scholarly journals Meta-iodobenzylguanidine induces growth inhibition and apoptosis of neuroendocrine gastrointestinal tumor cells

2002 ◽  
Vol 101 (3) ◽  
pp. 210-216 ◽  
Author(s):  
Michael Höpfner ◽  
Andreas P. Sutter ◽  
Nikolai I. Beck ◽  
Bettina Barthel ◽  
Kerstin Maaser ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Tumor Cells ◽  
Gastrointestinal Tumor ◽  
Neuroendocrine Gastrointestinal Tumor

Functional expression of heterodimeric GABAB-receptors in neuroendocrine gastrointestinal tumor cells: Evidence for a participation in neuroendocrine secretion

2001 ◽  
Vol 120 (5) ◽  
pp. A313
Author(s):  
Michael Hoepfner ◽  
Andreas Jansen ◽  
Karl-Heinz Herzig ◽  
Glassmeier Guenter ◽  
Bernhard Bettler ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Functional Expression ◽  
Gabab Receptors ◽  
Gastrointestinal Tumor ◽  
Neuroendocrine Gastrointestinal Tumor

Expression of dopamine receptors and transporter in neuroendocrine gastrointestinal tumor cells

Life Sciences ◽  
2002 ◽  
Vol 71 (6) ◽  
pp. 667-678 ◽  
Author(s):  
K Lemmer ◽  
G Ahnert-Hilger ◽  
M Höpfner ◽  
S Hoegerle ◽  
S Faiss ◽  
...  
Keyword(s):  
Dopamine Receptors ◽  
Tumor Cells ◽  
Gastrointestinal Tumor ◽  
Neuroendocrine Gastrointestinal Tumor

COMPARATIVE STUDY OF THE EFFECTS OF NOS INHIBITOR T1023 AND BEVACIZUMABUM ON GROWTH AND MORPHOLOGY OF LEWIS LUNG CARCINOMA

2019 ◽  
pp. 89-98
Author(s):  
М.В. Филимонова ◽  
В.В. Южаков ◽  
А.С. Филимонов ◽  
В.М. Макарчук ◽  
Л.Н. Бандурко ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Lung Carcinoma ◽  
Comparative Studies ◽  
Lewis Lung Carcinoma ◽  
Lewis Lung ◽  
Vegf Inhibitor ◽  
Nos Inhibitor ◽  
Experimental Group

