PubMed Health⌕ Search

Biomedical subjects

J Drevs

Publications and source records attributed to J Drevs.

15 recordsLinked to original sources
PubMed2006

The use of vascular biomarkers and imaging studies in the early clinical development of anti-tumour agents targeting angiogenesis.

Recent findings about the pathomechanisms of tumour angiogenesis have led to new therapeutic options in the treatment of malignant tumours. During the development of anti-angiogenic drugs, reporting ranged from healing cancer to completely ineffective drugs. In 2003 the first anti-angiogenic drug was approved. Several anti-angiogenic drugs are still in the clinical phase of development. In contrast to identifying the maximal tolerable dose, determination of the optimal biological dose--reaching biological activity at lower doses--has become the main target in the early development of anti-angiogenic agents. This has been evaluated by different biomarker techniques. As a new standard in anti-tumour treatment, a better understanding of imaging in the treatment monitoring for anti-angiogenic agents is important. Studies of tumour angiogenesis by tissue sampling rely on invasive procedures, adequate sampling and painstaking estimation of histological microvessel density. Attempts to develop wound healing assays to correlate angiogenesis in wounds with angiogenesis in tumour have been made but are still considered invasive and correlation of healthy with malignant tissue is still of limited validity. Several soluble markers of tumour angiogenesis were detected in various malignant diseases and were evaluated for assessing their use as surrogate markers in tumour angiogenesis. Further, soluble markers were investigated for visualizing them as imaging tools. Combining both, new soluble markers and imaging techniques, developing anticancer drugs and monitoring of therapy success becomes a dynamic process in which finally the patients' individual response can be achieved soon. Time-consuming delays for anatomically based restaging procedures can be avoided. Characterization of soluble biomarkers as well as different imaging techniques such as ultrasound, computed tomography (CT), magnetic resonance imaging and positron emission tomography combined with or without CT are reviewed in this manuscript.

Angiogenesis Inhibitors↗
PubMed2005

The VEGF receptor tyrosine kinase inhibitor, ZD6474, inhibits angiogenesis and affects microvascular architecture within an orthotopically implanted renal cell carcinoma.

The proangiogenic vascular endothelial growth factor-A (VEGF) is essential for the development of new tumor vessels. ZD6474 is a novel inhibitor of VEGF receptor-2 (VEGFR-2) tyrosine kinase activity, which also has additional activity against epidermal growth factor (EGF) receptor tyrosine kinase. The antitumor activity of different schedules of ZD6474 in a clinically relevant, metastasizing, murine renal cell carcinoma (RENCA) model was evaluated in this study. RENCA cells were inoculated into the left kidney of 24 mice (day 0). Daily ZD6474 (50 mg/kg p.o.) treatment was initiated 1 day or 10 days after tumor cell inoculation and continued until day 21. Following treatment, kidney weight and volume were assessed and blood vessel density determined by CD31 staining. Visible metastases in the lungs, spleen, and lymph nodes were quantified using a dissection microscope. In an additional study, animals were treated according to the same regimen and quantitative three-dimensional microvascular corrosion casting was performed to enable detailed assessment of the tumor vascular architecture. Therapy initiated on day 1 or day 10 resulted in a 79% and 59% reduction in primary tumor volume, a 79% and 60% reduction in the number of lung metastases, and a 58% and 59% reduction in vessel density of primary tumors compared with the control group, respectively. Corrosion casting proved a 5.4- and 3.2-fold lower vascular volume compared with untreated tumors, observations that paralleled with significant architectural alterations. In this RENCA model, ZD6474 was a highly active inhibitor of tumor angiogenesis, primary tumor growth and tumor metastasis.

Animals↗
PubMed2005

Soluble markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two phase I trials.

BACKGROUND: Plasma and serum biomarkers of angiogenesis and activated endothelial cells were evaluated to assess biological activity of PTK787/ZK 222584 (PTK/ZK), a novel oral angiogenesis inhibitor targeting all known vascular endothelial growth factor (VEGF) receptor tyrosine kinases. PATIENTS AND METHODS: Patients with colorectal cancer (CRC) (n=63) were enrolled into two phase I/II dose escalation trials of PTK/ZK in 28-day cycles until discontinuation. Patients with stable disease for > or =2 months were categorized as 'non-progressors'. Plasma markers of angiogenesis, VEGF-A and basic fibroblast growth factor (bFGF), and the serum markers of activated endothelial cells, sTIE-2 and sE-Selectin, were assessed at baseline, and pre-dose on days 1, 8, 15, 22 and 28 of every cycle, with additional assessments 10 h post-dose on days 1 and 15. The percentage change from baseline was subsequently correlated with AUC and C(max) of PTK/ZK on day 1, cycle 1 and clinical outcome. RESULTS: A dose-dependent increase in plasma VEGF-A and bFGF was observed in the first cycle of PTK/ZK treatment. The correlation of change in plasma VEGF-A with AUC and C(max) was characterized by an E(max) model, suggesting that a change of > or =150% from baseline VEGF-A correlated with non-progressive disease. Change from baseline plasma VEGF-A within the first cycle of treatment was significantly correlated with clinical outcome by logistic regression analysis (P=0.027). CONCLUSIONS: In patients with CRC treated with PTK/ZK, changes in plasma VEGF-A and bFGF demonstrate biological activity of PTK/ZK, may help to establish optimal dose and correlate with outcome.

