ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

We review the biological significance of transcription factors such as p53, Myc, E2F family and AP-1 (Jun/Fos) in anticancer drug-induced apoptosis. It is likely that the functional role of these transcription factors is complex in response to DNA damage depending on cancer cell type. Regulation of apoptosis following DNA damage is mediated by cell cycle arrest for DNA repair and subsequent signal transduction pathways leading to apoptosis, which is associated with mitochondrial dysfunction. Activation of transcription factors following anticancer drugs is located upstream of signal transduction pathways, thereby the downstream pathway is promoted, which is connected to activation or suppression of apoptosis-related proteins. Switching on apoptotic signals by anticancer drugs is amplified in mitochondria by releasing cytochromecfrom the ion channel to activate the caspase cascade, which is regulated by Bcl-2 families in the central gate for drug-induced apoptosis. Activation of transcription factors targeting downstream genes, some of which are apoptosis-related genes, can play a critical role in promoting apoptosis following treatment with anticancer drugs. The strategy of identification of downstream target proteins or transcription factors involved in apoptosis will be necessary for the development of an effective transcription factor-targeted chemotherapy for cancer.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Many conventional chemotherapeutics, such as the microtubule-stabilizing anticancer drug paclitaxel (Taxol), have been shown to have anti-angiogenic activity and clinical application of a continuous low dose of these agents has been suggested for cancer therapy. In this study, we show that paclitaxel selectively inhibits the proliferation of human endothelial cells (ECs) at ultra low concentrations (0.1–100 pM), with an IC50=0.1 pM, while it inhibits non-endothelial type human cells at 104- to 105-fold higher concentrations, with IC50=1–10 nM. The selectivity of paclitaxel inhibition of cell proliferation is also species specific, as mouse ECs are not sensitive to paclitaxel at ultra low concentrations. They are inhibited by higher concentrations of paclitaxel with IC50=1–10 nM. Inhibition of human ECs by paclitaxel at ultra low concentrations does not affect the cellular microtubule structure, and the treated cells do not show G2/M cell cycle arrest and apoptosis, suggesting a novel but as yet unidentified mechanism of action. In anin vitroangiogenesis assay, paclitaxel at ultra low concentrations blocks human ECs from forming sprouts and tubes in the three-dimensional fibrin matrix. In summary, paclitaxel selectively inhibits human EC proliferation andin vitroangiogenesis at low picomolar concentrations. The data support a clinical application of continuous ultra-low-dose paclitaxel to treat cancer.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Sulfasalazine (SASP) is a novel, potent inhibitor of cellular cystine uptake mediated by the xc−cystine/glutamate antiporter. Lymphoid cells cannot synthesize cyst(e)ine and depend for growth on its uptake from their micro-environment. We previously showed that SASP (0.2 mM) can abrogate lymphoma cell proliferationin vitroby specifically inhibiting xc−-mediated cystine uptake. Intraperitoneal administration of SASP to Noble rats markedly suppressed Nb2-U17 rat lymphoma transplant growth, notably without major toxicity to the hosts. Since Nb2-U17 cells are xc−-deficient, the growth arrest was apparently not due to SASP–tumor cell interaction, but possibly to interference with xc−-mediated cysteine secretion by somatic cells. In this study we found that replication of xc−-deficient Nb2-11 lymphoma cells can be sustainedin vitro, in the absence of cystine uptake enhancers, by co-culturing with IMR-90 fibroblasts known to secrete cysteine. SASP, at 0.15 and 0.2 mM, arrested replication of fibroblast-driven Nb2-11 cells by 93 and 100%, respectively, without impeding fibroblast proliferation. Addition of 2-mercapto-ethanol (60 μM), a cystine uptake enhancer, almost completely prevented this growth arrest, indicating that SASP specifically inhibited cysteine secretion by the fibroblasts, a process based on xc−-mediated cystine uptake. It is proposed that the lymphoma growth-inhibitory activity of SASPin vivoinvolves inhibition of cysteine secretion by tumor-associated somatic cells (macrophages, dendritic cells), leading to cysteine starvation of the tumor cells and apoptosis. The difference between the lymphoma cells and fibroblasts in sensitivity to SASP treatment is consistent with the marked antitumor effect of SASP lacking significant side effects.