Showing items related by title, author, creator and subject.

• Response of multiple recurrent TaT1 bladder cancer to intravesical apaziquone (EO9): Comparative analysis of tumour recurrence rates.

  Jain, A.; Phillips, Roger M.; Scally, Andy J.; Lenaz, G.; Beer, M.; Puri, Rajiv (2009)

  Objectives Previous studies have demonstrated that intravesical administration of apaziquone (EOquin) has ablative activity against superficial bladder cancer marker lesions with 8 out of 12 complete responses recorded. We present a comparison between the rates of tumor recurrence before and after treatment with apaziquone. Methods The rate of tumor recurrence after treatment with apaziquone was compared with each patient's historical record of recurrences obtained from a retrospective analysis of the patients' case notes. The time to each recurrence event before apaziquone treatment and the time to the first recurrence after apaziquone treatment were recorded, and the data were analyzed using a population-averaged linear regression model using Stata Release, version 9.2, software. Results Of the eight complete responses obtained in the Phase I study, tumor recurrence occurred in 4 patients and the remaining 4 patients remained disease free after a median follow-up of 31 months. The time to the first recurrence after apaziquone treatment was significantly longer (P <0.001) compared with the historical pattern and recurrence interval before apaziquone. Before apaziquone instillation, the mean ± SE recurrence rate and tumor rate per year was 1.5 ± 0.2 and 4.8 ± 1.2, respectively, and these decreased to 0.6 ± 0.25 and 1.5 ± 0.8, respectively, after apaziquone treatment (P <0.05). Conclusions The results of this study indicate that early recurrences after treatment with apaziquone are infrequent and the interval to recurrence is significantly greater compared with the historical recurrence times for these patients. Larger prospective randomised trials are warranted to confirm these results. Aapaziquone (EOquin, USAN, E09, 3-hydroxy-5-aziridinyl-1-methyl-2[indole-4,7-dione]¿prop-¿-en-¿-ol) belongs to a class of anticancer agents known as bioreductive drugs that require metabolism by cellular reductases to generate a cytotoxic species.1 Although it is chemically related to mitomycin C, apaziquone has a distinctly different mechanism of action and preclinical activity profile.1 and 2 The initial optimism generated by its preclinical activity profile rapidly evaporated after the demonstration that intravenously administered apaziquone was clinically inactive against a range of solid tumors in Phase II clinical trials.3 and 4 Several possible explanations were considered for its lack of efficacy, but poor drug delivery to the tumor because of the rapid pharmacokinetic elimination of apaziquone in conjunction with relatively poor penetration through avascular tissue was considered to be the principal reason.5 On the basis of the rationale that intravesical administration would circumvent the problem of drug delivery and any apaziquone absorbed into the blood stream would be rapidly cleared,6 a Phase I-II clinical pilot study of intravesical administration of apaziquone to superficial bladder tumors was established.7 The results of that trial demonstrated that intravesically administered apaziquone has ablative activity against superficial bladder transitional cell carcinoma (TCC) marker lesions.7 These results were confirmed and extended in a Phase II clinical trial of 47 patients with superficial bladder TCC, in which complete responses were obtained in 67% of patients.8 Because all the enrolled patients in the original trial7 had had multiple recurrences after previous intravesical chemotherapy and/or immunotherapy, the purpose of the present study was, first, to report the recurrences that occurred after apaziquone treatment and, second, to study the effect of apaziquone instillation on the recurrence rate by statistically comparing these results with the historical pattern of recurrences for each patient before treatment with apaziquone.
• Novel Ran-RCC1 inhibitory peptide-loaded nanoparticles have anti-cancer efficacy in vitro and in vivo

  Haggag, Y.A.; Matchett, K.B.; Falconer, Robert A.; Isreb, Mohammad; Jones, Jason; Faheem, A.; McCarron, P.; El-Tanani, Mohamed (2019-02)

  The delivery of anticancer agents to their subcellular sites of action is a significant challenge for effective cancer therapy. Peptides, which are integral to several oncogenic pathways, have significant potential to be utilised as cancer therapeutics due to their selectivity, high potency and lack of normal cell toxicity. Novel Ras protein-Regulator of chromosome condensation 1 (Ran-RCC1) inhibitory peptides designed to interact with Ran, a novel therapeutic target in breast cancer, were delivered by entrapment into polyethylene glycol-poly (lactic-co-glycolic acid) PEG-PLGA polymeric nanoparticles (NPs). A modified double emulsion solvent evaporation technique was used to optimise the physicochemical properties of these peptide-loaded biodegradable NPs. The anti-cancer activity of peptide-loaded NPs was studied in vitro using Ran-expressing metastatic breast (MDA-MB-231) and lung cancer (A549) cell lines, and in vivo using Solid Ehrlich Carcinoma-bearing mice. The anti-metastatic activity of peptide-loaded NPs was investigated using migration, invasion and colony formation assays in vitro. A PEG-PLGA-nanoparticle encapsulating N-terminal peptide showed a pronounced antitumor and anti-metastatic action in lung and breast cancer cells in vitro and caused a significant reduction of tumor volume and associated tumor growth inhibition of breast cancer model in vivo. These findings suggest that the novel inhibitory peptides encapsulated into PEGylated PLGA NPs are delivered effectively to interact and deactivate Ran. This novel Ran-targeting peptide construct shows significant potential for therapy of breast cancer and other cancers mediated by Ran overexpression.
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  Stem Cell Organoids in Primary Cultures of Human Non-Malignant and Malignant Colon

  Tariq, S.; Tahseen, M.; Hassan, M.; Masood, M.A.; Khattak, S.; Syed, A.A.; Ahmad, A.H.; Hussain, M.; Yusuf, M.A.; Sutton, Chris W. (2017-05-28)

  A sub-population of cells named cancer stem cells (CSCs) that initiate and promote tumour growth have been demonstrated to exist in several malignancies including colon carcinoma. The objective of our pilot study was to isolate CD133+CD26+CD44+ CSCs from patient colon tumours, culture spheres or organoids and observe their proliferation in primary cultures. Parallel cultures of non-cancer controls from colon normal lining and nonadenomatous polyps were set up. Magnetic activated cell sorting was used to isolate CD133+CD26+CD44+ cell populations followed by primary cell culturing under stem cell culture conditions. Number, cells/organoid and daughter generations of organoids were calculated using phase contrast microscope. Trypan blue exclusion method was used to test the viability of the cells. Both colon tumour and colon non-adenomatous polyp formed floating organoids in suspension; however non-adenomatous polyp cultures did not show self-renewal properties for more than 1 passage. Normal colon singlecell suspension did not create organoids. Metastatic colon tumours rapidly produce cancer cell organoids in less than 24 hours in larger numbers compared to non-metastatic colon tumours (1-3 weeks). Metastatic colon tumour organoids have the ability for proliferation for upto five daughter generations in primary culture compared to three generations for those grown from non-metastatic tumours. This in vitro CSC organoid model will help study colon cancer biology, in particular providing a valuable source of primary cell-derived tissue for studying personalized molecular profiling using ‘omics strategies to direct therapeutic intervention.