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Enhanced antitumor activity of low-dose continuous administration schedules of topotecan in prostate cancer.

ABSTRACT: PURPOSE:The objective of this study was to determine the antitumor effects of alternate dosing schedules of topotecan in prostate cancer. RESULTS:A concentration-dependent increase in cytotoxicity was observed in PC-3 and LNCaP cells after topotecan treatment using conventional and metronomic protocols. A significant increase in potency (2.4-18 fold, after 72 hr) was observed following metronomic dosing compared to conventional dosing administration in both cell lines. Metronomic dosing also increased the percentage of PC-3 cells in the G2/M, compared to control, but did not alter LNCaP cell cycle distribution. Metronomic dosing increased p21 protein expression in LNCaP and PC-3 cells compared to conventional dosing. The observed in vitro activity was confirmed using an in vivo model of human prostate cancer. Metronomic dosing and continuous infusion decreased tumor volume significantly (p < 0.05) compared to control and conventional topotecan treatment, but had no effect on tumor vascular staining. METHODS:The cytotoxicity of topotecan after conventional or metronomic dosing was determined by examining cellular morphology, mitochondrial enzymatic activity (MTT), total cellular protein (SRB), annexin V and propidium iodine (PI) staining, cell cycle and western blot analysis in human prostate cancer cell lines (PC-3 and LNCaP) and the effects metronomic or continuous infusion on tumor growth in an in vivo tumor xenograft model. CONCLUSIONS:These data support the hypothesis that low-dose continuous administration of topotecan increases potency compared to conventional dosing in prostate cancer. These data also suggest the novel finding that the enhanced antitumor activity of topotecan following low-dose exposure correlates to alterations in cell cycle and increased p21 expression.

SUBMITTER: Aljuffali IA

PROVIDER: S-EPMC3230472 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Enhanced antitumor activity of low-dose continuous administration schedules of topotecan in prostate cancer.

Aljuffali Ibrahim A IA Mock Jason N JN Costyn Leah J LJ Nguyen Ha H Nagy Tamas T Cummings Brian S BS Arnold Robert D RD

Cancer biology & therapy 20110901 5

<h4>Purpose</h4>The objective of this study was to determine the antitumor effects of alternate dosing schedules of topotecan in prostate cancer.<h4>Results</h4>A concentration-dependent increase in cytotoxicity was observed in PC-3 and LNCaP cells after topotecan treatment using conventional and metronomic protocols. A significant increase in potency (2.4-18 fold, after 72 hr) was observed following metronomic dosing compared to conventional dosing administration in both cell lines. Metronomic ...[more]

PMID: 21709443

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Project description:Key pointsOculomotor behaviours are commonly used to evaluate sensorimotor disruption due to ethanol (EtOH). The current study demonstrates the dose-dependent impairment in oculomotor and ocular behaviours across a range of ultra-low BACs (<0.035%). Processing of target speed and direction, as well as pursuit eye movements, are significantly impaired at 0.015% BAC, suggesting impaired neural activity within brain regions associated with the visual processing of motion. Catch-up saccades during steady visual tracking of the moving target compensate for the reduced vigour of smooth eye movements that occurs with the ingestion of low-dose alcohol. Saccade dynamics start to become 'sluggish' at as low as 0.035% BAC. Pupillary light responses appear unaffected at BAC levels up to 0.065%.AbstractChanges in oculomotor behaviours are often used as metrics of sensorimotor disruption due to ethanol (EtOH); however, previous studies have focused on deficits at blood-alcohol concentrations (BACs) above about 0.04%. We investigated the dose dependence of the impairment in oculomotor and ocular behaviours caused by EtOH administration across a range of ultra-low BACs (≤0.035%). We took repeated measures of oculomotor and ocular performance from sixteen participants, both pre- and post-EtOH administration. To assess the neurological impacts across a wide range of brain areas and pathways, our protocol measured 21 largely independent performance metrics extracted from a range of behavioural responses ranging from ocular tracking of radial step-ramp stimuli, to eccentric gaze holding, to pupillary responses evoked by light flashes. Our results show significant impairment of pursuit and visual motion processing at 0.015% BAC, reflecting degraded neural processing within extrastriate cortical pathways. However, catch-up saccades largely compensate for the tracking displacement shortfall caused by low pursuit gain, although there still is significant residual retinal slip and thus degraded dynamic acuity. Furthermore, although saccades are more frequent, their dynamics are more sluggish (i.e. show lower peak velocities) starting at BAC levels as low as 0.035%. Small effects in eccentric gaze holding and no effect in pupillary response dynamics were observed at levels below 0.07%, showing the higher sensitivity of the pursuit response to very low levels of blood alcohol, under the conditions of our study.

Dataset Information

Enhanced antitumor activity of low-dose continuous administration schedules of topotecan in prostate cancer.

Publications

Enhanced antitumor activity of low-dose continuous administration schedules of topotecan in prostate cancer.

Similar Datasets

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