Цель исследования - изучение механизмов противоопухолевой активности ингибитора NOS Т1023 и оценка перспективности его дальнейшей разработки. Методика. В качестве опухолевой модели использована эпидермоидная КЛЛ, штамм которой получен из банка опухолевых материалов ФГБУ РОНЦ им. Н.Н. Блохина и поддерживался на самцах мышей C57BL6j. КЛЛ трансплантировали самцам мышей F1 (CBA´C57BL6j) путем подкожного введения 1,5×106 клеток карциномы в 0,1 мл суспензии на основе среды 199 в область латеральной поверхности правого бедра. Для сравнительной оценки противоопухолевой эффективности использовали ингибитор NOS под шифром Т1023, синтезированный в лаборатории радиационной фармакологии МРНЦ им. А.Ф. Цыба, и VEGF-ингибитор бевацизумаб (БВЗ). Животным первой опытной группы ежедневно, со 2 по 20 сутки вводили соединение Т1023 (60 мг/кг, в/б); второй опытной группы - трижды, на 2, 5 и 10 сут вводили БВЗ (12 мг/кг, в/б); третьей опытной группы - по этим схемам и в таких же дозах вводили и Т1023, и БВЗ (при комбинированном применении Т1023 вводили через 4 ч после введения БВЗ). Контрольным животным в качестве плацебо со 2 по 20 сутки вводили 0,9% раствор натрия хлорида (0,2 мл, в/б). Противоопухолевые эффекты оценивали, сравнивая размеры опухолевых узлов, длительность задержки роста и индекс торможения роста опухоли у контрольных и опытных животных. Гистологические методы исследования включали иммуноокрашивание на PCNA, CD31, пимонидазол и морфометрический анализ микроскопических изображений. Результаты сравнительных исследований показали, что соединение Т1023 и VEGF-ингибитор бевацизумаб (БВЗ) оказывают однонаправленное влияние на карциному легких Льюис (КЛЛ), сопровождающееся торможением роста и подавлением метастазирования неоплазии. Воздействие и Т1023, и БВЗ вызывало снижение содержания сосудов в перитуморальных зонах и в «горячих точках» ангиогенеза, усиливало гипоксию паренхимы КЛЛ и стимулировало апоптоз опухолевых клеток. При комбинированном применении Т1023 и БВЗ их антинеопластическая эффективность в отношении ингибирования ангиогенеза и девитализации опухолевых клеток соответствовала аддитивному действию. Заключение. Результаты позволяют предполагать, что основой противоопухолевой активности Т1023 является антиангиогенное действие и свидетельствуют о перспективности применения ингибиторов NOS в ангиостатической терапии солидных злокачественных новообразований в сочетании с имеющимися антинеоваскулярными средствами. The aim. Study of mechanisms of NOS inhibitor T1023 antitumor activity and estimation of its prospects for further development. Methods. Epidermoid Lewis lung carcinoma (LLC) from N.N. Blokhin NMRCO bank of tumor materials was used as a tumor model. Maintenance of tumor cell culture was provided by intramuscular injection of tumor cells suspension to C57BL6j mice every 14 days. Then LLC cells were transplanted to male F1 mice (CBA´C57BL6j) by subcutaneous injection of 1,5×106 cells in 0,1 ml of 199 medium into the lateral surface of the right hip. Comparative studies of antitumor efficacy were carried out using NOS inhibitor T1023, synthesized in the laboratory of radiation pharmacology of A.F. Tsyb MRRC, and VEGF inhibitor Bevacizumab (BVZ). Mice from the first experimental group were injected intraperitoneally (ip) with compound T1023 at dose 60 mg / kg from day 2 to 20; animals from the second experimental group were treated with BVZ at dose 12 mg / kg ip at days 2, 5 and 10; the third experimental group received T1023 in combination with BVZ according to these schemes and at the same doses (T1023 was administered 4 hours after administration of BVZ). Mice from the control group received 0,9% sodium chloride solution (0,2 ml, ip) as a placebo daily from 2 to 20 days. Antitumor effects were assessed by comparing the tumor size, duration of tumor growth delay and the index of tumor growth inhibition in control and experimental groups. Histological examination methods included immunostaining on PCNA, CD31, pimonidazole and morphometric analysis of microscopic images. Results. Comparative studies have shown that compound T1023 and VEGF inhibitor Bevacizumab (BVZ) have unidirectional effects on Lewis lung carcinoma (LLC), accompanied by growth inhibition and suppression of metastasis of neoplasia. The effect of both T1023 and BVZ caused a decrease in vascular content in the peritumoral zones and in the “hot spots” of angiogenesis, increased the hypoxia in the LLC parenchyma, and stimulated apoptosis of tumor cells. The combined use of T1023 and BVZ, caused the antineoplastic efficacy against inhibition of angiogenesis and devitalization of tumor cells which was estimated as additive effect. Conclusion. The results suggest that the basis of antitumor activity of T1023 is the anti-angiogenic effect and indicate the prospects of using NOS inhibitors in the angiostatic therapy of solid malignant neoplasms in combination with available anti-neovascular agents.

scholarly journals Semi-Synthesis of Small Molecules of Aminocarbazoles: Tumor Growth Inhibition and Potential Impact on p53

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1637
Author(s):  
Solida Long ◽  
Joana B. Loureiro ◽  
Carla Carvalho ◽  
Luís Gales ◽  
Lucília Saraiva ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Small Molecules ◽  
Tumor Cells ◽  
Mutant P53 ◽  
Wild Type ◽  
Naturally Occurring ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Amino Derivatives ◽  
Carbazole Alkaloids

The tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. Small molecules that bind and stabilize those mutants may represent effective anticancer drugs. Herein, we report the tumor cell growth inhibitory activity of carbazole alkaloids and amino derivatives, as well as their potential activation of p53. Twelve aminocarbazole alkaloids were semi-synthesized from heptaphylline (1), 7-methoxy heptaphylline (2), and 7-methoxymukonal (3), isolated from Clausena harmandiana, using a reductive amination protocol. Naturally-occurring carbazoles 1–3 and their amino derivatives were evaluated for their potential effect on wild-type and mutant p53 activity using a yeast screening assay and on human tumor cell lines. Naturally-occurring carbazoles 1–3 showed the most potent growth inhibitory effects on wild-type p53-expressing cells, being heptaphylline (1) the most promising in all the investigated cell lines. However, compound 1 also showed growth inhibition against non-tumor cells. Conversely, semi-synthetic aminocarbazole 1d showed an interesting growth inhibitory activity in tumor cells expressing both wild-type and mutant p53, exhibiting low growth inhibition on non-tumor cells. The yeast assay showed a potential reactivation of mutant p53 by heptaphylline derivatives, including compound 1d. The results obtained indicate that carbazole alkaloids may represent a promising starting point to search for new mutp53-reactivating agents with promising applications in cancer therapy.

Efficacy of DAN-222, a novel investigational polymeric nanoparticle with topoisomerase I inhibitor, as monotherapy in breast cancer models and when combined with PARP inhibitor.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1081-1081
Author(s):  
Ashley P Wright ◽  
Jodi D Bradley ◽  
Timothy Hagerty ◽  
Emily A Wyatt
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Topoisomerase I ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Topoisomerase I Inhibitor ◽  
Polymeric Nanoparticle ◽  
Cancer Tumor

1081 Background: Patients with BRCA-positive HER2-negative breast cancer benefit from PARP inhibitor therapy, but additional benefit is still desired. PARP inhibition alone does not prevent all mechanisms for repairing damage to DNA such as homologous recombination repair. An attractive combination for treating such patients would be combining a topoisomerase I inhibitor with a PARP inhibitor given the dual mechanism this would provide for DNA damage and inhibited repair, leading to tumor cell death. This combination has been tried in multiple phase 1 studies, but myelotoxicity prevented the combination from being evaluated further. DAN-222 is a novel investigational polymeric nanoparticle conjugated with camptothecin, a topoisomerase I inhibitor, that provides significant accumulation of drug in tumor tissues via the enhanced permeability and retention (EPR) effect and significantly reduced bone marrow exposure compared to native chemotherapy. These observations underscore the potential advantages of DAN-222 alone as well as in combination with other agents such as PARP inhibitors in solid tumors. Here, we report the effects of DAN-222 monotherapy and in combination with a PARP inhibitor on the growth inhibition in an HRD+ TNBC breast cancer (MDA-MB-436) and an HRD- ovarian (OVCAR3) xenograft mouse model. Methods: HRD+ breast cancer tumor cells (MDA-MB-436) were implanted into female NCr nu/nu mice and HRD- ovarian cancer tumor cells (OVCAR3) were implanted into female CB.17 SCID mice. Mice were randomized to vehicle or treatment arms until tumors reached 2000 mm3 or day 45 (MDA-MB-436) or 1000mm3 or day 45 (OVCAR3). The groups evaluated include multiple dose levels of DAN-222 as monotherapy and those also combined with niraparib. Results: Results were consistent in both the HRD+ and HRD- tumor models with profound dose-response of DAN-222 monotherapy inhibiting tumor growth. Additionally, synergy was demonstrated when DAN-222 was combined with niraparib, clearly evident with low doses of both products when used in combination. The table below highlights the synergy of the combination of DAN-222 at 0.3 mg/kg and niraparib at 25 mg/kg above each agent alone on the tumor growth inhibition in the MDA-MB-436 xenograft. Conclusions: Combining a PARP inhibitor with a topoisomerase I inhibitor delivered via this polymeric nanoparticle delivery system (DAN-222) has synergistic efficacy in both HRD+ and HRD- xenograft tumor models. These data support continued development of DAN-222 to treat solid tumors and its combination use with PARP inhibitors.[Table: see text]

scholarly journals Highly Differentiated Anti-CD47 Antibody, AO-176, Potently Inhibits Hematologic Malignancies Alone and in Combination

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1844-1844
Author(s):  
John Richards ◽  
Myriam N Bouchlaka ◽  
Robyn J Puro ◽  
Ben J Capoccia ◽  
Ronald R Hiebsch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Tumor Growth Inhibition ◽  
Employment Equity ◽  
Equity Ownership

AO-176 is a highly differentiated, humanized anti-CD47 IgG2 antibody that is unique among agents in this class of checkpoint inhibitors. AO-176 works by blocking the "don't eat me" signal, the standard mechanism of anti-CD47 antibodies, but also by directly killing tumor cells. Importantly, AO-176 binds preferentially to tumor cells, compared to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Hematological neoplasms are the fourth most frequently diagnosed cancers in both men and women and account for approximately 10% of all cancers. Here we describe AO-176, a highly differentiated anti-CD47 antibody that potently targets hematologic cancers in vitro and in vivo. As a single agent, AO-176 not only promotes phagocytosis (15-45%, EC50 = 0.33-4.1 µg/ml) of hematologic tumor cell lines (acute myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, and T cell leukemia) but also directly targets and kills tumor cells (18-46% Annexin V positivity, EC50 = 0.63-10 µg/ml) in a non-ADCC manner. In combination with agents targeting CD20 (rituximab) or CD38 (daratumumab), AO-176 mediates enhanced phagocytosis of lymphoma and multiple myeloma cell lines, respectively. In vivo, AO-176 mediates potent monotherapy tumor growth inhibition of hematologic tumors including Raji B cell lymphoma and RPMI-8226 multiple myeloma xenograft models in a dose-dependent manner. Concomitant with tumor growth inhibition, immune cell infiltrates were observed with elevated numbers of macrophage and dendritic cells, along with increased pro-inflammatory cytokine levels in AO-176 treated animals. When combined with bortezomib, AO-176 was able to elicit complete tumor regression (100% CR in 10/10 animals treated with either 10 or 25 mg/kg AO-176 + 1 mg/kg bortezomib) with no detectable tumor out to 100 days at study termination. Overall survival was also greatly improved following combination therapy compared to animals treated with bortezomib or AO-176 alone. These data show that AO-176 exhibits promising monotherapy and combination therapy activity, both in vitro and in vivo, against hematologic cancers. These findings also add to the previously reported anti-tumor efficacy exhibited by AO-176 in solid tumor xenografts representing ovarian, gastric and breast cancer. With AO-176's highly differentiated MOA and binding characteristics, it may have the potential to improve upon the safety and efficacy profiles relative to other agents in this class. AO-176 is currently being evaluated in a Phase 1 clinical trial (NCT03834948) for the treatment of patients with select solid tumors. Disclosures Richards: Arch Oncology Inc.: Employment, Equity Ownership, Other: Salary. Bouchlaka:Arch Oncology Inc.: Consultancy, Equity Ownership. Puro:Arch Oncology Inc.: Employment, Equity Ownership. Capoccia:Arch Oncology Inc.: Employment, Equity Ownership. Hiebsch:Arch Oncology Inc.: Employment, Equity Ownership. Donio:Arch Oncology Inc.: Employment, Equity Ownership. Wilson:Arch Oncology Inc.: Employment, Equity Ownership. Chakraborty:Arch Oncology Inc.: Employment, Equity Ownership. Sung:Arch Oncology Inc.: Employment, Equity Ownership. Pereira:Arch Oncology Inc.: Employment, Equity Ownership.

Sign in / Sign up

Export Citation Format

Share Document