Nifuroxazide Mitigates Angiogenesis in Ehlrich’s Solid Carcinoma: Molecular Docking, Bioinformatic and Experimental Studies on Inhibition of Il-6/Jak2/Stat3 Signaling

Nifuroxazide is an antidiarrheal medication that has promising anticancer activity against diverse types of tumors. The present study tested the anticancer activity of nifuroxazide against Ehrlich’s mammary carcinoma grown in vivo. Furthermore, we investigated the effect of nifuroxazide on IL-6/jak2/STAT3 signaling and the possible impact on tumor angiogenesis. The biological study was supported by molecular docking and bioinformatic predictions for the possible effect of nifuroxazide on this signaling pathway. Female albino mice were injected with Ehrlich carcinoma cells to produce Ehrlich’s solid tumors (ESTs). The experimental groups were as follows: EST control, EST + nifuroxazide (5 mg/kg), and EST + nifuroxazide (10 mg/kg). Nifuroxazide was found to reduce tumor masses (730.83 ± 73.19 and 381.42 ± 109.69 mg vs. 1099.5 ± 310.83) and lessen tumor pathologies. Furthermore, nifuroxazide downregulated IL-6, TNF-α, NFk-β, angiostatin, and Jak2 proteins, and it also reduced tumoral VEGF, as indicated by ELISA and immunohistochemical analysis. Furthermore, nifuroxazide dose-dependently downregulated STAT3 phosphorylation (60% and 30% reductions, respectively). Collectively, the current experiment shed light on the antitumor activity of nifuroxazide against mammary solid carcinoma grown in vivo. The antitumor activity was at least partly mediated by inhibition of IL-6/Jak2/STAT3 signaling that affected angiogenesis (low VEGF and high angiostatin) in the EST. Therefore, nifuroxazide might be a promising antitumor medication if appropriate human studies will be conducted.

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Репрограммированые in vitro на М3 фенотип макрофаги останавливают рост солидной карциномы in vivo

ZHurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia» ◽

10.25557/0031-2991.2018.01.41-46 ◽

2018 ◽

pp. 41-46

Author(s):

А.А. Раецкая ◽

С.В. Калиш ◽

С.В. Лямина ◽

Е.В. Малышева ◽

О.П. Буданова ◽

...

Keyword(s):

Solid Tumor ◽

Antitumor Effect ◽

Tumor Development ◽

Significant Inhibition ◽

The Body ◽

Ehrlich Carcinoma ◽

Solid Carcinoma ◽

Ec Cells

Цель исследования. Доказательство гипотезы, что репрограммированные in vitro на М3 фенотип макрофаги при введении в организм будут существенно ограничивать развитие солидной карциномы in vivo . Методика. Рост солидной опухоли инициировали у мышей in vivo путем подкожной инъекции клеток карциномы Эрлиха (КЭ). Инъекцию макрофагов с нативным М0 фенотипом и с репрограммированным M3 фенотипом проводили в область формирования солидной КЭ. Репрограммирование проводили с помощью низких доз сыворотки, блокаторов факторов транскрипции STAT3/6 и SMAD3 и липополисахарида. Использовали две схемы введения макрофагов: раннее и позднее. При раннем введении макрофаги вводили на 1-е, 5-е, 10-е и 15-е сут. после инъекции клеток КЭ путем обкалывания макрофагами с четырех сторон область развития опухоли. При позднем введении, макрофаги вводили на 10-е, 15-е, 20-е и 25-е сут. Через 15 и 30 сут. после введения клеток КЭ солидную опухоль иссекали и измеряли ее объем. Эффект введения макрофагов оценивали качественно по визуальной и пальпаторной характеристикам солидной опухоли и количественно по изменению ее объема по сравнению с группой без введения макрофагов (контроль). Результаты. Установлено, что M3 макрофаги при раннем введении от начала развития опухоли оказывают выраженный антиопухолевый эффект in vivo , который был существенно более выражен, чем при позднем введении макрофагов. Заключение. Установлено, что введение репрограммированных макрофагов M3 ограничивает развитие солидной карциномы в экспериментах in vivo . Противоопухолевый эффект более выражен при раннем введении М3 макрофагов. Обнаруженные в работе факты делают перспективным разработку клинической версии биотехнологии ограничения роста опухоли, путем предварительного программирования антиопухолевого врожденного иммунного ответа «в пробирке». Aim. To verify a hypothesis that macrophages reprogrammed in vitro to the M3 phenotype and injected into the body substantially restrict the development of solid carcinoma in vivo . Methods. Growth of a solid tumor was initiated in mice in vivo with a subcutaneous injection of Ehrlich carcinoma (EC) cells. Macrophages with a native M0 phenotype or reprogrammed towards the M3 phenotype were injected into the region of developing solid EC. Reprogramming was performed using low doses of serum, STAT3/6 and SMAD3 transcription factor blockers, and lipopolysaccharide. Two schemes of macrophage administration were used: early and late. With the early administration, macrophages were injected on days 1, 5, 10, and 15 following the injection of EC cells at four sides of the tumor development area. With the late administration, macrophages were injected on days 10, 15, 20, and 25. At 15 and 30 days after the EC cell injection, the solid tumor was excised and its volume was measured. The effect of macrophage administration was assessed both qualitatively by visual and palpation characteristics of solid tumor and quantitatively by changes in the tumor volume compared with the group without the macrophage treatment. Results. M3 macrophages administered early after the onset of tumor development exerted a pronounced antitumor effect in vivo , which was significantly greater than the antitumor effect of the late administration of M3 macrophages. Conclusion. The observed significant inhibition of in vivo growth of solid carcinoma by M3 macrophages makes promising the development of a clinical version of the biotechnology for restriction of tumor growth by in vitro pre-programming of the antitumor, innate immune response.

