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1. |
Amifostine in clinical oncology: current use and future applications |
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Anti-Cancer Drugs,
Volume 13,
Issue 3,
2002,
Page 181-209
MI Koukourakis,
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摘要:
Amifostine (Ethyol®), an inorganic thiophosphate, is a selective broad-spectrum cytoprotector of normal tissues that provides cytoprotection against ionizing radiation and chemotherapeutic agents, thus preserving the efficacy of radiotherapy and chemotherapy. This review summarizes the preclinical data and clinical experience with amifostine, and provides insight into future clinical directions. Amifostine, an inactive pro-drug, is transformed to an active thiol after dephosphorylation by alkaline phosphatase found in the normal endothelium. The absence of alkaline phosphatase in the tumoral endothelium and stromal components, and the hypovascularity and acidity of the tumor environment, may explain its cytoprotective selectivity. The cytoprotective mechanism of amifostine is complicated, involving free radical scavenging, DNA protection and repair acceleration, and induction of cellular hypoxia. Intravenous administration of amifostine 740–900 mg/m2before chemotherapy and 250–350 mg/m2before each radiotherapy fraction are widely used regimens. The US Food and Drug Administration has approved the use of amifostine as a cytoprotector for cisplatin chemotherapy and for radiation-induced xerostomia. Ongoing trials are being conducted to determine the efficacy of amifostine in reducing radiation-induced mucositis and other toxicities. Novel schedules and routes of administration are under investigation, and may further simplify the use of amifostine and considerably broaden its applications.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
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2. |
The role of DNA repair in nitrogen mustard drug resistance |
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Anti-Cancer Drugs,
Volume 13,
Issue 3,
2002,
Page 211-220
Lawrence Panasci,
Zhi-Yuan Xu,
Vanessa Bello,
Raquel Aloyz,
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摘要:
The nitrogen mustards are an important class of DNA cross-linking agents, which are utilized in the treatment of many types of cancer. Unfortunately, resistance often develops in the treatment of patients and the tumor either never responds to or becomes refractory to these agents. Resistance to the nitrogen mustards in murine and human tumor cells has been reported to be secondary to alterations in (i) the transport of these agents, (ii) their reactivity, (iii) apoptosis and (iv) altered DNA repair activity. In the present review, we will discuss the role of DNA repair in nitrogen mustard resistance in cancer. The nitrogen mustards' lethality is based on the induction of DNA interstrand cross-links (ICLs). Two DNA repair pathways are known to be involved in removal of ICLs: non-homologous DNA end-joining (NHEJ) and Rad51-related homologous recombinational repair (HRR). The reports discussed here lead us to hypothesize that low NHEJ activity defines a hypersensitive state, while high NHEJ activity, along with increased HRR activity, contributes to the resistant state in chronic lymphocytic leukemia. Studies on human epithelial tumor cell lines suggest that HRR rather than NHEJ plays a role in nitrogen mustard sensitivity.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
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3. |
Perindopril: possible use in cancer therapy |
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Anti-Cancer Drugs,
Volume 13,
Issue 3,
2002,
Page 221-228
Hitoshi Yoshiji,
Shigeki Kuriyama,
Hiroshi Fukui,
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摘要:
Since angiogenesis is essential for the growth of any solid tumor, emerging efforts are being made to develop antiangiogenic therapy. To date, however, no antiangiogenic agent has become widely available for the clinical setting. Angiotensin I-converting enzyme (ACE) inhibitors are commonly used as antihypertensive agents and it has recently been suggested that they decrease the risk of cancer. Studies have found that an ACE inhibitor, perindopril, is a potent inhibitor of experimental tumor development and angiogenesis at a clinically comparable dose. The potent angiogenic factor, vascular endothelial growth factor (VEGF), is significantly suppressed by perindopril and also inhibits VEGF-induced tumor growth.In vitrostudies showed that perindopril is not cytotoxic to either tumor cells or endothelial cells. Since perindopril is already in widespread clinical use without serious side effects, it may represent a potential new strategy for anticancer therapy.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
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4. |
Immunotherapy of tumors with vaccines based on xenogeneic homologous molecules |
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Anti-Cancer Drugs,
Volume 13,
Issue 3,
2002,
Page 229-235
Yu-quan Wei,
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摘要:
