Biomedical subjects

Nicolas Solban

Publications and source records attributed to Nicolas Solban.

7 recordsLinked to original sources

PubMed2006

A mechanism-based combination therapy reduces local tumor growth and metastasis in an orthotopic model of prostate cancer.

Therapy-induced stimulation of angiogenic molecules can promote tumor angiogenesis leading to enhanced tumor growth and cancer metastasis. Several standard and emerging therapies, such as radiation and photodynamic therapy (PDT), can induce angiogenic molecules, thus limiting their effectiveness. PDT is approved for the treatment of several cancers; however, its induction of vascular endothelial growth factor (VEGF) creates conditions favorable to enhanced tumor growth and metastasis, therefore mitigating its cytotoxic and antivascular effects. This is the first report showing that subcurative PDT in an orthotopic model of prostate cancer (LNCaP) increases not only VEGF secretion (2.1-fold) but also the fraction of animals with lymph node metastases. PDT followed by administration of an antiangiogenic agent, TNP-470, abolished this increase and reduced local tumor growth. On the other hand, administration of TNP-470 before PDT was less effective at local tumor control. In addition, animals in all groups, except in the PDT + TNP-470 group, had a weight loss of >3 g at the time of sacrifice; the weight of the animals in the PDT + TNP-470 group did not change. The significant reduction (P < 0.05) in tumor weight and volume observed between the PDT + TNP-470 group and the control group suggests that the combination of PDT and antiangiogenic treatment administered in the appropriate sequence was not only more effective at controlling local tumor growth and metastases but also reduced disease-related toxicities. Such molecular response-based combinations merit further investigations as they enhance both monotherapies and lead to improved treatment outcomes.

Angiogenesis Inhibitors↗

PubMed2006

Mechanistic investigation and implications of photodynamic therapy induction of vascular endothelial growth factor in prostate cancer.

Photodynamic therapy (PDT) is now an approved therapeutic modality, and induction of vascular endothelial growth factor (VEGF) following subcurative PDT is of concern as VEGF may provide a survival stimulus to tumors. The processes that limit the efficacy of PDT warrant investigation so that mechanism-based interventions may be developed. This study investigates VEGF increase following subcurative PDT using the photosensitizer benzoporphyrin derivative (BPD) both in an in vitro and in an orthotopic model of prostate cancer using the human prostate cancer cell line LNCaP. The two subcurative doses used, 0.25 and 0.5 J/cm(2), mimicked subcurative PDT and elicited a 1.6- and 2.1-fold increase, respectively, in secreted VEGF 24 hours following PDT. Intracellular VEGF protein measurement and VEGF mRNA showed a 1.4- and 1.6-fold increase only at 0.5 J/cm(2). In vivo subcurative PDT showed an increase in VEGF by both immunohistochemistry and ELISA. In vitro analysis showed no activation of hypoxia-inducible factor-1alpha (HIF-1alpha) or cyclooxygenase-2 (COX-2) following subcurative PDT; furthermore, small interfering RNA inhibition of HIF-1alpha and COX-2 inhibitor treatment had no effect on PDT induction of VEGF. PDT in the presence of phosphatidylinositol 3-kinase/AKT inhibitor or mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase inhibitor still induced VEGF. However, subcurative PDT increased phosphorylated p38 and stress-activated protein kinase/c-Jun NH(2)-terminal kinase. The p38 MAPK inhibitor abolished PDT induction of VEGF. The results establish the importance of VEGF in subcurative BPD-PDT of prostate cancer and suggest possible molecular pathways for its induction. These findings should provide the basis for the development of molecular-based interventions for enhancing PDT and merit further studies.

Animals↗

PubMed2006

Targeted photodynamic therapy.

BACKGROUND AND OBJECTIVES: Photodynamic therapy (PDT) is an emerging modality for the treatment of various neoplastic and non-neoplastic pathologies. STUDY DESIGN/MATERIALS AND METHODS: PDT usually occurs when reactive oxygen species (ROS) generated from light-activated chemicals (photosensitizer, PS) destroy the target. For non-dermatologic applications the PS are delivered systemically and accumulate, at different concentrations, in most organs. RESULTS AND CONCLUSION: Typically there is a modest enhanced accumulation of the PS in tumor tissues, providing a first level of selectivity. Additional selectivity is provided by the confined illumination of the target area with the appropriate wavelength of light. For the treatment of pathologies in complex anatomical sites, such as in the peritoneal cavity, where restricted illumination is difficult; improved targeting of the PS is necessary to prevent damage to the surrounding healthy tissue. This article will focus on targeted PDT.

Animals↗

PubMed2005

HCaRG increases renal cell migration by a TGF-alpha autocrine loop mechanism.

