Biomedical subjects

H M W Verheul

Publications and source records attributed to H M W Verheul.

4 recordsLinked to original sources

PubMed2006

Angiogenesis inhibitors: perspectives for medical, surgical and radiation oncology.

In the past decade, many angiogenesis inhibitors have been developed for clinical use in oncology. Surgeons, radiotherapists as well as medical oncologists have been investigating with much effort and enthusiasm the translation of these agents from the preclinical setting into treatment strategies of patients. Recently, for the first time in history, the angiogenesis inhibitor bevacizumab (avastin), a humanized anti-vascular endothelial growth factor (VEGF) antibody, showed a survival benefit of 4.7 months in a phase III clinical trial in patients with advanced colorectal cancer when this agent was given in combination with chemotherapy. At the annual meeting of the American Association of Clinical Oncology 2005, similar results of bevacizumab in lung, breast and ovarian cancer clinical trials have been shown. These landmark studies proofed for the first time in the clinical setting that Dr. Folkman back in 1971 was right by proposing: "in order to stop tumor growth, one should attack its blood supply". Nowadays it seems trivial to propose such a hypothesis, at that time it was a very provocative hypothesis and it took more than 30 years to proof this hypothesis in the clinic. Although one may be excited about this major finding, there is no time to relax. The survival benefit of bevacizumab is only about 4 months. Therefore more potent antiangiogenic agents and more active treatment strategies are urgently warranted. Newer angiogenesis inhibitors that are currently in preclinical or early clinical development have shown in preclinical experiments improved antitumor activities. In addition, combinations of biological agents that interfere in multiple biological pathways in cancer growth including chemotherapy, are of major clinical interest as well. The multimodality approach in which surgeons, radiotherapists and medical oncologists collaborate needs to be explored as well. In a variety of cancer types, like breast colon and lung cancer, these specialists should design multimodality strategies based on current standard treatment in which they incorporate angiogenesis inhibitors in the right time frame of surgery and radiotherapy. In this review we will bring you up to date on the clinical development of angiogenesis inhibitors and we will summarize the multimodality strategies that are under development.

Angiogenesis Inhibitors↗

PubMed2004

Are tumours angiogenesis-dependent?

The final proof of principle that cancer patients can be effectively treated with angiogenesis inhibitors is eagerly awaited. Various preclinical in vivo experiments have proven that most tumours need new vessel formation in order to grow and to form metastases. First of all, tumours do not grow in avascular corneas until new blood vessels reach the implant. Secondly, the introduction of only one angiogenic gene can cause a switch from tumour dormancy to progressive tumour growth. Thirdly, tumour growth can be inhibited and sometimes tumour regression can be obtained just by attacking the vascular compartment with specific angiogenesis inhibitors. These three examples of preclinical experiments and many others have led to the conclusion that, in general, tumours are angiogenesis-dependent. Supported by disappointing clinical results, the angiogenesis dependency of tumours has been questioned, mainly because of the immaturity and the presumed lack of a functional blood supply (oxygen delivery and discarding of waste products) from a newly formed tumour vasculature. However, human tumours are highly heterogeneous in vascular architecture, differentiation, and functional blood supply. Vascular immaturity is a natural consequence of a genetically based unlimited expansion of tumour cells, compared to the well-regulated growth of different organs during embryonic development, for example. Unlimited tumour expansion and therefore the continuous stimulation of vessel outgrowth prevent endothelial cells from generating a mature vasculature, but instead continuously stimulate them to expand the vascular compartment of the growing tumour. In this review, the translation of angiogenesis inhibitors as a treatment for cancer from preclinical experiments to the clinic is evaluated. The preclinical evidence that tumours are angiogenesis-dependent is summarized and explanations are put forward for why the clinical results so far are not as exciting as was expected from preclinical studies. Reviewing the translation, one may conclude that human tumours are heterogeneous in their vascular architecture and function and that tumour-induced angiogenesis in humans is a more complex (multifactorially regulated) process compared with angiogenesis in preclinical cancer models.