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The pyridinyl imidazole p38 kinase inhibitor, SB203580, was initially used to block inflammatory cytokine synthesis. Here we report that SB203580 by itself could induce human promyeloid leukemic HL-60 cells to differentiate mainly along the granulocytic lineage, as evidenced by cellular morphological changes, and the concurrent expression of cell surface markers CD11b and CD14. This differentiation induction was time and dose dependent. After 12 h exposure to 10 μM SB203580, 12.5% of the cells became CD11b+as compared to only 2.6% in untreated control cells. By 96 h, CD11b+cells increased to 72.3%, and among them, 26% were CD14+. Morphologically, the cells were smaller in size with lower nuclear/cytoplasmic ratio. The nucleus was indented and nucleoli markedly reduced. However, 10 μM SB203580 had little effect on HL-60 cell growth and survival during the first 72 h, but by 96 h the percentage of cells in G1phase was markedly increased. These effects of SB203580 were not attributable to its inhibition of p38 kinase activity. Instead, the essential kinases in the extracellular signal-regulated kinase (ERK) pathway such as phospho-Raf-1, phospho-MEK1/2, phospho-ERK1/2 and phospho-p90RSK were all elevated dramatically shortly after cells were exposed to SB203580 and lasted for 24 h before declining. Pre-incubation of cells with 20 μM of PD98059 1 h before addition of SB203580 could completely block the expression of differentiation markers. Our results suggest that SB203580-induced differentiation in HL-60 cells was mediated by activation of MEK/ERK signaling. In conclusion, our data have shown that SB203580 possessed biological activities other than inhibition of p38 and these activities could make it a potential candidate as an inducing agent for cell differentiation in the therapeutic treatment of leukemia.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Chemotherapy resistance is a significant obstacle in lung cancer therapy, and has been found to frequently correlate with amplification and overexpression of the c-myconcogene. Earlier studies have shown that c-Myc inhibition alone is not always effective in cancer models. The purpose of this study was to test different dosing regimen, which included commonly used chemotherapeutic drugs in combination with c-Myc inhibition in a Lewis lung syngeneic drug-resistant murine tumor model. Inhibition of c-mycwas specifically achieved by using phosphorodiamidate Morpholino oligomer (PMOs), a novel, non-toxic antisense DNA chemistry for inhibition of gene expression by an RNase H-independent mechanism. When administration of cisplatin overlapped with c-mycPMO (AVI-4126) treatment there was no additional effect on tumor growth inhibition compared to cisplatin alone. In contrast, using a dosing regimen in which cisplatin or taxol treatment preceded AVI-4126, a dramatic decrease in tumor growth rate was observed with tumor areas less then 0.5 cm2in 60% of the animals at the end of the study. This effect was specific to c-Myc inhibition as other antisense PMOs against p21 or Rad51 showed no such effect in combination with chemotherapy. Immunoblot and HPLC-based analysis of tumor lysates at the end of the study confirmed c-Myc inhibition and detection of intact AVI-4126, respectively. In conclusion, AVI-4126 potentiates the efficacy of chemotherapeutic drugs in a manner that is schedule dependent.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Epidermal growth factor receptor (EGFR) plays an important role in cell division and cancer progression, as well as angiogenesis and metastasis. Since many tumor cells exhibit the EGFR on their surface, functional imaging of EGFR provides not only a non-invasive, reproducible, quantifiable alternative to biopsies, but it also greatly complements pharmacokinetic studies by correlating clinical responses with biological effects. Moreover, molecular endpoints of anti-EGFR therapy could be assessed effectively. C225 is a chimeric monoclonal antibody that targets the human extracellular EGFR and inhibits the growth of EGFR-expressing tumor cells. Also, it has been demonstrated that C225, in combination with chemotherapeutic drugs or radiotherapy, is effective in eradicating well-established tumors in nude mice. We have developed99mTc-labeled C225 using ethylenedicysteine (EC) as a chelator. This study aimed at measuring uptake of99mTc–EC–C225 in EGFR+tumor-bearing animal models and preliminary feasibility of imaging patients with head and neck carcinomas.In vitroWestern blot analysis and cytotoxicity assays were used to examine the integrity of EC–C225. Tissue distribution studies of99mTc–EC–C225 were evaluated in tumor-bearing rodents at 0.5–4 h.In vivobiodistribution of99mTc–EC–C225 in tumor-bearing rodents showed increased tumor-to-tissue ratios as a function of time.In vitroand biodistribution studies demonstrated the possibility of using99mTc–EC–C225 to assess EGFR expression. SPECT images confirmed that the tumors could be visualized with99mTc–EC–C225 from 0.5 to 4 h in tumor bearing rodents. We conclude that99mTc–EC–C225 may be useful to assess tumor EGFR expression. This may be useful in the future for selecting patients for treatment with C225.