We have shown previously that the hypertension-related, calcium-regulated gene (HCaRG) is involved in the control of renal cell proliferation and differentiation (Devlin AM, Solban N, Tremblay S, Gutkowska J, Schurch W, Orlov SN, Lewanczuk R, Hamet P, and Tremblay J. Am J Physiol Renal Physiol 284: F753-F762, 2003). To determine whether HCaRG plays a role in kidney repair after injury, we extended our studies on the cellular function of HCaRG by comparing cell migration of two kidney cell lines [HEK293 and Madin-Darby canine kidney (MDCK)-C7] stably transfected with the plasmid alone or with a plasmid containing HCaRG cDNA. HCaRG-expressing HEK293 cells, which undergo lower proliferation, migrated faster than control cells and presented greater adhesiveness to the extracellular matrix. Faster migration was also observed for the MDCK-C7 cells, after they were stably transfected with HCaRG cDNA. HCaRG overexpression induced major morphological changes in HEK293 cells, including the formation of lamellipodia. Expression microarrays of HCaRG-expressing HEK293 cells revealed the elevated expression of several genes known to be involved in cell migration and lamellipodia formation, including transforming growth factor-alpha (TGF-alpha), galectins, autotaxins and fibronectin. These cells exhibited augmented synthesis and release of activated TGF-alpha. Conditioned medium from HCaRG-expressing cells stimulated the migration and induced significant morphological changes in control cells, in part, through activation of the TFG-alpha/EGF receptor. Together, these data support a role for HCaRG in kidney repair after injury through its effect on renal cell migration and TGF-alpha secretion.

Animals↗

PubMed2005

Effect of tumor host microenvironment on photodynamic therapy in a rat prostate tumor model.

PURPOSE: Tumor host microenvironment plays an important role in tumor growth, metastasis, and response to cancer therapy. In this study, the influence of tumor host environment on tumor pathophysiology, photosensitizer distribution, and photodynamic therapy (PDT) treatment effect was examined in the metastatic at lymph node and lung (MatLyLu) rat prostate tumor. EXPERIMENTAL DESIGN: MatLyLu tumors implanted in different host environment [i.e., orthotopically (in the prostate) or s.c.] were compared for difference in vessel density, average vessel size, vascular permeability, tumor vascular endothelial growth factor production, and tumor oxygenation. Uptake of photosensitizer verteporfin in tumors in both sites was determined by fluorescence microscopy. To compare tumor response to PDT, both orthotopic and s.c. MatLyLu tumors were given the same doses of verteporfin and laser light treatment, and PDT-induced tumor necrotic area was measured histologically. RESULTS: Orthotopic MatLyLu tumors were found to grow faster, have higher vessel density and more permeable vasculature, have higher vascular endothelial growth factor protein levels, and have lower tumor hypoxic fraction than the s.c. tumors. Uptake of photosensitizer verteporfin in the orthotopic tumor was higher than in the s.c. tumors at 15 minutes after injection (1 mg/kg, i.v.), and became similar at 3 hours after injection. For the vascular targeting PDT treatment (0.25 mg/kg verteporfin, 50 J/cm(2) at 50 mW/cm(2), 15 minutes drug-light interval), there was no significant difference in PDT-induced tumor necrotic area between the orthotopic and s.c. tumors, with 85% to 90% necrosis in both types of tumors. However, tumor necrosis induced by the cellular targeting PDT (1 mg/kg verteporfin, 50 J/cm(2) at 50 mW/cm(2), 3 hours drug-light interval) was significantly different in the orthotopic (64%) versus the s.c. (29%) tumors. CONCLUSIONS: Tumor host environment can significantly affect photosensitizer verteporfin distribution and PDT treatment effect. Verteporfin-PDT regimen targeting tumor cells is more sensitive to such influence than the vascular targeting PDT. Our study showed the importance of tumor host environment in determining tumor physiologic properties and tumor response to PDT. To obtain clinically relevant information, orthotopic tumor model should be used in the experimental studies.

Animals↗

PubMed2004

In vivo flow cytometry: a new method for enumerating circulating cancer cells.

The fate of circulating tumor cells is an important determinant of their ability to form distant metastasis. Here, we demonstrate the use of in vivo flow cytometry as a powerful new method for detecting quantitatively circulating cancer cells. We specifically examine the circulation kinetics of two prostate cancer cell lines with different metastatic potential in mice and rats. We find that the cell line and the host environment affect the circulation kinetics of prostate cancer cells, with the intrinsic cell line properties determining the initial rate of cell depletion from the circulation and the host affecting cell circulation at later time points.

Animals↗

PubMed2002

HCaRG is a novel regulator of renal epithelial cell growth and differentiation causing G2M arrest.

We recently identified a novel calcium-regulated gene, HCaRG, that is highly expressed in the kidney and maps to a chromosomal locus determining kidney weight in rats. The mRNA levels of HCaRG negatively correlate with the proliferative status of the kidney cells. To investigate its role in renal epithelial cellular growth directly, we studied the human embryonic kidney cell line (HEK-293) stably transfected with either plasmid alone or plasmid containing rat HCaRG. [(3)H]thymidine incorporation was significantly lower in HCaRG clones. Although HCaRG clones exhibited some enhanced susceptibility to cell death, this was not the primary mechanism of reduced proliferation. Cell cycle analysis revealed a G(2)M phase accumulation in HCaRG clones that was associated with upregulation of p21(Cip1/WAF1) and downregulation of p27(Kip1). HCaRG clones had a greater protein content, larger cell size, and released 4.5- to 8-fold more of an atrial natriuretic peptide-like immunoreactivity compared with controls. In addition, HCaRG clones demonstrated the presence of differentiated junctions and a lower incidence of mitotic figures. Genistein treatment of wild-type HEK-293 cells mimicked several phenotypic characteristics associated with HCaRG overexpresssion, including increased cell size and increased release of atrial natriuretic peptide. Taken together, our results suggest that HCaRG is a regulator of renal epithelial cell growth and differentiation causing G(2)M cell cycle arrest.

Adaptor Proteins, Signal Transducing↗