Chemotherapeutics are the most effective treatment for metastatic tumours. However, the ability of cancer cells to become simultaneously resistant to different drugs--a trait known as multidrug resistance--remains a significant impediment to successful chemotherapy. Three decades of multidrug-resistance research have identified a myriad of ways in which cancer cells can elude chemotherapy, and it has become apparent that resistance exists against every effective drug, even our newest agents. Therefore, the ability to predict and circumvent drug resistance is likely to improve chemotherapy.

/pdf/multidrug-resistance-in-cancer-role-of-atp-dependent-1hpqky19xf.pdf

Multidrug resistance in cancer: role of ATP–dependent transporters

Solid tumors require blood vessels for growth, and many new cancer therapies are directed against the tumor vasculature. The widely held view is that these antiangiogenic therapies should destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. Here, I review emerging evidence supporting an alternative hypothesis-that certain antiangiogenic agents can also transiently "normalize" the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery. Drugs that induce vascular normalization can alleviate hypoxia and increase the efficacy of conventional therapies if both are carefully scheduled. A better understanding of the molecular and cellular underpinnings of vascular normalization may ultimately lead to more effective therapies not only for cancer but also for diseases with abnormal vasculature, as well as regenerative medicine, in which the goal is to create and maintain a functionally normal vasculature.

http://science.sciencemag.org/content/sci/307/5706/58.full.pdf

Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. Hypoxia has been shown to be a major inducer of VEGF gene transcription. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are high-affinity VEGF receptors. The role of VEGF in developmental angiogenesis is emphasized by the finding that loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF is critical also for reproductive and bone angiogenesis. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. In situ hybridization studies demonstrate expression of VEGF mRNA in the majority of human tumors. Anti-VEGF monoclonal antibodies and other VEGF inhibitors block the growth of several tumor cell lines in nude mice. Clinical trials with various VEGF inhibitors in a variety of malignancies are ongoing. Very recently, an anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the Food and Drug Administration as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.

/pdf/vascular-endothelial-growth-factor-basic-science-and-17gyy6h97s.pdf

Vascular endothelial growth factor: basic science and clinical progress.

The growth of blood vessels (a process known as angiogenesis) is essential for organ growth and repair. An imbalance in this process contributes to numerous malignant, inflammatory, ischaemic, infectious and immune disorders. Recently, the first anti-angiogenic agents have been approved for the treatment of cancer and blindness. Angiogenesis research will probably change the face of medicine in the next decades, with more than 500 million people worldwide predicted to benefit from pro- or anti-angiogenesis treatments.

Angiogenesis in life, disease and medicine

Vascular endothelial growth-factor receptors (VEGFRs) regulate the cardiovascular system. VEGFR1 is required for the recruitment of haematopoietic precursors and migration of monocytes and macrophages, whereas VEGFR2 and VEGFR3 are essential for the functions of vascular endothelial and lymphendothelial cells, respectively. Recent insights have shed light onto VEGFR signal transduction and the interplay between different VEGFRs and VEGF co-receptors in development, adult physiology and disease.

VEGF receptor signalling - in control of vascular function.

Nitric oxide (NO) plays a critical role in vascular endothelial growth factor (VEGF)-induced angiogenesis and vascular hyperpermeability. However, the relative contribution of different NO synthase (NOS) isoforms to these processes is not known. Here, we evaluated the relative contributions of endothelial and inducible NOS (eNOS and iNOS, respectively) to angiogenesis and permeability of VEGF-induced angiogenic vessels. The contribution of eNOS was assessed by using an eNOS-deficient mouse, and iNOS contribution was assessed by using a selective inhibitor [l-N(6)-(1-iminoethyl) lysine, l-NIL] and an iNOS-deficient mouse. Angiogenesis was induced by VEGF in type I collagen gels placed in the mouse cranial window. Angiogenesis, vessel diameter, blood flow rate, and vascular permeability were proportional to NO levels measured with microelectrodes: Wild-type (WT) > or = WT with l-NIL or iNOS(-/-) > eNOS(-/-) > or = eNOS(-/-) with l-NIL. The role of NOS in VEGF-induced acute vascular permeability increase in quiescent vessels also was determined by using eNOS- and iNOS-deficient mice. VEGF superfusion significantly increased permeability in both WT and iNOS(-/-) mice but not in eNOS(-/-) mice. These findings suggest that eNOS plays a predominant role in VEGF-induced angiogenesis and vascular permeability. Thus, selective modulation of eNOS activity is a promising strategy for altering angiogenesis and vascular permeability in vivo.

