand and post-strand DNA passage conditions. WEHI-3B/CPX cells do not express any character of multidrug resistance and represent a rare case of specific drug resistance to CPX. The specific resistance to CPX observed in these cells is related to a functional decrease of topoisomerase II cleavage activity. It could be consequent to a decreased binding affinity of CPX for the topoisomerase II-DNA complex or to a decreased affinity or specificity of topoisomerase II for its DNA cleavage sites.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
|
6. |
(S)-(−)-Bromofosfamide (CBM-11): synthesis and antitumor activity and toxicity in mice |
|
Anti-Cancer Drugs,
Volume 12,
Issue 5,
2001,
Page 453-458
Konrad Misiura,
Ryszard Kinas,
Halina Kus´nierczyk,
Czesłlaw Radzikowski,
Wojciech Stec,
Preview
|
PDF (110KB)
|
|
摘要:
(S)-(−)-Bromofosfamide (CBM-11), an enantiomerically pure bromo analog of ifosfamide, was found to be potent against several model tumors in mice. Therapeutic indices of CBM-11 were more favorable as compared to those received for ifosfamide.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
|
7. |
The bisphosphonate pamidronate is a potent inhibitor of human osteosarcoma cell growthin vitro |
|
Anti-Cancer Drugs,
Volume 12,
Issue 5,
2001,
Page 459-465
Jürgen Sonnemann,
Vera Eckervogt,
Borna Truckenbrod,
Joachim Boos,
Winfried Winkelmann,
Frans van Valen,
Preview
|
PDF (141KB)
|
|
摘要:
Bisphosphonates (BPs), such as pamidronate and clodronate, are an important class of drugs for the treatment of bone diseases. It is widely recognized that they inhibit bone resorption by suppressing the action of osteoclasts through antagonizing the mevalonate pathway, thereby reducing osteolytic bone metastases derived from different cancers, i.e. breast carcinoma and multiple myeloma. In contrast, the effects of BPs on primary bone tumors is an issue still to be resolved. Therefore, a systematic approach was set up to test the hypothesis that BPs could act directly on osteosarcoma cells. The effects of pamidronate and clodronate on seven osteosarcoma cell lines (HOS, MG-63, OST, SaOS-2, SJSA-1, U2OS and ZK-58) were studied. Pamidronate inhibited cell growth in a time- and dose-dependent manner, and decreased proliferation for up to 73% at 50 μM after 72 h, whereas its monophosphonate analog 3-aminopropyl phosphonate did not reduce cell viability at concentrations up to 2 mM. Clodronate showed less inhibitory effects (maximally 38% reduction at 1 mM after 72 h). Importantly, cell growth of fibroblasts was only very weakly affected by treatment with pamidronate. These results suggest that pamidronate may be a useful agent for the treatment of patients with osteosarcoma.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
|
8. |
Treatment of drug-resistant human neuroblastoma cells with cyclodextrin inclusion complexes of aphidicolin |
|
Anti-Cancer Drugs,
Volume 12,
Issue 5,
2001,
Page 467-473
Martin Michaelis,
Jaroslav Cinatl,
Jens-Uwe Vogel,
Pavla Pouckova,
Pablo Driever,
Jindrich Cinatl,
Preview
|
PDF (114KB)
|
|
摘要:
Treatment failure in most neuroblastoma (NB) patients is related to primary and/or acquired resistance to conventional chemotherapeutic agents. Aphidicolin (APH), a tetracyclic diterpene, exhibits specific cytotoxic action against NB cells. The purpose of this study was to compare antitumoral efficacy of APH in parental NB cell lines and cell subclones that exhibit drug resistance to vincristine (VCR), doxorubicin (DOX) and cisplatin. Due to poor solubility of APH in water, γ-cyclodextrin (γ-CD) inclusion complexes of APH were used for systemic treatment of xenotransplanted parental and VCR-resistant UKF-NB-3 tumours. APH and its γ-CD inclusion complexes inhibited growth of parental and drug-resistant NB cells at equimolar dosesin vitro. Growth of VCR-sensitive and -resistant NB tumors was inhibited at equal doses in a dose-dependent fashionin vivo. These results indicate that the specific cytotoxic activity of APH against NB cellsin vitroandin vivois independent of cellular mechanisms facilitating drug resistance to conventional chemotherapeutic drugs. Hence, taking into account our previous findings that APH acts synergistically with VCR and DOX, APH might be an additive tool for the therapy of NB and is suitable for evaluation in clinical studies of NB treatment protocols.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
|
9. |
Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells |
|
Anti-Cancer Drugs,
Volume 12,
Issue 5,
2001,
Page 475-483
Senia Johansson,
Petra Lindholm,
Joachim Gullbo,
Rolf Larsson,
Lars Bohlin,
Per Claeson,
Preview
|
PDF (126KB)
|
|
摘要:
The saponin digitonin, the aglycone digitoxigenin and five cardiac glycosides were evaluated for cytotoxicity using primary cultures of tumor cells from patients and a human cell line panel (representing different cytotoxic drug-resistance patterns). Of these seven compounds, proscillaridin A was the most potent (IC50: 6.4-76 nM), followed by digitoxin, and then ouabain, digoxin, lanatoside C, digitoxigenin and digitonin. Correlation analysis of the log IC50values for the cell lines in the panel showed that compound cytotoxicity was only slightly influenced by resistance mechanisms that involved P-glycoprotein, topoisomerase II, multidrug resistance-associated protein and glutathione-mediated drug resistance. Digitoxin and digoxin expressed selective toxicity against solid tumor cells from patients, while proscillaridin A expressed no selective toxicity against either solid or hematological tumor cells. The results revealed marked differences in cytotoxicity between the cardiac glycosides, both in potency and selectivity, and modes of action for cytotoxicity that differ from that of commonly used anticancer drugs.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
|
10. |
Pharmacokinetics of paclitaxel and cisplatin in a hemodialysis patient with recurrent ovarian cancer |
|
Anti-Cancer Drugs,
Volume 12,
Issue 5,
2001,
Page 485-487
Masatoshi Tomita,
Hitoshi Kurata,
Yoichi Aoki,
Kenichi Tanaka,
Jyunichiro Kazama,
Preview
|
PDF (83KB)
|
|
摘要:
This is the first report that the combination of paclitaxel and cisplatin is feasible in a patient with recurrent ovarian cancer undergoing hemodialysis. Paclitaxel at a dose of 150 mg/m2was administered as a 3-h continuous i.v. infusion. Thirty minutes after paclitaxel administration, cisplatin was administered at a dose of 30 mg/m2for 30 min. Hemodialysis was started 30 min after completion of the cisplatin infusion and performed for 5 h. The maximum plasma concentrations of paclitaxel, total platinum and free platinum were 3.26, 2.44 and 1.84 μg/ml, respectively. The AUC of paclitaxel and free platinum were 15.3 and 1.76 μg·h/ml, respectively. The pelvic tumor size was reduced by 42% on MRI after the second course of this therapy. Grade IV neutropenia and grade III thrombopenia were observed. We conclude that paclitaxel and cisplatin combination chemotherapy is efficacious and feasible for an ovarian cancer patient under hemodialysis.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
|
|