Angiogenesis Inducing Agents↗

PubMed2003

The new cardioprotector Monohydroxyethylrutoside protects against doxorubicin-induced inflammatory effects in vitro.

Besides its cardiotoxic effect, doxorubicin also elicits inflammatory effects in vivo. 7-Monohydroxyethylrutoside (monoHER) has recently been used as a protector against doxorubicin-induced cardiotoxicity in vivo. It is not known yet whether monoHER can also protect against doxorubicin-induced inflammatory effects. The aim of the present study was (1) to illustrate the inflammatory effects of doxorubicin in vitro and (2) to evaluate a possibly protective effect of monoHER. In order to demonstrate the inflammatory effects of doxorubicin and the possible protection of monoHER, proliferating human umbilical cord vascular endothelial cells (HUVECs) were incubated with different concentrations of doxorubicin ranging from 12.5 to 600 nM with(out) 200 micro M monoHER. Resting (confluent) HUVECs were incubated with (0.5-25 micro M) doxorubicin with(out) monoHER (0.2-1.2 mM) and the viability of endothelial cells and their propensity to adhere to neutrophils were measured 24 h after treatment. The localisation of adhered neutrophils was determined with immunofluorescence microscopy. To further characterise the mechanism of doxorubicin-induced neutrophil adhesion, the expression of the HUVECs surface adhesion molecules was determined after doxorubicin treatment. Doxorubicin decreased the viability and proliferation capacity of HUVECs in a concentration-dependent manner. The proliferating HUVECs were much more sensitive to doxorubicin (IC(50)=60.0+/-20.8 nM) than resting cells (LC(50)=4.0+/-0.3 micro M). Doxorubicin also increased the adhesion of neutrophils reaching a plateau value at a doxorubicin concentration of > or =0.4 micro M (P=0.0113). The induced neutrophil adhesion was accompanied by overexpression of VCAM and E-selectin but not ICAM. Although monoHER did not reverse the effect of doxorubicin on the proliferation of endothelial cells, it significantly protected resting HUVECs against the cytotoxic effect of doxorubicin (< or =25 micro M, P<0.0015). In addition, monoHER completely protected against the stimulatory effect of doxorubicin on neutrophil adhesion, and inhibited the doxorubin-induced expression of VCAM and E-selectin on the surface of treated HUVECs. This study illustrates that monoHER, which protects against doxorubicin's cardiotoxic effect, can also protect against doxorubicin-induced inflammatory effects. These data prompt further investigation about the possible link between doxorubicin-induced inflammatory effects and its cardiotoxicity in vivo.

Antineoplastic Agents↗

PubMed2003

Vascular endothelial growth factor and its inhibitors.

Originally identified for its ability to induce vascular permeability and stimulate endothelial cell growth, vascular endothelial growth factor (VEGF) is now recognized as a key factor required for growth of tumors and is involved in many other diseases, such as diabetes, arthritis, atherosclerosis and ischemic heart disease. In addition, recent studies show that VEGF is involved in stem cell recruitment and mobilization. A new role of VEGF has been postulated in enhancing the production and release into the circulation of endothelial progenitor cells derived from the bone marrow. These circulating endothelial cells may be targeted to angiogenic sites where they are being incorporated in new vessels. We provide an overview of the biological role of VEGF and summarize the different approaches that are under development to inhibit VEGF activity in the clinic, particularly antiangiogenic cancer treatment. Thus far, more than five inhibitors of the VEGF pathway have entered clinical phase I-III trials. Of these, bevacizumab, an antibody against VEGF, was shown to prolong survival in a phase III trial in renal cell cancer. Although very preliminary, a phase I trial found tumor regressions that were caused by an oral VEGF receptor tyrosine kinase inhibitor, SU11248. Taken together, these data seem very promising for the development of long-term nontoxic treatments against cancer.

Angiogenesis Inhibitors↗