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy (HITHOC) is studied in a phase I study in the treatment of malignant pleural mesothelioma and pleural thymoma. We studied the pharmacokinetics of doxorubicin and cisplatin used during the HITHOC procedure. Furthermore, the penetration characteristics of doxorubicin were examined. Between 1998 and 2001, 24 perfusions were performed with a solution containing doxorubicin and cisplatin for 90 min at 40–41°C. The dose was first based on square meters body surface, whereas in later studies a fixed concentration of the perfusion fluid was used. Samples of blood and perfusion fluid were collected for doxorubicin and cisplatin measurements. The penetration characteristics of doxorubicin in tissue were determined by fluorescence microscopy. The mean AUCperfusate:AUCplasmaratios for doxorubicin and cisplatin (ultrafiltration for plasma) were 99 and 59, respectively. During perfusion the concentration in the perfusate declined essentially according to first-order elimination kinetics for both doxorubicin and cisplatin with half-lives of 74 and 138 min, respectively. At the end of the perfusion, about 35 and 52% of the dose of doxorubicin and cisplatin, respectively, was recovered in the perfusion fluid. One patient developed a nephrotoxicity grade II. No leukopenia or hair loss was seen. Doxorubicin penetrated into the intercostal muscle specimen, albeit that there was considerable variation in distribution throughout the specimen. We conclude that HITHOC with doxorubicin and cisplatin is relatively a safe procedure with the advantage of high intrathoracic cytostatic drug concentrations, while having limited systemic side effects.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Anti-tubulin couplets have activity in hormone-resistant prostate cancer. This study was designed to define the dose-limiting toxicity (DLT) and recommended phase II dose (RPTD) of the unique triplet combination of paclitaxel, estramustine phosphate (EMP) and vinorelbine (Pacl-E-Vin). Patients with advanced malignancies who had failed standard therapy, ECOG performance status (PS 0–2) and adequate organ function were included. Dose of EMP was fixed at 300 mg/m2/dose p.o. t.i.d. on days 1–3 and 8–10. Vinorelbine dose was 20 mg/m2/day i.v. on days 3 and 10. Paclitaxel was dose escalated from 40 to 50 mg/m2/day i.v. on days 3 and 10. Cycles were repeated every 3 weeks. Twelve adults (median age 72) were entered on this study. Primary tumors included prostate (n=7), cervix (n=2), melanoma (n=1), colon (1) and lung with synchronous prostate cancer (n=1). Nine patients had received no prior chemotherapy, one had received a prior regimen and two had received two or more prior regimens. Of four evaluable patients at dose level 1, one patient had grade 3 neutropenia leading to the day 10 dose being withheld. Of five evaluable patients at dose level 2, there was one DLT (febrile neutropenia) and two grade 3 neutropenias leading to the day 10 dose being withheld. One patient had a lower extremity deep vein thrombosis. Other side effects were mild and reversible. Nine patients were evaluable for efficacy: three with prostate cancer had a greater than 50% prostate-specific antigen (PSA) response, and a patient with synchronous prostate and lung cancer had a greater than 50% PSA response. We conclude that the DLT of Pacl-E-Vin is neutropenia. RPTD is vinorelbine 20 mg/m2, paclitaxel 40 mg/m2, both administered on days 3 and 10, and EMP 900 mg/m2/day on days 1–3 and 8–10, q3w. Dose omission at day 10 followed by 20% dose reduction of paclitaxel and vinorelbine is recommended in the event of grade 3 neutropenia. Activity in hormone-refractory prostate cancer is promising and warrants phase II evaluation.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The aim was to evaluate clinical and subclinical cardiac toxicity of epirubicin–docetaxel (ET) combination. Breast cancer patients were given epirubicin (75 mg/m2for 15 min), followed 1 h later by a 1-h infusion of docetaxel (75 mg/m2) q3w as first-line treatment. Cardiac function was monitored using a 24-h ambulatory electrocardiogram (ECG), left ventricular ejection fraction (LVEF), physical examination and chest radiography. The median LVEF did not decrease during the course of the treatment: median LVEF was 64% prior to treatment and 68% after cycle 8. The 24-h ECG did not reveal any significant changes in heart rate variability. The number of extrasystoles or cardiac arrhythmia did not increase with the ET treatment. No patient experienced congestive heart failure during treatment or the mean follow-up of 34 months. We conclude that first-line ET caused no major cardiac changes during 6 months of treatment (8 cycles) or during follow-up. Twenty-four-hour ECG, combined with echocardiography to measure LVEF, was a feasible method for the close monitoring of the cardiac effects during chemotherapy.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID