Home About us Contact
|
Home About us Contact | ||
|
|
||
Advanced Cancers (advanced + cancers)
Selected AbstractsHuman colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansionEMBO MOLECULAR MEDICINE, Issue 6-7 2009Frédéric Varnat Abstract Human colon cancers often start as benign adenomas through loss of APC, leading to enhanced ,CATENIN (,CAT)/TCF function. These early lesions are efficiently managed but often progress to invasive carcinomas and incurable metastases through additional changes, the nature of which is unclear. We find that epithelial cells of human colon carcinomas (CCs) and their stem cells of all stages harbour an active HH-GLI pathway. Unexpectedly, they acquire a high HEDGEHOG-GLI (HH-GLI) signature coincident with the development of metastases. We show that the growth of CC xenografts, their recurrence and metastases require HH-GLI function, which induces a robust epithelial-to-mesenchymal transition (EMT). Moreover, using a novel tumour cell competition assay we show that the self-renewal of CC stem cells in vivo relies on HH-GLI activity. Our results indicate a key and essential role of the HH-GLI1 pathway in promoting CC growth, stem cell self-renewal and metastatic behavior in advanced cancers. Targeting HH-GLI1, directly or indirectly, is thus predicted to decrease tumour bulk and eradicate CC stem cells and metastases. [source] ERK inhibitor PD98059 enhances docetaxel-induced apoptosis of androgen-independent human prostate cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 3 2003Stanislav Zelivianski Abstract Anticancer drugs docetaxel and vinorelbine suppress cell growth by altering microtubule assembly and activating the proapoptotic signal pathway. Vinorelbine and docetaxel have been approved for treating several advanced cancers. However, their efficacy in the management of advanced hormone-refractory prostate cancer remains to be clarified. Microtubule damage by some anticancer drugs can activate the ERK survival pathway, which conversely compromises chemotherapeutic efficacy. We analyzed the effect of ERK inhibitors PD98059 and U0126 on vinorelbine- and docetaxel-induced cell growth suppression of androgen-independent prostate cancer cells. In androgen-independent C-81 LNCaP cells, inhibition of ERK by PD98059, but not U0126, plus docetaxel resulted in enhanced growth suppression by an additional 20% compared to the sum of each agent alone (p < 0.02). The combination treatment of docetaxel plus PD98059 also increased cellular apoptosis, which was in part due to the inactivation of Bcl-2 by increasing phosphorylated Bcl-2 by more than 6-fold and Bax expression by 3-fold over each agent alone. At these dosages, docetaxel alone caused only marginal phosphorylation of Bcl-2 (10%). Docetaxel plus U0126 had only 20% added effect on Bcl-2 phosphorylation compared to docetaxel alone. Nevertheless, both U0126 and PD98059 exhibited an enhanced effect on docetaxel-induced growth suppression in PC-3 cells. No enhanced effect was observed for vinorelbine plus PD98059 or U0126. Thus, the combination therapy of docetaxel plus PD98059 may represent a new anticancer strategy, requiring lower drug dosages compared to docetaxel monotherapy. This may lower the cytotoxicity and enhance tumor suppression in vivo. This finding of a combination effect could be of potential clinical importance in treating hormone-refractory prostate cancer. © 2003 Wiley-Liss, Inc. [source] Chlorpromazine and apigenin reduce adenovirus replication and decrease replication associated toxicityTHE JOURNAL OF GENE MEDICINE, Issue 1 2007Anna Kanerva Abstract Background Adenoviruses can cause severe toxicity in immunocompromised individuals. Although clinical trials have confirmed the potency and safety of selectively oncolytic adenoviruses for treatment of advanced cancers, increasingly effective agents could result in more toxicity and therefore it would be useful if replication could be abrogated if necessary. Methods We analyzed the effect of chlorpromazine, an inhibitor of clathrin-dependent endocytosis and apigenin, a cell cycle regulator, on adenovirus replication and toxicity. First, we evaluated the in vitro replication of a tumor targeted Rb-p16 pathway selective oncolytic adenovirus (Ad5/3-,24) and a wild-type adenovirus in normal cells, fresh liver samples and in ovarian cancer cell lines. Further, we analyzed the in vitro cell killing efficacy of adenoviruses in the presence and absence of the substances. Moreover, the effect on in vivo efficacy, replication and liver toxicity