Radiopotentiation Profiling of Multiple Inhibitors of the DNA Damage Response for Early Clinical Development.

Radiotherapy is an effective anticancer treatment, but combinations with targeted agents that maximize efficacy while sparing normal tissue are needed. Here, we assess the radiopotentiation profiles of DNA damage response inhibitors (DDRi) olaparib (PARP1/2), ceralasertib (ATR), adavosertib (WEE1), AZD0156 (ATM), and KU-60648 (DNA-PK). We performed a radiotherapy combination screen and assessed how drug concentration and cellular DDR deficiencies influence the radiopotentiation ability of DDRi.

Repeatability of 18F-FDG PET in a multicenter phase I study of patients with advanced gastrointestinal malignancies.

Unlabelled: (18)F-FDG PET is often used to monitor tumor response in multicenter oncology clinical trials. This study assessed the repeatability of several semiquantitative standardized uptake values (mean SUV [SUV(mean)], maximum SUV [SUV(max)], peak SUV [SUV(peak)], and the 3-dimensional isocontour at 70% of the maximum pixel value [SUV(70%)]) as measured by repeated baseline (18)F-FDG PET studies in a multicenter phase I oncology trial.

Methods: Double-baseline (18)F-FDG PET studies were acquired for 62 sequentially enrolled patients.

MR in oncology drug development.

This article reviews the use of MR in preclinical and clinical experiments to aid drug development. In particular it concentrates on the use of MR to study tumor microvasculature following treatment with anti-vascular agents and the use of MRS to study tumor metabolism following treatment with a variety of anti-cancer agents. The advantages and disadvantages of a variety of techniques including contrast- and noncontrast-enhanced methods are discussed and the data from clinical trials using these techniques are reviewed.

Combretastatin A4 phosphate has tumor antivascular activity in rat and man as demonstrated by dynamic magnetic resonance imaging.

Purpose: Combretastatin A4 phosphate (CA4P) is a novel vascular targeting agent. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) studies were performed to examine changes in parameters related to blood flow and vascular permeability in tumor and normal tissue after CA4P treatment.

Materials And Methods: Changes in kinetic DCE-MRI parameters (transfer constant [Ktrans] and area under contrast medium-time curve [AUC]) over 24 hours after treatment with CA4P were measured in 18 patients in a phase I trial and compared with those obtained in the rat P22 carcinosarcoma model, using the same imaging technique.

Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results.

Purpose: A phase I trial was performed with combretastatin A4 phosphate (CA4P), a novel tubulin-binding agent that has been shown to rapidly reduce blood flow in animal tumors.

Patients And Methods: The drug was delivered by a 10-minute weekly infusion for 3 weeks followed by a week gap, with intrapatient dose escalation. Dose escalation was accomplished by doubling until grade 2 toxicity was seen.

ZD6126: a novel vascular-targeting agent that causes selective destruction of tumor vasculature.

Physiological differences between tumor and normal vasculature provide a target for drug discovery. In particular, the immature nature of tumor vasculature may render it intrinsically sensitive to disruption by agents affecting the endothelial cell cytoskeleton, including tubulin-binding agents. In this article, we report the synthesis of a water-soluble phosphate prodrug, ZD6126, of the tubulin-binding agent N-acetylcolchinol.

Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging.

Purpose: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) causes vascular shutdown in preclinical models. Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies were performed in the phase I trials to examine changes related to blood flow and permeability in tumor and muscle.

Patients And Methods: Sixteen patients treated with DMXAA from 500 to 4,900 mg/m(2) had DCE-MRI examinations before and after treatment.

Reproducibility of dynamic contrast-enhanced MRI in human muscle and tumours: comparison of quantitative and semi-quantitative analysis.

The purpose of this study was to determine the reproducibility of dynamic contrast-enhanced (DCE)-MRI and compare quantitative kinetic parameters with semi-quantitative methods, and whole region-of-interest (ROI) with pixel analysis. Twenty-one patients with a range of tumour types underwent paired MRI examinations within a week, of which 16 pairs were evaluable. A proton density-weighted image was obtained prior to a dynamic series of 30 T(1)-weighted spoiled gradient echo images every 11.