Safety and anticancer activity of low dose regimen of NGRhTNF, a new vascular targeting agent, in solid advanced malignancies (NGR002 phase I trial)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3540-3540 ◽  
Author(s):  
C. Gallo-Stampino ◽  
G. Rizzardi ◽  
S. Toma ◽  
A. Corti ◽  
P. Scifo ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Vascular Permeability ◽  
Drug Exposure ◽  
Low Dose ◽  
Biological Effects ◽  
Cytotoxic Agents ◽  
Vascular Targeting ◽  
Frequent Event ◽  
Over Time ◽  
Vascular Targeting Agent

3540 Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding angiogenic vessels in solid tumours where NGRhTNF specific binding relies on dynamic interactions with TNF-receptors and aminopeptidase N (CD13). NGRhTNF combines activity on tumour vascular permeability and direct anticancer activity. Consistently, mouse preclinical data indicate significant synergy between low dose NGRhTNF and cytotoxic agents. Methods: 4 dose levels of NGRhTNF (0.2 up to 1.6 mcg/sqm) have been administered q 3 w in 16 patients. Main end-points included safety, anticancer activity and pharmacokinetic.Measurement of circulating tumor and endothelial cells (CTC and CEC), sTNFRI and s TNFRII, along with plasma cyto-chemokine profile have been performed. Results: 16 patients were enrolled (6F/10M);median age 60,range 43–73). Toxicity was limited to constitutional symptoms, and chills were the most frequent event (40%). Over a median follow-up of 15 weeks, stable disease was achieved in 44% of patients, with long lasting disease control in 2 cases (27 and 75 weeks, with establishment of indication to radical surgery after 75 weeks, presently tumor free after removal of the residual tumor mass). In these 2 patients, VEGF, MMP-9, CA125, significantly decreased over time. DCE-MRI indicates that NGRhTNF increases vascular permeability after first drug exposure, particularly at the dose of 0.4 mcg/sqm, while following multiple infusions it exerts an antivascular effect, as demonstrated by the decrease of Ktrans values. Moreover NGRhTNF is able to elicit inflammatory and immune responses over time, as indicated by the modulation of expression of multiple cyto-chemokines. Finally, changes in CTC levels over time consistently matched the clinical outcome. Conclusions: Low dose NGRhTNF has an optimal safety profile along with anticancer activity acting on tumour vasculature and inducing relevant biological effects, thus rendering the agent suitable for a development both as monotherapy and in combination with chemotherapeutics. The phase II program is due to start in early 2007. [Table: see text]

NGRhTNF, a new vascular targeting agent with a dual mechanism of action: preliminary clinical results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13052-13052
Author(s):  
C. Bordignon ◽  
F. Caligaris Capio ◽  
S. Toma ◽  
L. Manenti ◽  
P. Rizzardi ◽  
...  
Keyword(s):  
Phase I ◽  
Anticancer Activity ◽  
Vascular Permeability ◽  
Mechanism Of Action ◽  
Phase I Study ◽  
Low Dose ◽  
Moderate Intensity ◽  
Vascular Targeting ◽  
Dce Mri ◽  
Vascular Targeting Agent

13052 Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding solid tumor (lung, renal, and colorectal) neovasculature. NGRhTNF specific binding relies on dynamic interactions with TNF-receptors, aminopeptidase N (CD13) and a specific integrin: a combination of receptors expressed by the tumor neovasculature endothelium, but not on normal vessels. This combination provides NGRhTNF with unique biological properties: at low dose, increased tumor vascular permeability, and massive tumor necrosis at high dose. Mouse preclinical data confirmed these properties, revealing also strong synergy between low dose NGRhTNF and cytotoxic agents (antracyclines, platinum based compounds, etc.). Methods: Based on these data, a series of studies were designed. A multicentre phase I study with NGRhTNF as single agent -still in progress- aims at defining MTD and preliminary anticancer activity, within the EORTC network (EORTC 16041). A single center phase I study exploiting the low dose range (0.2–1.6 μg/m2) aims at defining safety and NGRhTNF activity on the tumor vascular permeability using DCE MRI (HSR NGR002). Results: Twelve advanced neoplastic patients were enrolled in the HSR NGR002 study. Up to the dose of 1.6 μg/m2, the only common toxicity was represented by constitutional symptoms such as infusion-associated chills (40%) of mild to moderate intensity. At the tested doses, NGRhTNF increased vascular permeability, as shown by changes in DCE MRI parameters (Ktrans and Kep), and modulated the expression of chemokines possessing antiangiogenic activity. NGRhTNF achieved stable disease in about 45% of highly refractory treated patients, and still ongoing long lasting disease control in 2 cases (7 and 9 months along with sharp decline of CA125 and VEGF). Conclusions: NGR-hTNF, a VTA with a unique mechanism of action, combines activity on tumor vascular permeability and direct anti-cancer effect. Preliminary data in humans confirm its favourable safety profile along with remarkable anticancer activity, thus rendering the agent suitable for a development program alone or in combination with chemotherapeutics. Phase II low dose combination studies will begin in 2006. [Table: see text]