of the adenoviruses was evaluated. Results We demonstrate in vitro and in vivo reduction of adenovirus replication and associated toxicity with chlorpromazine and apigenin. Effective doses were well within what would be predicted safe in humans. Conclusions Chlorpromazine and apigenin might reduce the replication of adenovirus, which could provide a safety switch in case replication-associated side effects are encountered in patients. In addition, these substances could be useful for the treatment of systemic adenoviral infections in immunosuppressed patients. Copyright © 2006 John Wiley & Sons, Ltd. [source] Clinical outcome following total laryngectomy for cancerANZ JOURNAL OF SURGERY, Issue 5 2003Francis T. Hall Background: Patients with advanced cancers of the larynx and hypopharynx have been treated with total laryngectomy at the Department of Head and Neck Surgery, Royal Prince Alfred Hospital, Sydney in the past. Increasingly, these patients are being managed with organ-sparing protocols using chemotherapy and radiotherapy. The aim of the present study was to review complication, recurrence and survival rates following total laryngectomy. Methods: Patients who had total laryngectomy for squamous carcinomas of the larynx or hypopharynx between 1987 and 1998 and whose clinicopathological data had been prospectively accessioned onto the computerized database of the Department of Head and Neck Surgery, Royal Prince Alfred Hospital, were reviewed. Patients whose laryngectomy was a salvage procedure for failed previous treatment were included. Results: A total of 147 patients met the inclusion criteria for the study, including 128 men and 19 women with a median age of 63 years. Primary cancers involved the larynx in 90 patients and hypopharynx in 57. There were 30 patients who had recurrent (n = 24) or persistent disease (n = 6) after previous treatment with radiotherapy (26 larynx cases and four hypopharynx cases). Pharyngo-cutaneous fistulas occurred in 26 cases (17.7%) and, using multivariate analysis, the incidence did not correlate with T stage, previous treatment or concomitant neck dissection. Local control rates were 86% for the larynx and 77% for the hypopharynx groups and neck control was 84% and 75%, respectively. Five-year survival for the larynx cancer group was 67% and this was significantly influenced by T stage and clinical and pathological N stage. Survival in the hypopharynx group was 37% at 5 years and this did not significantly correlate with T or N stage. There was a non-significant trend to improved survival among previously treated patients whose laryngectomy was a salvage procedure. Conclusion: Patients with cancer of the larynx had a significantly better survival following total laryngectomy than patients with hypopharyngeal cancer. Those whose laryngectomy was carried out as a salvage procedure following failed previous treatment did not have a worse outcome than previously untreated patients. [source] Trends in the curative treatment of localized prostate cancer after the introduction of prostate-specific antigen: data from the Rotterdam Cancer RegistryBJU INTERNATIONAL, Issue 4 2000S.J.J.C. Spapen Objective To investigate changes in the incidence and treatment of prostate cancer over the period in which new diagnostic tools were introduced and the attitude towards treatment was changing. Patients and methods Information on the extent of disease and treatment of patients diagnosed with prostate cancer within the Rotterdam region was retrieved from the Rotterdam Cancer Registry. Results In the period 1989,95, 4344 patients were diagnosed with prostate cancer and the age-standardized incidence increased from 62 to 125 per 100 000 men. This increase mainly comprised tumours localized to the prostate, while the incidence of advanced cancers remained stable. The proportion of poorly differentiated tumours decreased from 33% in 1989 to 24% in 1995. In the same period the number of patients receiving radiotherapy increased from 80 to 258, while the annual number of radical prostatectomies rose from 17 to 159. Radiotherapy was the preferred type of treatment in patients over 70 years of age, whereas radical prostatectomy was used more frequently in younger patients with localized tumours. Conclusion While the value of screening for prostate cancer remains in debate, incidence and treatment patterns are changing rapidly. Information on patterns of care is needed to interpret future mortality data and to plan resources for adequate health care. [source] | |||||||||||||