摘要:

The two major steps in our study on the treatment of bladder tumors by photodynamic therapy (PDT) were the development of a new bladder tumor model in Fischer rats by implantation of tumor cells and the use of fluorescence spectroscopy, a semi-quantitative and non-invasive method, in order to determine the time after general or local administration of a photosensitizer when the tumor:normal bladder ratio was at its highest. 5-Aminolevulinic acid (5-ALA) (250 mg/kg body weight) was injected i.p. or instilled directly into the bladder cavity for 1, 2 or 4 h and fluorescence was measuredin situon normal and bladder tumor tissues every 30 min for 8–10 h after administration, with a special miniaturized optical-fiber captor. The better tumor:normal bladder ratios were 2.85±1.2 at 3.5 h after i.p. administration and 3.96±1.04 after bladder instillation for 4 h, respectively. These results were confirmed by fluorescence microscopy. PDT with the same dose of 5-ALA as in this pharmacokinetic study must also be carried out in order to compare the toxicity of the two administration routes of the photosensitizer and to determine which one is the better for this bladder tumor model.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Changes in glucose metabolism during diabetes are linked to an increased risk for the development of cancer. Increased activity of aldose reductase, the rate-limiting polyol pathway enzyme that converts glucose into sorbitol, mediates pathologies associated with diabetes and is thought to be involved in increased resistance to chemotherapeutic drugs. Thus, increased intracellular sorbitol levels may serve a protective function in cancer cells. In these studies we determined whether an inhibitor of aldose reductase could enhance the effectiveness of anticancer agents. Our findings indicate that treatment with the aldose reductase inhibitor, ethyl 1-benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate (EBPC), enhances the cytotoxic effects of the anticancer agents doxorubicin and cisplatin in HeLa cervical carcinoma cells. To establish a mechanistic basis for the increased cytotoxicity by EBPC, we examined the activity of the extracellular signal-regulated kinase (ERK) pathway, which is an important regulator of cell growth. Interestingly, treatment with EBPC in combination with the chemotherapeutic drugs increased ERK activity as compared to treatment with the chemotherapeutic drugs, suggesting a possible role for the ERK pathway in mediating doxorubicin- or cisplatin-induced cell death. Consistent with this possibility, inhibition of ERK activation by the MEK inhibitor, U0126, reversed the EBPC-mediated enhancement of cell death. In summary, these data provide evidence that adjuvant therapy with aldose reductase inhibitors improves the effectiveness of chemotherapeutic drugs, possibly through an ERK pathway-mediated mechanism.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Current chemotherapy of advanced non-small cell lung cancer produces only a modest increase in survival time. New approaches are needed to improve its effectiveness. During tumorigenesis, silencing of tumor suppressor genes can occur by aberrant methylation. The DNA methylation inhibitor, 5-aza-2′-deoxycytidine (5-AZA-CdR), can reactivate the expression of these genes. Nucleosomes containing unacetylated positively charged histones bind tightly to DNA producing a compact configuration, which inhibits transcription. Phenylbutyrate (PB), an inhibitor of histone deacetylase (HDAC), increases histone acetylation, neutralizing its positive charge and resulting in DNA with a more open structure, which favors transcription. It has been reported that 5-AZA-CdR in combination with HDAC inhibitor can increase the expression of silent tumor suppressor genes. The objective of our study was to determine if these agents, in combination, produce an enhancement of their antitumor activity. We evaluated the antineoplastic activity of 5-AZA-CdR and PB alone or in combination on human A549 and Calu-6 lung carcinoma cell lines by inhibition of DNA synthesis and clonogenic assays. 5-AZA-CdR and PB in combination produced a greater inhibition of DNA synthesis than either agent alone. Also, in a clonogenic assay the combination of these drugs showed a significant synergistic antitumor effect. These results provide a rationale to investigate the combination of 5-AZA-CdR and PB in patients with advanced lung cancer.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Phosphodiesterase (PDE) 3s have been characterized in human squamous cell carcinoma KB cells. PDE3 activity was detected in homogenates of KB cells. PDE3A and 3B mRNAs were detected by RT-PCR in RNA from KB cells; the nucleotide sequences of the fragments were identical to those of human PDE3A and 3B. Immunoblotting with anti-PDE3 antibodies detected both PDE3A- and 3B-immunoreactive proteins in KB cells. The PDE3-specific inhibitor, cilostamide, inhibited the proliferation of KB cells. Our results indicate that PDE3s may be important regulators of the growth of KB cells. Therefore, PDE3 inhibitors may be potential new drugs for antiproliferative therapies in squamous cell carcinoma in the head and neck.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Rhabdomyosarcoma (RMS) cell lines were transduced with an adenoviral vector containing the wild-type p53 (wtp53) cDNA (Ad-p53) and then exposed to four cytotoxic agents: actinomycin D, vincristine, 5-fluorouracil and bleomycin. Potentiation of cytotoxicity following wild-type p53 expression varied from 0- to 20-fold for different drugs and between cell lines. It appeared that alveolar RMS cells (n=2) were more susceptible to p53-mediated chemosensitization than embryonal RMS cells (n=3), although this was independent of pax3–FKHR expression. Overall, cells that were most chemosensitive prior to Ad-p53 exposure were those that were most susceptible to p53 potentiation of cytotoxicity. The different results obtained with these RMS cell lines does not appear to be related to expression of pax3–FKHR, p21, Bax or Bcl-2 but may in part be due to differential regulation of p53 target genes, such as MDM2. In conclusion, exogenous wild-type expression selectively chemosensitizes RMS cells to cytotoxic agents. However, expression of transcriptionally active wtp53 does not predict a chemosensitive phenotype.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

An international meeting focused on farnesyl transferase inhibitors (FTIs) was held in Naples on 12 April 2002 and represented an excellent occasion to gather most of the clinicians who are involved in clinical trials with this class of new compounds. Oncogene mutations of therasgene occur in approximately 30% of all human cancers and may have prognostic significance. Ras protein is normally synthesized as pro-Ras, which undergoes a number of post-translational modifications, among which farnesylation. Processed Ras proteins localize to the inner surface of the plasma membrane, and function as a molecular switch that cycles between an inactive and an active form. When in its active form, either because of the binding of an external ligand or because of its constitutive activation, Ras activates several downstream effectors, such as Raf-1, Rac, Rho and phospahtidylinositol-3 kinase, which mediate important cellular functions, such as proliferation, cytoskeletal organization and others. Interruption of the Ras signaling pathway can be basically achieved in three ways, i.e. inhibition of Ras protein expression through antisense oligonucleotides, prevention of Ras membrane localization and inhibition of Ras downstream effectors. SCH 66336 (lonafarnib; Sarasar), a tricyclic orally active FTI, has been the first of these compounds to undergo clinical development. The toxicity profile observed in all completed phase I/II trials has been fairly similar, since gastrointestinal tract toxicity (nausea, vomiting and diarrhea) and fatigue have generally qualified as dose-limiting toxicity (DLT). One objective response in a patient with pretreated non-small cell lung cancer (NSCLC) was observed. Based on preclinical evidence of synergism between lonafarnib and other anticancer agents, combination studies have been started. In particular, lonafarnib has been combined both with gemcitabine and with paclitaxel in phase I studies. Nausea, vomiting, diarrhea and myelosuppression represented DLTs in these studies, in which an encouraging clinical activity was observed, in particular in pancreatic carcinoma (lonafarnib plus gemcitabine) and in NSCLC (lonafarnib plus paclitaxel). R115777 (Zarnestra) is another novel orally active FT competitive inhibitor in clinical development. Single-agent phase I/II studies have shown that myelotoxicity and neurotoxicity are DLTs, intermittent schedule is probably better tolerated and antitumor activity is observed particularly in breast cancer. A number of combination studies with R115777 have been carried out; taken as a whole, they show that the drug can be easily combined with several anticancer agents and phase III trials exploring the potential benefit from incorporation of R115777 into active chemotherapy regimens are indicated. Two other FTIs are in an earlier stage of clinical development. BMS-214662 has the main advantage of being cytotoxic in nature, rather than cytostatic; in particular, potentin vivoantitumor activity in human tumor xenografts of different histologies has been reported. A major drawback for BMS-214662 is its severe gastrointestinal and liver toxicities, which prevent the achievement of adequate systemic exposures following the oral route. L-778,123 has been stopped in its clinical development due to its severe and unexpected toxicity, i.e. grade 4 thrombocytopenia and significant Q–T prolongation.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID