Mathematical and computational models of drug transport in tumours

The ability to predict how far a drug will penetrate into the tumour microenvironment within its pharmacokinetic (PK) lifespan would provide valuable information about therapeutic response. As the PK profile is directly related to the route and schedule of drug administration, an in silico tool that can predict the drug administration schedule that results in optimal drug delivery to tumours would streamline clinical trial design. This paper investigates the application of mathematical and computational modelling techniques to help improve our understanding of the fundamental mechanisms underlying drug delivery, and compares the performance of a simple model with more complex approaches. Three models of drug transport are developed, all based on the same drug binding model and parametrized by bespoke in vitro experiments. Their predictions, compared for a ‘tumour cord’ geometry, are qualitatively and quantitatively similar. We assess the effect of varying the PK profile of the supplied drug, and the binding affinity of the drug to tumour cells, on the concentration of drug reaching cells and the accumulated exposure of cells to drug at arbitrary distances from a supplying blood vessel. This is a contribution towards developing a useful drug transport modelling tool for informing strategies for the treatment of tumour cells which are ‘pharmacokinetically resistant’ to chemotherapeutic strategies

Ab initio calculation of the neutron-proton mass difference

The existence and stability of atoms rely on the fact that neutrons are more massive than protons. The measured mass difference is only 0.14\% of the average of the two masses. A slightly smaller or larger value would have led to a dramatically different universe. Here, we show that this difference results from the competition between electromagnetic and mass isospin breaking effects. We performed lattice quantum-chromodynamics and quantum-electrodynamics computations with four nondegenerate Wilson fermion flavors and computed the neutron-proton mass-splitting with an accuracy of $300$ kilo-electron volts, which is greater than $0$ by $5$ standard deviations. We also determine the splittings in the $\Sigma$, $\Xi$, $D$ and $\Xi_{cc}$ isospin multiplets, exceeding in some cases the precision of experimental measurements.Comment: 57 pages, 15 figures, 6 tables, revised versio

Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours

BACKGROUND: Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling. Two first-in-human trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD), safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers. METHODS: These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected tumours; RBD [weekly dosing]). Primary endpoints were MTD/RBD. RESULTS: Study 1280.1 involved 61 patients (part I: xentuzumab 10–1800 mg weekly, n = 48; part II: 1000 mg weekly, n = 13); study 1280.2, 64 patients (part I: 10–3600 mg three-weekly, n = 33; part II: 1000 mg weekly, n = 31). One dose-limiting toxicity occurred; the MTD was not reached for either schedule. Adverse events were generally grade 1/2, mostly gastrointestinal. Xentuzumab showed dose-proportional pharmacokinetics. Total plasma IGF-1 increased dose dependently, plateauing at ~1000 mg/week; at ≥450 mg/week, IGF bioactivity was almost undetectable. Two partial responses occurred (poorly differentiated nasopharyngeal carcinoma and peripheral primitive neuroectodermal tumour). Integration of biomarker and response data by Bayesian Logistic Regression Modeling (BLRM) confirmed the RBD. CONCLUSIONS: Xentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM. Xentuzumab showed preliminary anti-tumour activity

Protein kinase C: a target for anticancer drugs?

Protein kinase C (PKC) is a family of serine/threonine kinases that is involved in the transduction of signals for cell proliferation and differentiation. The important role of PKC in processes relevant to neoplastic transformation, carcinogenesis and tumour cell invasion renders it a potentially suitable target for anticancer therapy. Furthermore, there is accumulating evidence that selective targeting of PKC may improve the therapeutic efficacy of established neoplastic agents and sensitise cells to ionising radiation. This article reviews the rationale for targeting PKC, focuses on its role in breast cancer and reviews the preclinical and clinical data available for the efficacy of PKC inhibition

Matrix metalloproteinase inhibitors: past lessons and future prospects in breast cancer

The matrix metalloproteinases (MMPs) play a central role in invasion and metastasis. However, despite striking activity in preclinical models, the clinical development of the matrix metalloproteinase inhibitors (MMPIs) has been difficult. The results of important phase III trials are now emerging and it is therefore opportune to review the current state of the MMPIs. In this article the evidence for the role of MMPs in the progression of breast cancer, the development of the MMPIs and the recent phase III results are discussed. Despite the problems encountered it is hoped that the MMPIs may yet provide another mechanism for the long-term control of micrometastatic disease. Furthermore, important lessons can be learnt from their development that are relevant to the development of other biological agents

The oral fluorinated pyrimidines

The fluorinated pyrimidines have played a major role in the treatment of many common tumors since 5-fluorouracil (5FU) was first introduced. Studies of the cellular and clinical pharmacology of 5FU have led to an improved understanding of the mechanisms of action of this agent. This knowledge has allowed the optimal and rational development of fluoropyrimidine therapy, with significant therapeutic advances in recent years. Efforts to improve the therapeutic index of 5FU have included alteration of schedule, and the addition of biochemical modulators such as folinic acid. Although protracted continuous infusion of 5FU has led to better response rates and decreased toxicity, the administration of 5FU by protracted infusion is not only costly, but also inconvenient to the patient. Furthermore it is often associated with infectious and thrombotic complications related to the required indwelling intravenous catheter. Protracted oral administration is a rational route for administering 5FU, being preferred by the patient and the pharmaco-economist. The unpredictable and low oral bioavailability of 5FU initially discouraged this form of treatment. This problem has now been overcome by the new generation of oral fluoropyrimidines. Two main strategies have been pursued: 1) The administration of an inactive prodrug of 5FU, which is absorbed intact, and subsequently converted to 5FU. Capecitabine is converted to 5FU by a 3 step enzymatic process. 2) The administration of 5FU with an inhibitor of dihydropyrimidine dehydrogenase (DPD) to minimise the erratic absorption and variable clearance of 5FU: the preparations UFT, S1, and ethinyluracil/5FU contain an oral fluoropyrimidine co-administered orally with inhibitors of this enzyme. The development and characteristics of these agents are discussed

Variation in survival of women with breast cancer: Health Board remains a factor at 10 years

Multivariate survival analysis of women with breast cancer diagnosed in 1987 with at least 10 years follow-up confirmed variations depending on the Health Board of their treatment. Differences in survival according to surgical caseload/specialization or deprivation were not statistically significant