Phase I and DCE-MRI evaluation of CDP791, a di-Fab PEG conjugate that inhibits VEGFR2

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3523-3523 ◽  
Author(s):  
G. C. Jayson ◽  
C. Ton ◽  
G. J. Parker ◽  
A. Jackson ◽  
S. Mullamitha ◽  
...  
Keyword(s):  
Blood Flow ◽  
Tumor Growth ◽  
Vascular Permeability ◽  
Dose Level ◽  
Plasma Concentrations ◽  
Growth Patterns ◽  
Tumor Growth Inhibition ◽  
Dce Mri ◽  
Dependent Inhibition ◽  
Inhibition Of Tumor Growth

3523 Background: VEGF inhibitors are of proven clinical value. However, very few drugs specifically inhibit VEGFR2. CDP791 is a di-Fab PEG conjugate that binds VEGFR2 with a Kd of 49pM. Methods: We performed a single site, open label, dose-escalation study of CDP791. Cohorts of patients received between 0.3 and 30 mg/kg every 3 weeks until disease progression. DCE-MRI was performed at each dose level. Results: Thirty-one patients with colorectal, ovarian or renal cancer or other tumors were treated. There was no observed dose limiting toxicity or maximum tolerated dose. At doses of 10mg/kg or above, 7/16 patients developed cutaneous hemangiomata that regressed upon drug withdrawal. Biopsy of these confirmed that CDP791 was co-located with unphosphorylated VEGFR2. DCE-MRI revealed a dose- dependent inhibition of tumor growth over 20 days post-treatment, although there was no measurable change in Ktrans, an indicator of blood flow and capillary permeability. Fourteen patients received extended treatment and 5 (with renal (x2), colorectal, endometrial cancer and melanoma) had stable disease after 6 cycles. Plasma concentrations of CDP791 >10mcg/mL were sustained across the 21-day cycle for doses 10mg/kg and above. Conclusions: CDP791 is a pure VEGFR2 antagonist that is well tolerated up to doses of 30mg/kg. The drug is mechanistically active, associated with hemangiomata and dose-level dependent inhibition of tumor growth but not with reduction in vascular permeability or blood flow on DCE-MRI. These data imply that the drug is active in patients but challenge our understanding of the regulation of tumor vascular permeability. In addition, they suggest that serial 3-dimensional measurements of short-term tumor growth patterns are a sensitive method to detect biological therapy-related tumor growth inhibition. [Table: see text]

Primary tumor dependent inhibition of tumor growth, angiogenesis, and perfusion of secondary breast cancer in bone

2011 ◽  
Vol 29 (8) ◽  
pp. 1251-1258 ◽  
Author(s):  
Christian Schaefer ◽  
Malte Schroeder ◽  
Ina Fuhrhop ◽  
Lennart Viezens ◽  
Jasmin Otten ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Primary Tumor ◽  
Dependent Inhibition ◽  
Inhibition Of Tumor Growth ◽  
Secondary Breast Cancer

scholarly journals new bIologIcal model of moderate InhIbItIon of tumor and metastases growth wIth prolonged leukopenIa In mIce

2016 ◽  
Vol 1 (5) ◽  
pp. 121-125
Author(s):  
Зуева ◽  
Elena Zueva ◽  
Разина ◽  
Tatyana Razina ◽  
Ермакова ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Lung Carcinoma ◽  
Lewis Lung Carcinoma ◽  
Tumor Therapy ◽  
Biological Model ◽  
Tumor Growth Inhibition ◽  
Lewis Lung ◽  
Inhibition Of Tumor Growth ◽  
Toxic Manifestation ◽  
Cyclophosphamide Dose

A new biological model of moderate inhibition of tumor growth and metastases with prolonged leukopenia on C57Bl/6 mice with the Lewis Lung Carcinoma was designed. The model was created by the injection of cyclophosphamide (dose 83.3mg/kg) on 6th, 12th, 18th days after tumor cells transplantation on animals. Experiment showed that 3-fold cyclo-phosphamide use leads to growth of primary tumor and metastases inhibition. Tumor growth inhibition was 34% on 21st day after cyclophosphamide inject. The number of metastases decreased by 4.7times (p<0,01). Metastatic area reduced. Metastasis frequency made 100%. In addition, the course of cyclophosphamide application caused inhibition of granulocytic and lymphoid hematopoiesis. The reducing the number of segmented neutrophils and lymphocytes was showed on the 3rd day after 1, 2 and 3 injections of cyclophosphamide. The model can be used to study the efficacy of drugs in tumor therapy and in correction of such toxic manifestation of chemotherapy as leukopenia.

Bridging sunitinib exposure to time-to-tumor progression in hepatocellular carcinoma patients with mathematical modeling of an angiogenic biomarker.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14690-e14690
Author(s):  
Sihem Ait-Oudhia ◽  
Donald E. Mager ◽  
Garin Tomaszewski ◽  
Adrienne E. Groman ◽  
Patricia D. Zagst ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Time Course ◽  
Drug Exposure ◽  
Plasma Concentrations ◽  
Target Range ◽  
Tumor Growth Inhibition ◽  
Time To Tumor Progression

e14690 Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with 250,000 new annual cases in the US. Sunitinib (SU), an oral tyrosine kinase inhibitor, inhibits tumor cell proliferation, selectively binds to the angiogenesis biomarker (VEGFR2), and is metabolized to an equipotent metabolite (SU12662). The objective of this study is to utilize mathematical modeling to bridge drug exposure and VEGFR2 dynamics to tumor growth inhibition (TGI) and time-to-tumor progression (TTP). Methods: Plasma concentrations of SU, SU12662, and VEGFR2, and tumor growth and TTP measurements were obtained from a phase-II study in 16 patients with unresectable HCC. SU was administered at 37.5 mg daily 7-days prior to chemoembolization, then on days 15-35. A MAP Bayesian approach was utilized to model SU and SU12662 pharmacokinetics (PK), both captured with a two-compartment model including linear clearances. Inhibition of VEGFR2 production was mediated by predicted active unbound concentrations (ACub) of SU and SU12662. VEGFR2 concentrations were the driver for TGI. The TTP probability was modeled with exponential hazard function dependent on a time varying covariate -the difference in VEGFR2 concentration from its baseline (ΔVEGFR2). Results: Drug and metabolite clearances (CLd, CLm) were estimated at 30.3 (19, %RSE) and 19.7L/h (14). Their volumes of distribution (Vd, Vm) were 1,780 (39) and 1840L (25). SU exposure was within target range for VEGFR2 inhibition. VEGFR2 half-life in plasma was calculated at 4h. The slope (α) for ACub effect on VEGFR2 production was 0.77(µg/mL)-1 (14). The ΔVEGFR2 effect on TGI was assumed maximal, whereas its potency (ΔIC50) was estimated at 1.83x10-2µg/mL (41). The between-subjects variabilities were 37.4, 51, 44.7, 64.8, 21, and 36% for CLd, CLm, Vd, Vm, α, and ΔIC50. The median observed tumor size baseline was 91 mm3. The simulated mean TTP was 7 months. Conclusions: The time-course of SU, SU12662, and VEGFR2 were captured well with final PK/pharmacodynamic models. VEGFR2 profiles successfully linked drug exposure to TGI and TTP. This model may serve as a general platform for the dynamics of anti-angiogenic drugs.

Combinatorial treatment with CTO and temozolomide in sc-implanted human LOX 1MVI melanoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19006-e19006
Author(s):  
Rashida A. Karmali ◽  
Yulia Maxuitenko ◽  
Greg Gorman
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Calcium Influx ◽  
Dependent Inhibition ◽  
Melanoma Model ◽  
Dose Dependent Inhibition ◽  
Inhibition Of Tumor Growth ◽  
Induction Of Apoptosis ◽  
Oxide Synthase ◽  
Dose Dependent

