Angiostasis-induced vascular normalization can improve photodynamic therapy

In a recent issue, Cellular and Molecular Life Sciences published on the combination of photodynamic therapy (PDT) and anti-angiogenesis for the treatment of cancer [1]. In this paper, Bhuvaneswari and colleagues elegantly review this field. The idea behind combining these two therapeutic strategies is based on the observation that PDT can lead to vessel closure, and hence hypoxia, as well as other tissue damage resulting in inflammation. This combination of hypoxia and inflammation can in turn cause the enhanced release of angiogenic growth factors (vascular endothelial growth factor, VEGF) followed by the regrowth of the targeted neoplastic tissue. Thus, it appeared logical to try to block the VEGF pathways after PDT, for instance by applying antibodies against VEGF. This type of combination therapy is not limited to the treatment of cancer. Indeed, for the treatment of certain forms of exudative macular degeneration, recently published results from a phase II clinical study demonstrate great promise for the combination of PDT (Visudyne) together with anti-VEGF-A therapy using humanized antibody fragments (Lucentis). PDT as a monotherapy has clearly been shown to be effective in treating some early stage superficial cancers. However, for more advanced cancers, where PDT monotherapy appears to be less effective, the usefulness of the photodynamic approach followed by anti-VEGF therapy has not yet been extensively demonstrated in the clinic.ISSN:1420-682XISSN:1420-907

Angiogenesis in gynecological cancers and the options for anti-angiogenesis therapy.

Angiogenesis is required in cancer, including gynecological cancers, for the growth of primary tumors and secondary metastases. Development of anti-angiogenesis therapy in gynecological cancers and improvement of its efficacy have been a major focus of fundamental and clinical research. However, survival benefits of current anti-angiogenic agents, such as bevacizumab, in patients with gynecological cancer, are modest. Therefore, a better understanding of angiogenesis and the tumor microenvironment in gynecological cancers is urgently needed to develop more effective anti-angiogenic therapies, either or not in combination with other therapeutic approaches. We describe the molecular aspects of (tumor) blood vessel formation and the tumor microenvironment and provide an extensive clinical overview of current anti-angiogenic therapies for gynecological cancers. We discuss the different phenotypes of angiogenic endothelial cells as potential therapeutic targets, strategies aimed at intervention in their metabolism, and approaches targeting their (inflammatory) tumor microenvironment

Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer.

Drug combinations can improve angiostatic cancer treatment efficacy and enable the reduction of side effects and drug resistance. Combining drugs is non-trivial due to the high number of possibilities. We applied a feedback system control (FSC) technique with a population-based stochastic search algorithm to navigate through the large parametric space of nine angiostatic drugs at four concentrations to identify optimal low-dose drug combinations. This implied an iterative approach of in vitro testing of endothelial cell viability and algorithm-based analysis. The optimal synergistic drug combination, containing erlotinib, BEZ-235 and RAPTA-C, was reached in a small number of iterations. Final drug combinations showed enhanced endothelial cell specificity and synergistically inhibited proliferation (p < 0.001), but not migration of endothelial cells, and forced enhanced numbers of endothelial cells to undergo apoptosis (p < 0.01). Successful translation of this drug combination was achieved in two preclinical in vivo tumor models. Tumor growth was inhibited synergistically and significantly (p < 0.05 and p < 0.01, respectively) using reduced drug doses as compared to optimal single-drug concentrations. At the applied conditions, single-drug monotherapies had no or negligible activity in these models. We suggest that FSC can be used for rapid identification of effective, reduced dose, multi-drug combinations for the treatment of cancer and other diseases

Transverse Beam Spin Asymmetries in Forward-Angle Elastic Electron-Proton Scattering

We have measured the beam-normal single-spin asymmetry in elastic scattering of transversely-polarized 3 GeV electrons from unpolarized protons at Q^2 = 0.15, 0.25 (GeV/c)^2. The results are inconsistent with calculations solely using the elastic nucleon intermediate state, and generally agree with calculations with significant inelastic hadronic intermediate state contributions. A_n provides a direct probe of the imaginary component of the 2-gamma exchange amplitude, the complete description of which is important in the interpretation of data from precision electron-scattering experiments.Comment: 5 pages, 3 figures, submitted to Physical Review Letters; shortened to meet PRL length limit, clarified some text after referee's comment

Strange Quark Contributions to Parity-Violating Asymmetries in the Forward G0 Electron-Proton Scattering Experiment

We have measured parity-violating asymmetries in elastic electron-proton scattering over the range of momentum transfers 0.12 < Q^2 < 1.0 GeV^2. These asymmetries, arising from interference of the electromagnetic and neutral weak interactions, are sensitive to strange quark contributions to the currents of the proton. The measurements were made at JLab using a toroidal spectrometer to detect the recoiling protons from a liquid hydrogen target. The results indicate non-zero, Q^2 dependent, strange quark contributions and provide new information beyond that obtained in previous experiments.Comment: 5 pages, 2 figure

The G0 Experiment: Apparatus for Parity-Violating Electron Scattering Measurements at Forward and Backward Angles

In the G0 experiment, performed at Jefferson Lab, the parity-violating elastic scattering of electrons from protons and quasi-elastic scattering from deuterons is measured in order to determine the neutral weak currents of the nucleon. Asymmetries as small as 1 part per million in the scattering of a polarized electron beam are determined using a dedicated apparatus. It consists of specialized beam-monitoring and control systems, a cryogenic hydrogen (or deuterium) target, and a superconducting, toroidal magnetic spectrometer equipped with plastic scintillation and aerogel Cerenkov detectors, as well as fast readout electronics for the measurement of individual events. The overall design and performance of this experimental system is discussed.Comment: Submitted to Nuclear Instruments and Method

Strange Quark Contributions to Parity-Violating Asymmetries in the Forward G0 Electron-Proton Scattering Experiment

We have measured parity-violating asymmetries in elastic electron-proton scattering over the range of momentum transfers 0.12 ≤ Q2 ≤ 1.0 GeV2. These asymmetries, arising from interference of the electromagnetic and neutral weak interactions, are sensitive to strange quark contributions to the currents of the proton. The measurements were made at JLab using a toroidal spectrom- eter to detect the recoiling protons from a liquid hydrogen target. The results indicate non-zero, Q2 dependent, strange quark contributions and provide new information beyond that obtained in previous experiments