ANTITUMOR ACTIVITY OF SOME DERIVATIVES OF INDOLO[2,3-A]CARBAZOLES N-GLYCOSIDES WITH XYLOSE CARBOHYDRATE RESIDUE

Introduction. The search for new antineoplastic agents in a series of indolo[2,3-a]-carbazole derivatives is an urgent and promising direction, since compounds with antitumor activity have been found in this class. In the chemical fusion laboratory, N.N. Blokhin National Medical Research Center оf the Ministry of Health of Russia has developed an original and effective method for the synthesis of glycosides of indolo[2,3-a]-pyrrolo[3,4-c]carbazoles, which makes it possible to synthesize derivatives of N-glycosides of indolo[2,3-a]carbazoles with different substituents in the heterocyclic parts including at the maleimide nitrogen atom and with different carbohydrate residues.The purpose of the study – the primary assessment of the antitumor activity of new derivatives of indolocarbazoles with a carbohydrate residue xylose in models of tumor growth mice.Materials and methods. The compounds studied at transplanted tumors of mice: the Lewis epidermoid carcinoma (LLC), colon cancer ACATOL, cervical cancer RSHM-5, breast adenocarcinoma CA-755. Studies were performed on immunocompetent mice: males and females of BDF1 hybrids (C57Bl/6 × DBA/2), females CBA/Lac and Balb/c. Compound solutions were prepared ex tempore and administered to the mice intraperitoneally at a dose of 60 mg/kg daily for five days. The antitumor effect was evaluated as to of tumor growth inhibition and increase of life span of the treated animals as compared with the control ones.Results. Eight compounds studied, containing D-xylose as a carbohydrate component and various substituents at the maleimide nitrogen atom, showed different degrees of antitumor activity. Two derivatives have been identified: N-[5,7-dioxo-12-(β-D-xylopyranosyl)-indole[2,3-a]pyrrolo[3,4-c]carbazol-6-il]benzamide (compound 4) and N-[5,7-dioxo-12-(β-D-xylopyranosyl)-5,7,12,13-tetrahydro-6H-indole[2,3-a]pyrrolo[3,4-c]carbazole-6-il]pyridin-2-carboxamide (compound 8), which showed high antitumor activity on 4 solid tumors of mice with a duration of effect of 12 days or more. The most pronounced antitumor effect was obtained in compounds 4 and 8 in RSHM-5 and Ca-755, tumor growth inhibition was amounted, respectively: in RSHM-5 – 68–82 % and 80–72 %; for Ca-755 – 57–62 % and 86–68 % (p <0.05).Conclusion. For further research, we chose the compound (N-[5,7-dioxo-12-(β-D-xilopiranosil)-5,7,12,13-tetrahydro-6H-indole[2,3-a] pyrrolo[3,4-c]carbazol-6-il]pyridin-2-carboxamide).

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Telotristat ethyl to enhance cytotoxic chemotherapy response in preclinical cholangiocarcinoma models.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.331 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 331-331

Author(s):

Niranjan Awasthi ◽

Margaret Schwarz ◽

Roderich E. Schwarz

Keyword(s):

Antitumor Activity ◽

Tumor Growth ◽

Growth Inhibition ◽

Peritoneal Dissemination ◽

Primary Liver Cancer ◽

Tumor Growth Inhibition ◽

Chemotherapy Response ◽

Current Standard ◽

First Line Therapy ◽

Survival Studies

331 Background: Cholangiocarcinoma (CCA) is the second-most common primary liver cancer after hepatocellular carcinoma. It has a poor prognosis with a 5-year survival rate of 5-15%. The current standard first-line therapy for advanced unresectable CCA is a combination of gemcitabine and cisplatin (GemCis) chemotherapy that leads to a median survival of 6-12 months. Nanoparticle albumin-bound paclitaxel ( nab-paclitaxel, NPT) is an approved therapy for breast, NSCLC and pancreatic cancer. Elevated levels of serotonin have been reported in CCA that has protumorigenic activity. We tested the hypothesis that telotristat ethyl (TE), an inhibitor of serotonin biosynthesis, has antitumor activity in CCA and it augments GemCis and nab-paclitaxel response in preclinical CCA models. Methods: Tumor growth experiments were performed in mice subcutaneous CCA intrahepatic CCLP-1 xenografts, extrahepatic TFK-1 xenografts and patient-derived xenografts. Animal survival studies were performed using human CCA intrahepatic CCLP-1 cells in the peritoneal dissemination model in NOD/SCID mice. Results: In intrahepatic CCLP-1 subcutaneous xenografts, compared with controls, reduction in tumor growth was observed by TE (53%), GemCis (53%) or NPT (69%). The combination of TE with GemCis or NPT exhibited an additive tumor growth inhibition response, GemCis+TE (85%) and NPT+TE (90%). In extrahepatic TFK-1 subcutaneous xenografts, TE led to a significant reduction in tumor growth (51%), while GemCis and NPT reduced tumor growth by 37% and 56%, respectively. Again, an additive tumor growth inhibition effect was observed by the addition of TE to chemotherapy, GemCis+TE (67%) and NPT+TE (74%). In CCA patient-derived subcutaneous xenografts, GemCis caused the greatest tumor growth reduction (80%) followed by NPT (57%) and TE (40%). Combinations increased tumor inhibition further: GemCis+TE (95%) and NPT+TE (91%). Mouse survival in peritoneal dissemination xenografts was only marginally enhanced by TE (11%) or GemCis (9%) while NPT led to a substantial extension (60%). Interestingly, the combination of TE with GemCis or NPT demonstrated a further extension in mice survival: GemCis+TE (26%) and NPT+TE (68%). Conclusions: TE had antitumor activity and it enhanced chemotherapy effects in several CCA preclinical models indicating that this therapeutic combination has the potential to ameliorate clinical therapy for CCAs of different origin.

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Antitumor activity of nanoparticle albumin-bound paclitaxel in experimental gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.33 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 33-33 ◽

Cited By ~ 1

Author(s):

Changhua Zhang ◽

Katherine T Ostapoff ◽

Niranjan Awasthi ◽

Margaret A. Schwarz ◽

Roderich Schwarz

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Antitumor Activity ◽

Tumor Growth ◽

Growth Inhibition ◽

Tumor Growth Inhibition ◽

Human Gastric Cancer ◽

Targeting Therapy ◽

Paclitaxel Treatment

33 Background: Gastric cancer is the second most common cause of cancer related death worldwide and lacks highly effective adjuvant or definitive systemic treatment for advanced disease. Nab-paclitaxel is a novel microtubule-targeting cytotoxic agent and not tested in gastric cancer as of yet. Methods: Human gastric cancer cell lines AGS, NCI-N87 and SNU16 were studied for treatment effects on cell proliferation, mitotic arrests and apoptosis in vitro and vivo. Tumor growth and survival studies were performed in murine xenografts. Results: Nab-paclitaxel inhibited cell proliferation with an IC50 of 2.01 nM in SNU16, 23.3 nM in AGS and 48.69 nM in NCI-N87 cells after 72-hour treatment, which was lower than that of oxaliplatin (1.05 μM to 1.51μM) and epirubicin (0.12 μM to 0.25 μM). Nab-paclitaxel treatment caused increased expression of the mitotic-spindle associated phospho-stathmin, nuclear fragmentation or karyopyknosis, and apoptotic events as confirmed through increased expression of cleaved-PARP and caspase-3. After a two-week nab-paclitaxel, oxaliplatin or epirubicin treatment, the local tumor growth inhibition rate was 77, 17.2 and 21.4 percent, respectively (p=0.002). Effects of therapy on tumoral proliferative and apoptotic indices corresponded with tumor growth inhibition data, while expression of phospho-stathmin also increased in tissues. There was an increase in median animal survival after nab-paclitaxel treatment (86 days) compared to controls (24 days, p=0.0004) or to oxaliplatin therapy (37.5 days, p=0.0005). Conclusions: The strong antitumor activity of nab-paclitaxel in experimental gastric cancer supports such microtubule-targeting therapy for clinical application. Nab-paclitaxel benefits were observed independent from phosphorylated stathmin expression at baseline, putting into question the consideration of nab-paclitaxel use in gastric cancer based on this putative biomarker.

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EFFECT OF THE MYCELIUM EXTRACT FROM DUDDINGTONIA FLAGRANS FUNGUS ON SUBCUTANEOUS XENOGRAFT OF HUMAN C33a CERVICAL CARCINOMA CELLS

Siberian Journal of Oncology ◽

10.21294/1814-4861-2020-19-6-93-98 ◽

2020 ◽

Vol 19 (6) ◽

pp. 93-98

Author(s):

O. I. Solovieva ◽

E. L. Zavjalov ◽

T. V. Teplyakova ◽

L. R. Lebedev ◽

I A. Razumov

Keyword(s):

Tumor Growth ◽

Growth Inhibition ◽

Cervical Carcinoma ◽

Subcutaneous Injection ◽

Antitumor Effect ◽

Water Extract ◽

Carcinoma Cells ◽

Tumor Growth Inhibition ◽

Duddingtonia Flagrans ◽

Antitumor Effects

The purpose of the study was to analyze the antitumor effects of the extract of mycelium from Duddingtonia flagrans (strain F-882) on xenografts of human C33a cervical cancer cells.Material and Methods. To evaluate the antitumor effect, we used the absolute values of xenograft volumes and calculated the tumor growth inhibition and the index of tumor growth.Results. At the first stage of the experiment, a 4-week subcutaneous injection of the water extract of F-882 resulted in an almost twofold slowdown in xenograft growth, with the tumor growth inhibition value of 50.6 %. In the second stage of the experiment, a 2.5-week subcutaneous injection followed by a 1.5-week intratumoral injection of F-882 also caused the tumor growth inhibition. After completing F-882 injections, the effect of tumor growth inhibition continued for 2.5 weeks and the tumor growth inhibition value was 58.7 %.Conclusion. The mycelium extract F-882 was shown to have an antitumor effect on subcutaneous xenografts of human C33a cervical carcinoma cells.

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In vivo activity of R1530 (R) alone and in combination with bevacizumab (B) and peginterferon alfa-2a (P) in a renal cell carcinoma (RCC) xenograft model

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e14629 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e14629-e14629

Author(s):

B. Higgins ◽

K. Packman ◽

Y. Zhang ◽

H. Char ◽

M. Simcox ◽

...

Keyword(s):

Antitumor Activity ◽

Tumor Growth ◽

Growth Inhibition ◽

Cancer Cell ◽

Single Agent ◽

Xenograft Model ◽

Human Tumor ◽

Tumor Growth Inhibition ◽

High Dose ◽

Wide Range

e14629 Background: R1530 is a multikinase inhibitor currently in clinical phase I testing. Its inhibitory profile includes several kinases that play critical roles in cancer cell growth and division as well as tumor angiogenesis. These properties translate into a potent cytotoxicity in a wide range of cancer cell lines in vitro and tumor growth inhibition in human tumor xenografts. Preclinical studies were conducted to evaluate the effects of R alone and in combination with B and P in the Caki-1 RCC xenograft model. Methods: We initially evaluated the antitumor activity of optimal dose (OD) and 1/2 OD R alone and with OD B. This was followed up with testing of OD & 1/2 OD P ± OD B, along with triplets of 1/2 OD P + OD B + 1/2 OD R and OD P + OD B + 1/2 OD R. A final study compared 1/2 OD R to OD R triplets to attempt to increase tumor growth inhibition (TGI) and increase life span (ILS). Results: No doublets or triplets tested showed antagonism or enhanced toxicity. Antitumor activity and survival results are listed below (Table). Conclusions: 1/2 OD R + OD B or OD R + OD B doublets gave better TGI and ILS than monotherapy. Comparing these two doublets, TGI is better in the high dose combination but ILS is equivalent. All TGI and ILS are better in doublet P + B combinations over respective single agent arms except for TGI (but not ILS) for 1/2 OD P vs its correlative doublet with B. The OD P + B doublet gave better TGI and ILS than 1/2 OD P + B doublet. TGI and ILS do not differ between triplets containing OD R + 1/2 OD or OD P or for triplets containing the OD P + 1/2 OD or OD R. Therefore, either agent can be alternatively dose reduced without a loss of tumor response or detriment to survival in this preclinical model of RCC. [Table: see text] [Table: see text]

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