e19006 Background: Carboxyamidotriazole orotate (CTO) is the orotic acid salt of 5-amino-1.(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1, 2, 3-triazole-4-carboxamide. CTO possesses increased solubility. The antiproliferative and antimetastatic effects of CTO are related to inhibition of receptor –opertated calcium channel- mediated calcium influx. CTO can inhibit calcium sensitive signal transduction in the VEGF and the PI3K pathways, inhibition of FGF-2-induced tyrosine kinase, VEGF-mediated activation of phospholipase Cγ, generation of IP3 and nitric oxide synthase activation, and induction of apoptosis in imatinib mesylate resistant CML cells by downregulating bcr-abl. Methods: Different combinations of CTO and temozolomide (TEM) were first tested in female athymic NCr-nu/nu mice to evaluate tolerance of the combination. The tolerated combinations were then tested to evaluate the antitumor activity against subcutaneously –implanted human LOX 1MVI melanoma xenografts. Results: Oral CTO at doses of 513 or 342 mg/kg/dose Q1Dx14 resulted in inhibition of tumor growth (p<0.001 and p=0.004). Oral TEM at doses of 90 and 60mg/kg/dose Q4Dx3 resulted in dose-dependent inhibition of tumor growth (p<0.001 and p<0.001). Oral CTO at 513 or 342 mg/kg/dose in combination with TEM 90mg/kg/dose resulted in comparable tumor inhibition to TEM alone. However, oral CTO at 513mg/kg/dose in combination with TEM 60mg/kg/dose resulted in additive antitumor activity compared to each drug alone. Also, CTO at 342mg/kg/dose in combination with TEM 60mg/kg/dose had more than additive antitumor activity and was statistically different from the group treated with TEM 60mg/kg/dose alone (p=0.001). Conclusions: These results suggest that CTO enhances the sensitivity of TEM and may permit use of lower doses of TEM to obtain an optimum antitumor effect in combination therapy thus reducing toxicity of high TEM doses in this melanoma model.

scholarly journals Isotype-Dependent Inhibition of Tumor Growth In Vivo by Monoclonal Antibodies to Death Receptor 4

2001 ◽  
Vol 166 (8) ◽  
pp. 4891-4898 ◽  
Author(s):  
Anan Chuntharapai ◽  
Kelly Dodge ◽  
Katharine Grimmer ◽  
Kurt Schroeder ◽  
Scot A. Marsters ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Tumor Growth ◽  
Death Receptor ◽  
Dependent Inhibition ◽  
Inhibition Of Tumor Growth ◽  
Death Receptor 4

scholarly journals A CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self antigens

Blood ◽  
2011 ◽  
Vol 118 (18) ◽  
pp. 4853-4862 ◽  
Author(s):  
Helene Pere ◽  
Yves Montier ◽  
Jagadeesh Bayry ◽  
Francoise Quintin-Colonna ◽  
Nathalie Merillon ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Hematologic Malignancies ◽  
Clinical Development ◽  
Peripheral Tolerance ◽  
Tumor Growth Inhibition ◽  
Inhibition Of Tumor Growth ◽  
Therapeutic Settings ◽  
Small Chemical

Abstract Regulatory T cells (Tregs) may impede cancer vaccine efficacy in hematologic malignancies and cancer. CCR4 antagonists, an emergent class of Treg inhibitor, have been shown to block recruitment of Tregs mediated by CCL22 and CCL17. Our aim was to demonstrate the ability of a CCR4 antagonist (a small chemical molecule identified in silico) when combined with vaccines to break peripheral tolerance controlled by Tregs, a prerequisite for the induction of CD8+ T cells against self Ags. Immunization of transgenic or normal mice expressing tumor-associated self Ags (Her2/neu, OVA, gp100) with a CCR4 antagonist combined with various vaccines led to the induction of effector CD8+ T cells and partial inhibition of tumor growth expressing self Ags in both prophylactic and therapeutic settings. The CCR4 antagonist was more efficient than cyclophosphamide to elicit anti-self CD8+ T cells. We also showed that the population of Tregs expressing CCR4 corresponded to memory (CD44high) and activated (ICOS+) Tregs, an important population to be targeted to modulate Treg activity. CCR4 antagonist represents a competitive class of Treg inhibitor able to induce functional anti-self CD8+ T cells and tumor growth inhibition when combined with vaccines. High expression of CCR4 on human Tregs also supports the clinical development of this strategy.