https://www.pnas.org/content/pnas/98/5/2604.full.pdf

Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability

The large size of many novel therapeutics impairs their transport through the tumor extracellular matrix and thus limits their therapeutic effectiveness. We propose that extracellular matrix composition, structure, and distribution determine the transport properties in tumors. Furthermore, because the characteristics of the extracellular matrix largely depend on the tumor–host interactions, we postulate that diffusion of macromolecules will vary with tumor type as well as anatomical location. Diffusion coefficients of macromolecules and liposomes in tumors growing in cranial windows (CWs) and dorsal chambers (DCs) were measured by fluorescence recovery after photobleaching. For the same tumor types, diffusion of large molecules was significantly faster in CW than in DC tumors. The greater diffusional hindrance in DC tumors was correlated with higher levels of collagen type I and its organization into fibrils. For molecules with diameters comparable to the interfibrillar space the diffusion was 5- to 10-fold slower in DC than in CW tumors. The slower diffusion in DC tumors was associated with a higher density of host stromal cells that synthesize and organize collagen type I. Our results point to the necessity of developing site-specific drug carriers to improve the delivery of molecular medicine to solid tumors.

https://www.pnas.org/content/pnas/98/8/4628.full.pdf

Role of tumor-host interactions in interstitial diffusion of macromolecules: cranial vs. subcutaneous tumors.

Malignant tumours secrete factors that enable them to commandeer their own blood supply (angiogenesis), and blocking the action of these factors can inhibit tumour growth. But because tumours may become resistant to treatments that target individual angiogenic factors by switching over to other angiogenic molecules, a cocktail of multiple anti-angiogenic agents should be more effective. Here we show that herceptin, a monoclonal antibody against the cell-surface receptor HER2 (for human epidermal growth factor receptor-2; ref. 4), induces normalization and regression of the vasculature in an experimental human breast tumour that overexpresses HER2 in mice, and that it works by modulating the effects of different pro- and anti-angiogenic factors. As a single agent that acts against multiple targets, herceptin, or drugs like it, may offer a simple alternative to combination anti-angiogenic treatments.

Tumour biology: herceptin acts as an anti-angiogenic cocktail.

Preclinical studies typically use human tumor xenografts or murine tumor isografts.Tumor growth may be accelerated by in vivo passage, thus making these tumors more sensitive to some therapies than the original tumors. In the present study, by comparing the effects of DC101, an antimurine vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody, on spontaneous autochthonous tumors and their early generation transplants, we show that this growth acceleration is diminished by DC101 treatment. Spontaneous autochthonous tumors in aged C3H mice consisted of s.c. sarcomas and adenocarcinomas, and their growth rate was accelerated by in vivo passages. Anti-VEGFR2 treatment decreased vessel density, increased apoptosis, and reduced tumor growth in large (500 mm3) spontaneous autochthonous tumors. Anti-VEGFR2 treatment significantly delayed tumor growth and extended animal survival. Tumor growth acceleration by in vivo passage was diminished by DC101 treatment. To our knowledge, this is the first evaluation of antiangiogenic therapy in a spontaneous autochthonous tumor model, which may more closely resemble human tumors. Additionally, this is the first study to compare treatment response between the parental tumor and its isografts. Although passaged tumors behave differently, it is encouraging that the tumor growth rates under DC101 treatment are comparable among different passage generations.

https://cancerres.aacrjournals.org/content/canres/63/4/747.full.pdf

Responses to antiangiogenesis treatment of spontaneous autochthonous tumors and their isografts.

The invention provides improved compositions (e.g., combinations of signal transduction inhibitors) and methods for the prevention, stabilization, or treatment of cancer or other angiogenesis related diseases. In particular, the present methods use combination therapies to modulate the expression or activity of multiple mRNA molecules or proteins associated with angiogenesis or cancer in a mammal (e.g., a human)

Yotaro Izumi

Papers

Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability

Role of tumor-host interactions in interstitial diffusion of macromolecules: cranial vs. subcutaneous tumors.

Tumour biology: herceptin acts as an anti-angiogenic cocktail.

Responses to antiangiogenesis treatment of spontaneous autochthonous tumors and their isografts.

Use of signal transduction inhibitors and combination therapies for the prevention or treatment of cancer and angiogenesis related diseases