PRECLINICAL STUDY OF ANTITUMOR ACTIVITY OF INDOLOCARBAZOLES N-GLYCOSIDES DERIVATIVE LCS-1208. REPORT II

e14699 Background: INNO-D07001 is a novel oral gemcitabine formulation which was developed to enhance the oral bioavailability of gemcitabine and it has been successfully demonstrated in both beagle dogs as well as nude mice. The objectives of this study were to examine the antitumor activity of this novel gemcitabine oral formulation in human xenograft models of pancreatic tumors with different daily doses as well as various dosing schedules. Methods: The INNO-D07001 dosing solutions (gemcitabine oral formulation) were formulated freshly before treatment and water for injection (USP) was used as the diluent. There were seven groups in the study and it was ten female NCr-nu/nu mice (with human CFPAC-1 pancreatic tumor) per group. Two doses (5 mg/kg and 10 mg/kg) and three dosing schedules (Q1D, Q2D, and Q3D) were examined. Water for injection (by oral administration) was used as the blank control and Gemzar (180 mg/kg by I.V.) was used as the active control. All INNO-D07001 dosing solutions were administered to mice by P.O. and, on the other hand, Gemzar was administered to mice by I.V. All animals were designed to receive doses for 12 days based on different doses and dosing schedules. Total body weights and tumor sizes were recorded continuously for evaluating the toxicity and antitumor activity, respectively, of INNO-D07001. Results: Oral administration of INNO-D07001 once daily at doses of 10 and 5 mg/kg/dose was not tolerated. In contrast, oral administration of INNO-D07001 on a Q2Dx6 schedule at a dose of 10 mg/kg/dose and on a Q3Dx4 schedule at doses of 10 and 5 mg/kg/dose was well tolerated. Moreover, the INNO-D07001 treatment at a dose of 10 mg/kg/dose on a Q2Dx6 schedule produced statistically significant inhibition of tumor growth (i.e. more than 60% inhibition rate comparing to the blank control) on the last treatment day. Conclusions: The novel gemcitabine oral formulation (INNO-D07001) is well tolerated and effective at a dose of 10 mg/kg/dose on a Q2Dx6 schedule to show the significant inhibition of pancreatic tumor growth. Future preclinical study in toxicity evaluation with repeating doses is ongoing in order to provide adequate safety information before entering phase I clinical study.

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ANTITUMOR ACTIVITY OF ANTI-INTEGRIN PROTEIN SAV-RGD ON XENOGRAFTED HUMAN SKIN MELANOMA WITH INTEGRIN AVG3 EXPRESSION

Problems in oncology ◽

10.37469/0507-3758-2019-65-3-458-462 ◽

2019 ◽

Vol 65 (3) ◽

pp. 458-462

Author(s):

Yelena Treshchalina ◽

Natalya Andronova ◽

Galina Smirnova ◽

Yelena Sholokhova ◽

Nikolay Tupitsyn ◽

...

Keyword(s):

Antitumor Activity ◽

Human Skin ◽

Anticancer Agents ◽

Combined Therapy ◽

Preclinical Study ◽

Amelanotic Melanoma ◽

Receptor Expression ◽

Skin Melanoma

Anti-integrins are considered as potential anticancer agents capable of inhibiting differentiation and proliferation of various malignant cells, including disseminated melanoma. The possibility of including anti-integrins with different RGD-motives in combined therapy schedules is discussed. We have studied the oridinal recombinant lyophilized protein SAV-RGD (lyo-SAV-RGD), specifically binding to melanoma cells by means of the Tripeptide Arg-Gly-Asp. As models of melanoma of the skin selected amalonaticus MeWo/mel- and pigmented melCher/mel+ with prospectively certain expression of the marker, giving subcutaneous xenograft in mice Balb/c nude. Objective: to evaluate the antitumor activity of lyo-SAV-RGD in vivo on human skin melanoma models melCher and MeWo with different melanogenesis ability and integrin avB3 expression. Both melanomas in vitro were shown to express integrin avB3 detected in melCher/mel+ cells with fluorescent-labeled rat antibodies Luc.H11 according to the expression component integrins avp3, p3-chain (CD61), and MeWo cells/mel- antibodies 23С6. In a high therapeutic total dose of 900 mg/kg, lyo-SAV-RGD inhibited growth of both melanomas in vivo with satisfactory tolerability. Compared to melCher/mel+, MeWo/mel-: T/Cmin=30% (p<0.05) versus T/ Cmin=50% (p=0.001) was more sensitive to treatment. The effect on melCher/mel+ was obtained only in the exponential phase of tumor growth. The results obtained allow us to consider it expedient to conduct an in-depth preclinical study of anti-integrin SAV-RGD, focused on the most aggressive disseminated amelanotic melanoma of the skin, regardless of the nature of blocking receptor expression.

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Strong Antitumor Activity of Bevacizumab and Aflibercept in Neuroendocrine Carcinomas: In-Depth Preclinical Study

Neuroendocrinology ◽

10.1159/000500591 ◽

2019 ◽

Vol 110 (1-2) ◽

pp. 50-62 ◽

Cited By ~ 1

Author(s):

María Rodríguez-Remírez ◽

Laura del Puerto-Nevado ◽

María Jesús Fernández Aceñero ◽

Hakimeh Ebrahimi-Nik ◽

Marlid Cruz-Ramos ◽

...

Keyword(s):

Antitumor Activity ◽

Tumor Growth ◽

Therapeutic Option ◽

Human Cell Line ◽

Preclinical Study ◽

Tumor Control ◽

Tumor Growth Inhibition ◽

Bevacizumab Treatment ◽

Strong Antitumor Activity

Background: Neuroendocrine carcinoma (NEC) is a rare and very aggressive tumor. It has been greatly understudied, and very little is known about optimal treatment strategy for patients with this disease. The purpose of this study was to evaluate in vivo whether anti-vascular endothelial growth factor (VEGF) drugs could be a therapeutic alternative for these tumors with a poor prognosis. Methods: We have developed 2 xenograft models using either human cell line derived from lung (H460) or from colon (COLO320) NEC to assess the effect of 2 antiangiogenic drugs, aflibercept and bevacizumab, on tumor growth and their pathological characteristics. Additionally, tumors were subjected to immunohistochemistry staining and proteins were measured with Western blot and ELISA. Results: Both aflibercept and bevacizumab showed significant antitumor activity (p < 0.001). In the H460 model, aflibercept resulted in 94% tumor growth inhibition (TGI) and bevacizumab treatment resulted in 72.2% TGI. Similarly, in the COLO320 model, aflibercept and bevacizumab resulted in 89.3 and 84% TGI, respectively. Moreover, antitumor activity occurs early after treatment initiation. Using Tumor Control Index score, which address the kinetics of tumor growth in a way comparable to the methods used in human clinical studies, we confirmed that both drugs inhibit significantly tumor growth. When tumor stabilization was evaluated, aflibercept shows higher ability to stabilize NEC tumors than bevacizumab. Conclusion: Results derived from this study strongly support anti-VEGF therapies, especially aflibercept, as a novel therapeutic option in NECs. Further studies are necessary, but our observations encourage the evaluation of antiangiogenics in clinical trials combined with standard chemotherapy.

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SHR3680, a novel antiandrogen, for the treatment of metastatic castration-resistant prostate cancer (mCRPC): A phase I/II study.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.90 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 90-90

Author(s):

Xiaojian Qin ◽

Weiqing Han ◽

Hong Luo ◽

Chuanjun Du ◽

Qing Zou ◽

...

Keyword(s):

Antitumor Activity ◽

Adverse Events ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Preclinical Study ◽

Phase 2 ◽

Castration Resistant Prostate Cancer ◽

Radiological Progression ◽

Psa Response ◽

Visceral Metastases

90 Background: SHR3680 is a novel and pure androgen-receptor (AR) antagonist that shows a potent antitumor activity against CRPC but with much less brain distribution than enzalutamide in preclinical study. In this first-in-human phase 1/2 study, the safety and efficacy of SHR3680 were assessed in patients with mCRPC. Methods: This phase 1/2 study was conducted in 11 hospitals in China. Patients with progressive mCRPC that was not previously treated with novel AR-targeted agents were eligible for this study. In the phase 1 part, patients received oral SHR3680 at a starting daily dose of 40 mg, which was subsequently escalated to 80 mg, 160 mg, 240 mg, 360 mg, and 480 mg. In phase 2, patients were randomized to receive one of three daily doses of SHR3680 (80 mg, 160 mg, and 240 mg). The primary endpoint in phase 1 was safety and tolerability, and in phase 2 was the proportion of patients with a PSA response (≥50% decrease of PSA level at week 12). Results: From Apr 2016 to Sep 2018, a total of 197 patients (median age 67 years, range 45−80; visceral metastases in 29 patients; previous chemotherapy history in 80 patients) were enrolled (phase 1, n = 18; phase 2, n = 179). No dose-limiting toxicities were reported and the maximum tolerated dose was not reached. Most adverse events were grade 1/2 (87.3%). The most common adverse events were anemia (22.8%), back pain (16.2%), and proteinuria (13.2%). The antitumor activity was observed at all doses, including PSA response in 134 (68.7%) of 195 evaluable patients, stabilized bone disease in 169 (86.7%) of 195 patients at week 12, and responses in soft tissue lesions in 22 (36.7%) of 60 patients. No obvious dose-related activity benefits were found. As of Sep 26, 2019, the median time to PSA progression was 36 weeks (95% CI 24−47), while that to radiological progression was 73 weeks (95% CI 49−96). As expected, patients without previous chemotherapy showed relatively longer time to PSA and radiological progression than those with previous chemotherapy. Conclusions: SHR3680 is safe and well tolerated, and exhibits high efficacy in mCRPC patients. Clinical trial information: NCT02691975.

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Efficacy of a novel second-generation somatostatin-dopamine chimera (TBR-065) in human medullary thyroid cancer: a preclinical study

Neuroendocrinology ◽

10.1159/000512366 ◽

2020 ◽

Author(s):

Alessandra Dicitore ◽

Maria Celeste Cantone ◽

Germano Gaudenzi ◽

Davide Saronni ◽

Silvia Carra ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Thyroid Cancer ◽

Antitumor Activity ◽

Cell Lines ◽

Second Generation ◽

Medullary Thyroid Cancer ◽

Preclinical Study ◽

Medullary Thyroid ◽

Calcitonin Secretion

Introduction: Somatostatin and dopamine receptors have a pivotal role in control of hormone secretion and cell proliferation in different neuroendocrine neoplasms, including medullary thyroid cancer (MTC). In the present preclinical study, we evaluated the antitumor activity of TBR-065 (formerly BIM-23B065), a second-generation somatostatin-dopamine chimera, in two human MTC cell lines. Methods: the effects of lanreotide (LAN) and TBR-065 on the cell growth proliferation, calcitonin secretion, cell cycle, apoptosis, cell migration and tumor-induced angiogenesis have been evaluated through MTT assay, DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, ECLIA assay, wound-healing assay and zebrafish platform, respectively. Results: TBR-065 exerted a more prominent antitumor activity compared to LAN in both MTC cell lines, as shown by inhibition of cell proliferation (maximal inhibition in TT: -50.3% and -37.6%, respectively; in MZ-CRC-1: -58.8% and -27%, respectively) and migration (in TT: -42.7% and -22.9%, respectively; in MZ-CRC-1: -75.5% and -58.2%, respectively). Only the new chimera decreased significantly the fraction of cells in S phase (TT: -33.8%, MZ-CRC-1: -18.8%), and increased cells in G2/M phase (TT: +13%, MZ-CRC-1: +30.5%). In addition, TBR-065 exerted a more prominent pro-apoptotic effect compared to LAN in TT cells. A concomitant decrease of calcitonin secretion was observed after 2 days of incubation with both drugs, with a more relevant effect of TBR-065. However, neither LAN nor TBR-065 showed any effect on tumor-induced angiogenesis, as evaluated using a zebrafish/tumor xenograft model. Discussion/Conclusion: In MTC cell lines a second generation somatostatin-dopamine analogue, TBR-065, exerts a more relevant anti-tumor activity, as compared with LAN, through modulation of cell cycle, induction of apoptosis and reduction in migration. Further studies are required to establish whether TBR-065 has comparable potent inhibitory effects on tumor growth in vivo.

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Antitumor Activity of Theophylline in Combination with Paclitaxel: A Preclinical Study on Melanoma Experimental Lung Metastasis

Cancer Biotherapy & Radiopharmaceuticals ◽

10.1089/cbr.2010.0787 ◽

2010 ◽

Vol 25 (4) ◽

pp. 497-503 ◽

Cited By ~ 11

Author(s):

Alessandro Lentini ◽

Claudio Tabolacci ◽

Palma Mattioli ◽

Bruno Provenzano ◽

Simone Beninati

Keyword(s):

Antitumor Activity ◽

Lung Metastasis ◽

Preclinical Study

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Preclinical Study of Immunological Isoxazole Derivatives as a Potential Support for Melanoma Chemotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms222010920 ◽

2021 ◽

Vol 22 (20) ◽

pp. 10920

Author(s):

Izabela Jęśkowiak ◽

Benita Wiatrak ◽

Adam Szeląg ◽

Marcin Mączyński

Keyword(s):

Antitumor Activity ◽

Cell Cultures ◽

Metastatic Potential ◽

Preclinical Study ◽

Glycoprotein P ◽

Migration Assay ◽

A375 Cell ◽

Melanoma Metastases ◽

Apoptotic Activity ◽

Isoxazole Derivatives

(1) Background: Melanoma is an aggressive neoplasm derived from melanocyte precursors with a high metastatic potential. Responses to chemotherapy and immunotherapy for melanoma remain weak, underlining the urgent need to develop new therapeutic strategies for the treatment of melanoma. (2) Methods: The viability of NHDF and A375 cell cultures after the administration of the tested isoxazole derivatives was assessed after 24-h and 48-h incubation periods with the test compounds in the MTT test. ROS and NO scavenging analyses, a glycoprotein-P activity analysis, a migration assay, a test of apoptosis, and a multiple-criteria decision analysis were also performed. (3) Results: All compounds that were tested resulted in a slower migration of melanoma neoplastic cells. The mechanism of the antitumor activity of the tested compounds was confirmed—i.e., the pro-apoptotic activity of the compounds in A375 cell cultures. Compound O7K qualified for further research. (4) Conclusions: All the tested compounds inhibited the formation of melanoma metastases and demonstrated the ability to reduce the risk of developing drug resistance in the tumor. The MCDA results showed that O7K showed the strongest antitumor activity.

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PRECLINICAL STUDY OF INDOLOCARBAZOLES N-GLYCOSIDES DERIVATIVE LCS-1208 ANTITUMOR ACTIVITY. REPORT I

Russian Journal of Biotherapy ◽

10.17650/1726-9784-2015-14-2-71-77 ◽

2015 ◽

Vol 14 (2) ◽

pp. 71-77 ◽

Cited By ~ 2

Author(s):

M. P. Kiseleva ◽

Z. S. Shprakh ◽

L. M. Borisova ◽

I. Yu. Kubasova ◽

A. V. Lantsova ◽

...

Keyword(s):

Antitumor Activity ◽

Intravenous Administration ◽

Dosage Form ◽

Antitumor Effect ◽

Preclinical Study ◽

Tumor Growth Inhibition ◽

Pharmaceutical Dosage Form ◽

Established Tumor ◽

End Of Treatment ◽

Activity Report

This article presents the results of preclinical study of antitumor activity of indolo[2,3-a]carbazoles N-glycosides derivative (LCS-1208) in pharmaceutical dosage form for intravenous administration - lyophilisate for injection. LCS-1208 high antitumor efficiency has been shown by different regimens of administration on tumors of diverse histogenesis: LCS-1208 exhibited increase of life span (ILS) 76% on lympoblastosis P-388 and ILS 76 % and 33 % recovery of Fisher lympadenosis L5178Y by 25 mg/kg daily intravenous administration during 5 days. Whereas LCS-1208 demonstrated high antitumor efficiency on solid tumors by 150 mg/kg single intravenous dosing: on LLC - tumor growth inhibition (TGI) 95% - 81% during 9 days and on RShM-5 (TGI 74% - 56% during 9 days). LCS-1208 appeared statistically significant TGI 51 % and 47 % on 3rd and 7th days after 150 mg/kg single intravenous dosing on established tumor. Comparative study of LCS-1208 substance and dosage form by intraperitoneal injection has shown that decrease of therapeutic dose to 110 mg/kg, which doesn’t induce death of animals, resulted only in dosage form antitumor effect (TGI 74-75 % during 8 days after the end of treatment).

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ANTITUMOR EFFECT OF HYDROGEL CISPLATIN ON ZEJDEL ASCITES HEPATOMA

Russian Journal of Biotherapy ◽

10.17650/1726-9784-2016-15-4-96-101 ◽

2016 ◽

Vol 15 (4) ◽

pp. 96-101 ◽

Cited By ~ 1

Author(s):

M. Yu. Reutovich ◽

Yu. P. Istomin ◽

O. V. Krasko ◽

H. M. Treshalina ◽

P. M. Bychkovsky ◽

...

Keyword(s):

Complete Remission ◽

Antitumor Activity ◽

Dose Range ◽

Growth Control ◽

Maximum Tolerated Dose ◽

Preclinical Study ◽

Ascites Hepatoma ◽

Risk Of Death ◽

Single Intraperitoneal Injection ◽

Intraperitoneal Therapy

Aims and objectives. During regional intraperitoneal chemotherapy cytostatics in prolonged dosage form, in particular, on the basis of various biodegradable hydrogels, such as dextran phosphate are applied. Aim of the study - a comparative evaluation of the antitumor activity ofcisplatin and cisplatin in prolonged dextran phosphate hydrogel form on Zajdel ascites hepatoma. Materials and methods. On 49 white no inbreed rats (n = 7) with implanted intraperitoneal Zajdel ascites hepatoma the antitumor activity of cisplatin in prolonged dextran phosphate hydrogel form with single intraperitoneal injection of the dosage from 3 to 8 mg/kg (≈ maximum tolerated dose, MTD) was evaluated in comparison with officinal cisplatin. The treatment efficacy was assessed by a statistically significant standard criteria: the absence of ascites by 32nd day of the experiment (complete remission) and an increase in life span of rats with ascites (T/C >_125 %, «treatment/control») in comparison with the rats without treatment (tumor growth control, where T/C = 100 %) or treated with officinal cisplatin. Macroscopic, pathomorphological and statistical analysis of the results were used. Results. It has been shown that hydrogel form of cisplatin compared to cisplatin was significantly more effective: complete remission 4/7-6/7 vs 0/7, T/C = 140-188 % vs 91-101 %, the volume of ascites 13,6 ± 6,6 ml vs 50,0 ± 7,9 ml (p = 0,004) because of a better tolerance. Regression analysis confirms that hydrogel form of cisplatin in used dose range significantly improves the rats survival with Zajdel ascites hepatoma, reducing the risk of death from tumor in 7-35 times and the relative risk with the dose of 5,5 mg/kg in 36 times (95 % CI3,86 + 327,60) (p = 0,002-0,005). Conclusions. The data obtained allow considering the hydrogel form of cisplatin as a promising prolonged this drug form of cisplatin by the intraperitoneal therapy and recommending it to preclinical study.

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