Combined treatment with the 5 alpha-reductase inhibitor PNU 157706 and the antiandrogen flutamide on the Dunning R3327 prostatic carcinoma in rats.

1999 ◽  
pp. 429-435 ◽  
Author(s):  
T Zaccheo ◽  
D Giudici ◽  
E di Salle
Keyword(s):  
Tumor Growth ◽  
Growth Inhibition ◽  
Prostatic Carcinoma ◽  
Reductase Inhibitor ◽  
Combined Treatment ◽  
Ventral Prostate ◽  
Tumor Growth Inhibition ◽  
Concomitant Treatment ◽  
Inhibition Of Tumor Growth ◽  
Prostatic Tumor

The steroid 5 alpha-reductase enzyme catalyzes the conversion of testosterone to the potent androgen 5 alpha-dihydrotestosterone (DHT). PNU 157706, a novel, potent and selective dual 5 alpha-reductase inhibitor, was reported to be effective in inhibiting the growth of established tumors in the Dunning R3327 rat prostatic carcinoma model. We have studied the efficacy of combined treatment with PNU 157706 and the antiandrogen flutamide in this prostatic tumor in rats. Rats with tumor diameters of about 1 cm were treated orally 6 days a week for 9 weeks with PNU 157706 (10 mg/kg per day) alone or in combination with flutamide (1 and 5 mg/kg per day). Animals were killed 24 h after the last treatment and ventral prostates were removed for testosterone and DHT determination. PNU 157706 reduced the growth of established tumors by 36%; flutamide showed a slight effect at 1 mg/kg per day (24% inhibition), while at the dose of 5 mg/kg per day it reduced tumor growth by 48%. The combination of PNU 157706 with the lower dose of flutamide caused an additive tumor growth inhibition (60%) and the combination with the higher dose of flutamide resulted in a better inhibition of tumor growth (68%) than did either treatment alone. Castration resulted in marked tumor growth inhibition (76%). Ventral prostate weight was more markedly reduced by PNU 157706 treatment than by flutamide; combined treatment was as effective as castration. Prostatic DHT content was markedly reduced by PNU 157706 (93%), whereas prostatic testosterone increased (137%). Concomitant treatment with flutamide partially antagonized the testosterone increase induced by PNU 157706 and did not modify the already considerable suppression of DHT. These data show that the inhibitory effects of PNU 157706 and flutamide on Dunning prostatic tumor growth are additive, thus supporting the rationale of this combination therapy in advanced prostate cancer, in order to achieve adequate androgen blockade with minimal side-effects.

scholarly journals Antitumor efficiency of contact radiotherapy in combination with a chlorin-based photosensitizer in experiment

2021 ◽  
Vol 10 (2) ◽  
pp. 25-33
Author(s):  
D. A. Tzerkovsky ◽  
Ya. L. Protopovich ◽  
D. I. Kozlovsky ◽  
V. A. Suslova
Keyword(s):  
Radiation Therapy ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Model ◽  
Growth Patterns ◽  
Antitumor Efficacy ◽  
Laboratory Animals ◽  
Tumor Growth Inhibition ◽  
Histological Structure ◽  
Complete Tumor

