The slow dissociation of DNA threading intercalators makes them interesting as model compounds in the search for new DNA targeting drugs, as there appears to be a correlation between slow dissociation and biological activity. Thus, it would be of great value to understand the mechanisms controlling threading intercalation, and for this purpose we have investigated how the length of the bridging ligand of binuclear ruthenium threading intercalators affects their DNA binding properties. We have synthesised a new binuclear ruthenium threading intercalator with slower dissociation kinetics from ct-DNA than has ever been observed for any ruthenium complex with any type of DNA, a property that we attribute to the increased distance between the ruthenium centres of the new complex. By comparison with previously studied ruthenium complexes, we further conclude that elongation of the bridging ligand reduces the sensitivity of the threading interaction to DNA flexibility, resulting in a decreased AT selectivity for the new complex. We also find that the length of the bridging ligand affects the enantioselectivity with increasing preference for the ΔΔ enantiomer as the bridging ligand becomes longer.
Introduction An increasing number of postmenopausal women are diagnosed with breast cancer at an older age (≥ 70 years). There is a lack of synthesised health utility data to support decision-making for managing breast cancer in this older population. This study aimed to identify the availability of, and the subsequent impact of age on, health state utility values (HSUVs) measured by the EQ-5D for older women with early-stage breast cancer. Method This systematic review identified EQ-5D (3L or 5L version) HSUVs for postmenopausal women with early-stage breast cancer. Studies were identified from a previous systematic review (inception to 2009) and an electronic database search (Medline and Embase; 2009 to September 2021). Mean HSUVs were summarised by health state. Quality appraisal was performed on studies reporting HSUVs for older ages (≥ 70 years). Multivariable meta-regression assessed the association between HSUVs and age, health state, treatments received, and time of measuring the utility values (greater or less than one year post-treatment). Results Fifty EQ-5D HSUVs were identified from 13 studies. Mean HSUVs decreased as health state worsened: from the stable (mean=0.83) to progression (mean=0.79) and advanced (mean=0.68) states. Two studies reported six HSUVs estimated from the sample of women with a mean age ≥ 70. Meta-regression model fit improved by including age as an independent variable and attenuated the estimated utility decrements associated with worse health states. Utility decrements for the progression and advanced states were -0.052 (95%CI: -0.097, -0.007) and -0.143 (95%CI: -0.264, -0.022) respectively. The breast cancer-specific utility decrement associated with a one-year increase in age was -0.001 (95%CI: -0.004, 0.002). Conclusion Relevant and accurate HSUVs are essential to help support decision-making about the most effective and cost-effective ways to manage early-stage breast cancer in older women. Age has a vital role in determining health utility values in this population. This study provides analysts and decision-makers with HSUVs and utility decrements that reflect the disease process in this older population.
Objective To appraise the sources of evidence and methods to estimate input parameter values in decision-analytic model-based cost-effectiveness analyses of treatments for primary breast cancer (PBC) in older patients (≥ 70 years old). Methods Two electronic databases (Ovid Medline, Ovid EMBASE) were searched (inception until 5 September-2021) to identify model-based full economic evaluations of treatments for older women with PBC as part of their base-case target population or age-subgroup analysis. Data sources and methods to estimate four types of input parameters including health-related quality of life (HRQoL); natural history; treatment effect; resource use were extracted and appraised. Quality assessment was completed by reference to the Consolidated Health Economic Evaluation Reporting Standards. Results Seven model-based economic evaluations were included (older patients as part of their base-case (n = 3) or subgroup (n = 4) analysis). Data from younger patients (< 70 years) were used frequently to estimate input parameters. Different methods were adopted to adjust these estimates for an older population (HRQoL: disutility multipliers, additive utility decrements; Natural history: calibration of absolute values, one-way sensitivity analyses; Treatment effect: observational data analysis, age-specific behavioural parameters, plausible scenario analyses; Resource use: matched control observational data analysis, age-dependent follow-up costs). Conclusion Improving estimated input parameters for older PBC patients will improve estimates of cost-effectiveness, decision uncertainty, and the value of further research. The methods reported in this review can inform future cost-effectiveness analyses to overcome data challenges for this population. A better understanding of the value of treatments for these patients will improve population health outcomes, clinical decision-making, and resource allocation decisions.
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