This review summarizes and discusses a new vaccine strategy based on xenogeneic homologous molecules by the breaking of immune tolerance against the growth factors or their receptors associated with tumor growth in a cross-reaction between the xenogeneic homologs and self-molecules. The xenogeneic vaccine may circumvent the fact that few tumor-specific antigens have been identified in human solid tumors and that the host usually shows immune tolerance to self-molecules as antigens. It may be of importance for the further exploration of the applications of xenogeneic homologous genes identified in human and other animal genome sequence projects in cancer therapy.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
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5. |
Vacuolar H+-ATPase: functional mechanisms and potential as a target for cancer chemotherapy |
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Anti-Cancer Drugs,
Volume 13,
Issue 3,
2002,
Page 237-243
Takayuki Torigoe,
Hiroto Izumi,
Tomoko Ise,
Tadashi Murakami,
Hidetaka Uramoto,
Hiroshi Ishiguchi,
Yoichiro Yoshida,
Mizuho Tanabe,
Minoru Nomoto,
Kimitoshi Kohno,
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摘要:
Tumor cellsin vivooften exist in a hypoxic microenvironment with a lower extracellular pH than that surrounding normal cells. Ability to upregulate proton extrusion may be important for tumor cell survival. Such microenvironmental factors may be involved in the development of resistant subpopulations of tumor cells. In solid tumors, both intracellular and extracellular pH differ between drug-sensitive and -resistant cells, and pH appears critical to the therapeutic effectiveness of anticancer agents. Four major types of pH regulators have been identified in tumor cells: the sodium–proton antiporter, the bicarbonate transporter, the proton–lactate symporter and proton pumps. Understanding mechanisms regulating tumor acidity opens up novel opportunities for cancer chemotherapy. In this minireview, we describe the structure and function of certain proton pumps overexpressed in many tumors—vacuolar H+-ATPases—and consider their potential as targets for cancer chemotherapy.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
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6. |
Bisphosphonates inhibit stromelysin-1 (MMP-3), matrix metalloelastase (MMP-12), collagenase-3 (MMP-13) and enamelysin (MMP-20), but not urokinase-type plasminogen activator, and diminish invasion and migration of human malignant and endothelial cell lines |
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Anti-Cancer Drugs,
Volume 13,
Issue 3,
2002,
Page 245-254
Pia Heikkilä,
Olli Teronen,
Merja Moilanen,
Yrjö Konttinen,
Roeland Hanemaaijer,
Minna Laitinen,
Päivi Maisi,
Gabri van der Pluijm,
John Bartlett,
Tuula Salo,
Timo Sorsa,
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摘要:
Bisphosphonates (clodronate, alendronate, pamidronate and zoledronate) at therapeutically attainable non-cytotoxic concentrations inhibited MMP-3, -12, -13 and -20 as well as MMP-1, -2, -8 and -9, but not urokinase-type plasminogen activator (uPA), a serine proteinase and a pro-MMP activator. Dose-dependent inhibition was shown by three independent MMP assays. The inhibition was reduced in the presence of an increased concentration of Ca2+when compared to physiologic Ca2+concentration. Alendronate inhibited thein vitroinvasion (Matrigel) of human HT1080 fibrosarcoma and C8161 melanoma cells, and the random migration of these malignant and endothelial cell lines capable of expressing MMPs and uPA. The concentration of alendronate required to inhibit 50% of the activity (IC50=40–70 μM) of MMPs corresponded to the IC50of down-regulation ofin vitroinvasion and migration. The ability of bisphosphonates to down-regulate thein vitroinvasion and random migration was comparable or slighty better in relation to the selective gelatinase inhibitor CTTHWGFTLC peptide. Alendronate but not CTTHWGFTLC peptide promoted the adhesion of HT1080 fibrosarcoma and C8161 melanoma cell lines on fibronectin. Bisphosphonates are broad-spectrum MMP inhibitors and this inhibition involves cation chelation. Bisphosphonates further exert antimetastatic, anti-invasive and cell adhesion-promoting properties, which may prevent metastases not only into hard tissues but also to soft tissues.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
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7. |
The doxorubicin cardioprotective agent dexrazoxane (ICRF-187) induces endopolyploidy in rat neonatal myocytes through inhibition of DNA topoisomerase II |
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Anti-Cancer Drugs,
Volume 13,
Issue 3,
2002,
Page 255-258
Brian Hasinoff,
Kazuyo Takeda,
Victor Ferrans,
Zu-Xi Yu,
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摘要:
Dexrazoxane (ICRF-187), which is clinically used to reduce doxorubicin-induced cardiotoxicity, is also a potent catalytic inhibitor of DNA topoisomerase II. In this study we showed that dexrazoxane inhibited the division of neonatal rat ventricular myocytes in culture, and resulted in nuclear multilobulation (demonstrated by three-dimensional reconstruction of confocal images) and marked increases in nuclear size and DNA ploidy levels (as shown by flow cytometry). It was concluded that dexrazoxane interfered with cell division in cardiac myocytes by virtue of its ability to inhibit topoisomerase II.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
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8. |
Biochemical and molecular effects of UCN-01 in combination with 5-fluorodeoxyuridine in A431 human epidermoid cancer cells |
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Anti-Cancer Drugs,
Volume 13,
Issue 3,
2002,
Page 259-270