Authors have studied the antitumor efficacy of contact radiation therapy (CRT) in combination with a chlorin-based photosensitizer (PS) in an experiment on laboratory animals with transplanted tumors. The experimental study was performed in 50 white outbred rats weighing 250±50 g. Subcutaneously transplanted Pliss lymphosarcoma (PLS) and alveolar liver cancer RS1 (RS1) were used as tumor models. Chlorinbased PS photolon (RUE «Belmedpreparaty», Republic Belarus) was injected intravenously at a dose of 2.5 mg/kg. The radiation sessions were carried out 2.5–4 hours (depending on the tumor model) after the administration of the PS using the device «microSelectron HDR V3 Digital» («Nucletron», Netherlands) with a 192-Ir radiation source in single focal doses 5 and 10 Gy. All laboratory animals (for PLS and RS1) were subdivided into 5 groups of 5 animals each: intact control, CRT 5 Gy, CRT 10 Gy, PS + CRT 5 Gy, PS + CRT 10 Gy. For the PLS tumor model – on the 14th day from the beginning of the experiment Vav. in groups were 26.31±5.81; 22.45±6.97; 18.99±4.86; 10.75±5.18 and 28.06±2.85 cm3, respectively (p˂0.05). The coefficients of tumor growth inhibition in the experimental groups were 14.67%, 27.82%, 59.14% and 6.65%, respectively. The frequency of complete tumor regressions 60 days after the start of the experiment was 0%, 20%, 20%, 60%, and 20%, respectively. On RS1 tumor model – on the 14th day from the beginning of the experiment Vav. in groups were 4.48±1.03; 0.80±0.21; 0.29±0.09; 0.19±0.07 and 0.32±0.08 cm3, respectively (p=0.009). The coefficients of tumor growth inhibition in the experimental groups were 82.14%, 93.53%, 95.76% and 92.86%, respectively. The frequency of complete tumor regressions 60 days after the start of the experiment was 0%, 0%, 20%, 0%, and 0%, respectively. Systemic administration of chlorin-based PS before the CRT session increases the antitumor efficacy of radiation therapy in animals with transplantable tumors of different histological structure and growth patterns. The data obtained indicate that further studies of the radiosensitizing properties of PS are promising.

scholarly journals EFFECTS OF 5-HYDROXYPYRIMIDINE DERIVATIVE ON GROWTH AND METASTASIS OF MELANOMA B16 IN C57BL/6 MICE

2021 ◽  
Vol 20 (3) ◽  
pp. 66-72
Author(s):  
R. V. Zhurikov ◽  
L. P. Kovalenko ◽  
S. V. Nikitin ◽  
A. D. Durnev
Keyword(s):  
Tumor Growth ◽  
Single Injection ◽  
Tumor Development ◽  
Positive Control ◽  
Significant Inhibition ◽  
Tumor Growth Inhibition ◽  
Antimetastatic Activity ◽  
Melanoma B16 ◽  
Melanoma Model ◽  
Inhibition Of Tumor Growth

Introduction. Suppression of activation of an alternative immune response is promising approach of tumor immunotherapy. In this study we evaluated antitumor and antimetastatic activity of SNK-411.Objective. Evaluation of antitumor and antimetastatic activity of 5-hydroxypyrimidine derivative SNK-411 in mouse melanoma B16 model.Materials and methods. Antitumor and antimetastatic activity of the SNK-411 were studied in tests on male C57BL/6 mice using the B16-F10 melanoma model. SNK-411 was injected intraperitoneally at doses of 10 and 25 mg/kg from day 2 to day 15 of melanoma development. Doxorubicin was injected at dose of 4 mg/kg on day 2 of tumor development to act as positive control. Antitumor and antimetastatic activity were studied by calculation of tumor growth inhibition and metastasis inhibition index (MII).Results. SNK-411 at doses of 10 and 25 mg/kg and in combination with single injection of doxorubicin in dose of 4 mg/kg showed antimetastatic activity. MII in SNK-411 at 10 mg/kg dose was 72 %, at dose of 25 mg/kg was 82,9 %. The combination of 14-day course of intraperitoneal injections of SNK-411 at dose of 10 mg/kg and injection of doxorubicin 4 mg/kg revealed MII 97,1 %, in half of mice in this group metastasis were not observed on 21st day of melanoma development. All results are statistically significant. There was no significant inhibition of tumor growth in all groups.Conclusion. SNK-411 has antimetastatic activity in tests on melanoma B16 model. Further investigation is required. 

Sign in / Sign up

Export Citation Format

Share Document