Aged↗
PubMed2003

Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of Cilengitide (EMD 121974), a novel inhibitor of the integrins alphavbeta3 and alphavbeta5 in patients with advanced solid tumours.

A single-agent dose escalating phase I and pharmacokinetic study with Cilengitide, an inhibitor of the integrins alphavbeta3 and alphavbeta5, was performed to determine its safety and toxicity. Cilengitide was administered as a one-hour infusion twice weekly without interruption to patients with histologically- or cytologically-confirmed metastatic solid tumours. Plasma pharmacokinetics were determined at days 1 and 15. 37 patients were enrolled into the study. Dose levels studied were 30, 60, 120, 180, 240, 400, 600, 850, 1200, and 1600 mg/m(2)/infusion. There was no dose-limiting toxicity (DLT). Pharmacokinetics were dose-independent and time-invariant. Apparent terminal half-life ranged from 3 to 5 h. At 120 mg/m(2)/infusion, peak plasma concentrations were attained that optimally inhibited tumour growth in preclinical models. Cilengitide can be safely administered using a continuous twice-weekly infusion regimen. As DLT was not reached, future trials should explore Cilengitide at different doses.

Adult↗
PubMed2003

Angiogenesis and the ET-1/ETA receptor system: immunohistochemical expression analysis in bone metastases from patients with different primary tumors.

Angiogenesis is necessary for the growth of primary tumors and the formation of metastases. It is well known that vascular endothelial growth factor (VEGF) and its receptors play a major role in this process. To date, the formation of bone metastases has been poorly understood. Tumor cells must interact with the microenvironment of the bone and new blood vessels must spread. The ET/ET(A) (endothelin) receptor system seems to play an important role in this process. Specimens from metastatic bone lesions and non-malignant bone tissue were analyzed by histological and immunohistochemical staining. Sections were stained with antibodies against CD31, Flt-1, KDR, endothelin-1 (ET-1) and endothelin receptor A (ET(A)). Our studies show that there is an increased microvessel density (MVD) in metastatic bone lesions from different primary tumors in contrast to normal bone tissue. In nearly all tumor formations of the bone, ET-1 and its receptor ET(A) was found by immunohistochemistry. We also performed immunohistochemical staining for the VEGF-receptors Flt-1 and KDR. In conclusion, there is an increased vessel density in metastatic bone lesions in contrast to normal bone tissue. The ET/ET(A) system can be detected in nearly all bone specimens and is upregulated in metastatic bone lesions in contrast to healthy bone tissue.

Bone Neoplasms↗
PubMed2002

Antiangiogenesis: current clinical data and future perspectives.

Neovascularization is a prerequisite for progressive growth of solid tumors and their metastases. This process is tightly regulated by a large number of proangiogenic and antiangiogenic factors such as VEGF, bFGF and matrix-metalloproteinases. The inhibition of angiogenesis is an innovative therapeutic approach and could represent a powerful adjunct to traditional therapy of malignant tumors. Preclinical trials have been very successful but in clinical studies meaningful response rates could only be shown in some cases. This might indicate the existence of different angiogenic phenotypes in humans. It seems that at present only a part of the interactions between the angiogenic cytokines are known. In addition, new receptor/ligand systems which regulate the neovascularization are being described. This article presents an overview of the most important angiogenically active substances, preclinical and clinical data, surrogate markers as well as future perspectives.

Angiogenesis Inhibitors↗
PubMed2001

Development and in vitro efficacy of novel MMP2 and MMP9 specific doxorubicin albumin conjugates.