Jean Grem,
Kathleen Danenberg,
Vivian Kao,
Peter Danenberg,
Diana Nguyen,
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摘要:
Concurrent and pre-exposure of A431 human epidermoid cancer cells to UCN-01, an investigational anticancer drug, with 5-fluoro-–2′-deoxyuridine (FdUrd), which targets thymidylate synthase, produced more than additive cytotoxicty. A 24-h exposure to 10 nM FdUrd led to inhibition of TS, a 2.5-fold increase in total thymidylate synthase protein content, profound dTTP depletion and a 6.3-fold increase in the ratio of dATP to dTTP, but did not cause single-strand breaks in DNA. However, FdUrd enhanced UCN-01-associated DNA strand breaks. Concurrent thymidine exposure led to repletion of dTTP pools, and cytoprotection against FdUrd alone and with UCN-01. UCN-01 arrested cells in G1, decreased the percentage of FdUrd-treated cells in S phase and reduced FdUrd-DNA incorporation, suggesting the latter was not important for cytotoxicity. Delayed induction of high molecular mass DNA fragmentation and poly(ADP-ribose) polymerase cleavage was observed with the combination of UCN-01 and FdUrd. These findings suggest that while FdUrd-mediated deoxynucleotide imbalance alone was insufficient to induce apoptosis in this p53-mutant cell line, it magnified UCN-01's effects, most likely by interfering with DNA repair. The clinical evaluation of UCN-01 combined with 5-fluoropyrimidines may be of interest.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
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9. |
The effect of DNA-alkylating agents on gene expression from two integrated reporter genes in a mouse mammary tumor line |
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Anti-Cancer Drugs,
Volume 13,
Issue 3,
2002,
Page 271-280
Michael Gieseg,
Charley de Bock,
Pamela Turner,
Lynette Ferguson,
William Denny,
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摘要:
A model system was developed to investigate the effects of DNA alkylating agents on cellular gene expression. The cytomegalovirus immediate-early promoter (CMV) and the mouse mammary tumor virus promoter (MMTV) were coupled separately to the luciferase reporter gene and stably expressed in cultured cells. The change in luciferase activity was used as a measure of gene expression inhibition. Seven well-characterized DNA alkylating agents of varied DNA adduct-forming ability were evaluated in this system. The major groove binders/intercalators (that form guanine adducts) increased CMV–luciferase activity above background, while minor groove binders (that form adenine adducts) all decreased it. The MMTV–luciferase activity was remarkably different to the CMV–luciferase activity and was inhibited to the greatest extent by the minor groove alkylators. One of these, a polybenzamide with spatially separated alkylating groups, inhibited gene expression to a greater extent than inhibition of general DNA or RNA synthesis.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
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10. |
Role of&ggr;-glutamyltranspeptidase on the response of poorly and moderately differentiated rhabdomyosarcoma cell lines to buthionine sulfoximine-induced inhibition of glutathione synthesis |
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Anti-Cancer Drugs,
Volume 13,
Issue 3,
2002,
Page 281-291
Begoña Castro,
Ana Alonso-Varona,
Maite del Olmo,
Pedro Bilbao,
Teodoro Palomares,
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摘要:
Glutathione (GSH) is involved in many cellular functions, including cell growth and differentiation. GSH also plays an important role in the protection of cells against oxidative damage and hence in determining the sensitivity of cells to the cytotoxicity of anticancer agents. Because of this, induction of GSH depletion has been proposed as a good strategy for sensitizing tumor cells to antitumor agents. The aim of the present work is to study the effect of buthionine sulfoximine (BSO, a specific cellular GSH-depleting agent) in two rat tumor cell lines derived from the same rhabdomyosarcoma tumor model, the moderately differentiated and low metastatic F21 cell line, and the poorly differentiated and high metastatic S4MH cell line, to investigate the influence of the degree of differentiation in the induction of GSH depletion-based therapy. We observed that, whereas in the S4MH cell line BSO induced a dose-dependent inhibition of both cell growthin vitroand tumorigenic potentialin vivo, in F21 cells the administration of moderate doses of BSO enhanced tumor growth and only at high doses was there a slight reduction of their tumorigenic potential. These effects were in consonance with the fact that the activity of&ggr;-glutamyltranspeptidase (&ggr;-GT) present in the F21 cells was 4 times higher than in the S4MH cells. Indeed, inhibition of&ggr;-GT activity by acivicin not only abrogated the BSO-induced increase of GSH content and of cell growth, but also the combination of acivicin + BSO significantly decreased intracellular GSH levels and cell proliferation, and induced F21 cells to apoptosis. These studies suggest that, as occurs in the rhabdomyosarcoma tumor model,&ggr;-GT levels and the degree of differentiation of tumor cells might influence the response of tumor cells to inducers of GSH depletion, and should be taken into account in therapies based on GSH metabolism.
ISSN:0959-4973
出版商:OVID
年代:2002
数据来源: OVID
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