Optimal safety profile and anticancer activity of NGRhTNF coupled with doxorubicin (NGR003 modified phase I combo trial)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14056-14056
Author(s):  
G. Rizzardi ◽  
V. Gregorc ◽  
G. Vitali ◽  
C. Gallo Stampino ◽  
C. van Herpen ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Vascular Permeability ◽  
Safety Profile ◽  
Low Dose ◽  
Specific Binding ◽  
Cytotoxic Agents ◽  
Dynamic Interactions ◽  
Grade Ii ◽  
Pretreated Patients ◽  
Combination Studies

14056 Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding angiogenic vessels in solid tumors, where NGRhTNF specific binding relies on dynamic interactions with TNF-receptors and aminopeptidase N (CD13). NGRhTNF combines activity on tumour vascular permeability and direct anticancer activity. At low dose, NGRhTNF increases tumour vascular permeability. Consistently, mouse preclinical data indicate significant synergy between low dose NGRhTNF and cytotoxic agents. Thus, we tested NGRhTNF in combination with doxorubicin. Methods: 4 doses of NGRhTNF (0.2, 0.4, 0.8 and 1.6 μg/m2) in combination with doxorubicin (75 mg/m2) have been administered every 3 weeks in 15 patients.Main end- points included safety, anticancer activity and pharmacokinetic. Measurement of circulating tumour (CTC) and endothelial cells, sTNF receptors, along with plasma chemokine profile are being performed. Results: All patients were enrolled (5F/10M). Toxicity was limited to constitutional symptoms, most frequently chills. After a median follow-up of 12 weeks (range 3–28), 5 episodes of chills (1 grade I and 4 grade II) were reported in 4/15 patients.One episode of grade I hypertension was reported. Of note, the toxicity profile commonly-associated to doxorubicin has not been exacerbated. Stabilization of disease occurred in 10/15 patients lasting 13 weeks (range 6–28 with 5 patients still ongoing at December 2006). In addition, partial response was achieved in 2 patients, lasting 23 and 14 (still ongoing) weeks, respectively. It is worth noting that anticancer activity was observed in 12/15 patients of whom 9 had previously received anthracycline-containing regimens and 5 were anthracycline-resistant suggesting a role of NGRhTNF in inducing tumour sensitivity to doxorubicin. Finally, changes in CTC levels over time consistently matched the clinical outcome. Conclusions: Coupling NGRhTNF with doxorubicin induced anticancer activity along with an optimal safety profile in pretreated patients providing support for the phase II combination studies addressing diseases suitable for anthracycline treatment such as sarcoma and ovarian cancer, and planned to start in early 2007. No significant financial relationships to disclose.

A phase I study to define the optimal low dose of NGR-hTNF, a novel vascular targeting agent (VTA), in combination with cisplatin in patients (pts) with solid tumors

2008 ◽  
Vol 26 (15_suppl) ◽  
pp. 14647-14647 ◽  
Author(s):  
F. G. De Braud ◽  
V. Gregorc ◽  
T. M. De Pas ◽  
G. Citterio ◽  
R. Scalamogna ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Low Dose ◽  
Vascular Targeting ◽  
Vascular Targeting Agent

scholarly journals Pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5-amines as Potential Cytotoxic Agents against Human Neuroblastoma

2021 ◽  
Vol 14 (8) ◽  
pp. 750
Author(s):  
Zahira Tber ◽  
Mohammed Loubidi ◽  
Jabrane Jouha ◽  
Ismail Hdoufane ◽  
Mümin Alper Erdogan ◽  
...  
Keyword(s):  
Cell Line ◽  
Drug Exposure ◽  
Caspase 3 ◽  
Biological Activities ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cell Line ◽  
Cytotoxic Agents ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Parp 1

We report herein the evaluation of various pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5-amines as potential cytotoxic agents. These molecules were obtained by developing the multicomponent Groebke–Blackburn–Bienaymé reaction to yield various pyrido[2′,1′:2,3]imidazo[4,5-c]quinolines which are isosteres of ellipticine whose biological activities are well established. To evaluate the anticancer potential of these pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5-amine derivatives in the human neuroblastoma cell line, the cytotoxicity was examined using the WST-1 assay after 72 h drug exposure. A clonogenic assay was used to assess the ability of treated cells to proliferate and form colonies. Protein expressions (Bax, bcl-2, cleaved caspase-3, cleaved PARP-1) were analyzed using Western blotting. The colony number decrease in cells was 50.54%, 37.88% and 27.12% following exposure to compounds 2d, 2g and 4b respectively at 10 μM. We also show that treating the neuroblastoma cell line with these compounds resulted in a significant alteration in caspase-3 and PARP-1 cleavage.

Synthesis, investigation of biological effects and in silico studies of new benzimidazole derivatives as aromatase inhibitors

2020 ◽  
Vol 75 (9-10) ◽  
pp. 353-362
Author(s):  
Begüm Nurpelin Sağlık ◽  
Ahmet Mücahit Şen ◽  
Asaf Evrim Evren ◽  
Ulviye Acar Çevik ◽  
Derya Osmaniye ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
In Silico ◽  
Biological Effects ◽  
Docking Studies ◽  
Benzimidazole Derivatives ◽  
Binding Modes ◽  
Reference Drug ◽  
In Silico Studies ◽  
New Compounds ◽  
Mcf 7

AbstractInhibition of aromatase enzymes is very important in the prevention of estrogen-related diseases and the regulation of estrogen levels. Aromatase enzyme is involved in the final stage of the biosynthesis of estrogen, in the conversion of androgens to estrogen. The development of new compounds for the inhibition of aromatase enzymes is an important area for medicinal chemists in this respect. In the present study, new benzimidazole derivatives have been designed and synthesized which have reported anticancer activity in the literature. Their anticancer activity was evaluated against human A549 and MCF-7 cell lines by MTT assay. In the series, concerning MCF-7 cell line, the most potent compounds were the 4-benzylpiperidine derivatives 2c, 2g, and 2k with IC50 values of 0.032 ± 0.001, 0.024 ± 0.001, and 0.035 ± 0.001 µM, respectively, compared to the reference drug cisplatin (IC50 = 0.021 ± 0.001 µM). Then, these compounds were subject to further in silico aromatase enzyme inhibition assays to determine the possible binding modes and interactions underlying their activity. Thanks to molecular docking studies, the effectiveness of these compounds against aromatase enzyme could be simulated. Consequently, it has been found that these compounds can be settled very properly to the active site of the aromatase enzyme.

Targeting mitochondria to overcome conventional and bortezomib/proteasome inhibitor PS-341 resistance in multiple myeloma (MM) cells

Blood ◽  
2004 ◽  
Vol 104 (8) ◽  
pp. 2458-2466 ◽  
Author(s):  
Dharminder Chauhan ◽  
Guilan Li ◽  
Klaus Podar ◽  
Teru Hideshima ◽  
Constantine Mitsiades ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Exposure ◽  
Low Dose ◽  
Benzodiazepine Receptors ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Superoxide Generation ◽  
Insulin Growth Factor ◽  
Bortezomib Treatment ◽  
Induced Apoptosis

Abstract Bortezomib (PS-341), a selective inhibitor of proteasomes, induces apoptosis in multiple myeloma (MM) cells; however, prolonged drug exposure may result in cumulative toxicity and the development of chemoresistance. Here we show that combining PK-11195 (PK), an antagonist to mitochondrial peripheral benzodiazepine receptors (PBRs), with bortezomib triggers synergistic anti-MM activity even in doxorubicin-, melphalan-, thalidomide-, dexamethasone-, and bortezomib-resistant MM cells. No significant cytotoxicity was noted in normal lymphocytes. Low-dose combined PK and bortezomib treatment overcomes the growth, survival, and drug resistance conferred by interleukin-6 or insulin growth factor within the MM bone marrow milieu. The mechanism of PK + bortezomib–induced apoptosis includes: loss of mitochondrial membrane potential; superoxide generation; release of mitochondrial proteins cytochrome-c (cyto-c) and Smac; and activation of caspases-8/-9/-3. Furthermore, PK + bortezomib activates c-Jun NH2 terminal kinase (JNK), which translocates to mitochondria, thereby facilitating release of cyto-c and Smac from mitochondria to cytosol. Blocking JNK, by either dominant-negative mutant (DN-JNK) or cotreatment with a specific JNK inhibitor SP600125, abrogates both PK + bortezomib–induced release of cyto-c/Smac and induction of apoptosis. Together, these preclinical studies suggest that combining bortezomib with PK may enhance its clinical efficacy, reduce attendant toxicity, and overcome conventional and bortezomib resistance in patients with relapsed refractory MM.

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