Two doxorubicin albumin conjugates (A-DP1 and A-DP2), which differ in their substrate specificity for the matrix metalloproteinases MMP2 and MMP9, were prepared by binding maleimide doxorubicin peptide derivatives to the cysteine-34 position of human serum albumin. The incorporated octapeptide, Gly-Pro-Gln-Arg-Ile-Ala-Gly-Gln, in A-DP2 is not cleaved by activated MMP2 and MMP9 in contrast to Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln incorporated in A-DP1 that is cleaved efficiently by activated MMP2 and MMP9 liberating a doxorubicin tetrapeptide. A-DP1 showed antiproliferative activity in a murine renal cell carcinoma line in the low micromolar range (IC(50) value approximately 0.2 microM).

Albumins↗
PubMed2000

Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model.

Antiangiogenic therapy is a promising new strategy to inhibit tumor growth and formation of metastases. Vascular endothelial growth factor (VEGF) and its receptors, VEGF-receptor 1 (VEGF-R1; FLT-1) and VEGF-R2 (KDR), have been shown to play a major role in tumor angiogenesis. PTK787/ZK 222584, a specific inhibitor of both VEGF-receptor tyrosine kinases, was investigated for its antitumoral and antiangiogenic activity in a murine renal cell carcinoma model. After intrarenal application of the renal carcinoma cells, mice develop a primary tumor and metastases to the lung and to the abdominal lymph nodes. Daily oral therapy with PTK787/ZK 222584 at a dose of 50 mg/kg resulted in a significant decrease of 61 and 67% in primary tumors after 14 and 21 days, respectively. The occurrence of lung metastases was significantly inhibited at both time points (98% reduction and 78% reduction, respectively). After 14 days, no lymph node metastases developed in the PTK787/ZK 222584-treated group, whereas after 21 days of treatment, the lymph node metastases were reduced by 87%. Vessel density in tumor tissues, detected by immunohistochemistry with an anti-CD31 antibody, was significantly decreased by PTK787/ZK 222584. Using color Doppler imaging ultrasound, significant changes in blood flow in the tumor feeding renal artery were found under treatment with PTK787/ZK 222584. Blood flow changes correlated with changes in vessel density but not with tumor volume. The compound was well tolerated in all in vivo experiments and had no significant effects on body weight or general well-being of the animals. This was in contrast to the animals treated with the antiangiogenic agent TNP-470. s.c. therapy with 30 mg/kg TNP-470 every other day had to be discontinued after 13 days because of animal weight loss (>20%) and ataxia. These results demonstrate that PTK787/ZK 222584 is a potent inhibitor of tumor growth, metastases formation, and tumor vascularization in murine renal cell carcinoma. Furthermore, we have been able to demonstrate that color Doppler imaging ultrasound can be used to measure blood flow to a tumor and that flow correlates with vessel density. Thus, this may be a valuable noninvasive method for monitoring the effects of antiangiogenic agents such as PTK787/ZK 222584 on tumor vasculature.

Angiogenesis Inhibitors↗
PubMed2000

PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration.

PTK787/ZK 222584 (1-[4-chloroanilino]-4-[4-pyridylmethyl] phthalazine succinate) is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, such as the platelet-derived growth factor (PDGF) receptor beta tyrosine kinase, c-Kit, and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families, such as epidermal growth factor receptor, fibroblast growth factor receptor-1, c-Met, and Tie-2, or intracellular kinases such as c-Src, c-Abl, and protein kinase C-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of kinase insert domain-containing receptor (KDR), endothelial cell proliferation, migration, and survival in the nanomolar range in cell-based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or antiproliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once-daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown s.c. in nude mice, as well as a murine renal carcinoma and its metastases in a syngeneic, orthotopic model. Histological examination of tumors revealed inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent or impair hematopoetic recovery after concomitant cytotoxic anti-cancer agent challenge. This novel compound has therapeutic potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.

Angiogenesis Inhibitors↗
PubMed1994

Pharmacokinetic behavior and antineoplastic activity of liposomal hexadecylphosphocholine.

Hexadecylphosphocholine (HePC) shows remarkable antineoplastic efficacy in Sprague-Dawley rats bearing methylnitrosourea-induced mammary carcinoma. Unfortunately, this is accompanied by detrimental side effects that include gastrointestinal damage, body weight loss, and thrombophlebitis after i.v. injection, which has precluded the use of the HePC in humans, where nausea and vomiting can occur at noneffective dose levels. We have developed small unilamellar vesicles (SUVs) composed of HePC, cholesterol, and 1,2-dipalmitoyl-sn-gly-cero-3-phosphoglycerol, which can be given p.o. and i.v. In contrast to the free drug, the toxicity of liposomal HePC is shown to be greatly reduced, and there is no risk of thrombophlebitis. Single administration of equimolar HePC doses results in differing pharmacokinetic values for free HePC (p.o.) and HePC-SUVs (p.o., i.v.).

Administration, Oral↗