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ANTITUMOR EFFECT OF COLLOIDAL SILVER BISILICATE IN EXPERIMENTAL IN VITRO AND IN VIVO STUDIES

Problems in oncology ◽

10.37469/0507-3758-2019-65-5-760-765 ◽

2019 ◽

Vol 65 (5) ◽

pp. 760-765

Author(s):

Margarita Tyndyk ◽

Irina Popovich ◽

A. Malek ◽

R. Samsonov ◽

N. Germanov ◽

...

Keyword(s):

Antitumor Activity ◽

Tumor Growth ◽

Tumor Cells ◽

Human Tumor ◽

Significant Inhibition ◽

In Vivo Studies ◽

Ehrlich Carcinoma ◽

In Vivo Experiments

The paper presents the results of the research on the antitumor activity of a new drug - atomic clusters of silver (ACS), the colloidal solution of nanostructured silver bisilicate Ag6Si2O7 with particles size of 1-2 nm in deionized water. In vitro studies to evaluate the effect of various ACS concentrations in human tumor cells cultures (breast cancer, colon carcinoma and prostate cancer) were conducted. The highest antitumor activity of ACS was observed in dilutions from 2.7 mg/l to 5.1 mg/l, resulting in the death of tumor cells in all studied cell cultures. In vivo experiments on transplanted Ehrlich carcinoma model in mice consuming 0.75 mg/kg ACS with drinking water revealed significant inhibition of tumor growth since the 14th day of experiment (maximally by 52% on the 28th day, p < 0.05) in comparison with control. Subcutaneous injections of 2.5 mg/kg ACS inhibited Ehrlich's tumor growth on the 7th and 10th days of the experiment (p < 0.05) as compared to control.

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P01.16 Effects of the STAT3 inhibitors on senescent tumour cells

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-itoc7.29 ◽

2020 ◽

Vol 8 (Suppl 2) ◽

pp. A16.1-A16

Author(s):

O Sapega ◽

R Mikyskova ◽

K Musilek ◽

J Bieblova ◽

Z Hodny ◽

...

Keyword(s):

Cell Proliferation ◽

Czech Republic ◽

Cell Lines ◽

Cellular Senescence ◽

Tumour Cells ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Stat3 Phosphorylation

BackgroundCellular senescence is the process of cell proliferation arrest. Premature cellular senescence can be induced by chemotherapy, irradiation and, under certain circumstances, by cytokines. Senescent cells produce a number of secreted proteins and growth factors that may either stimulate or inhibit cell proliferation. One of the major cytokines that play role in regulation of cellular senescence is IL-6. IL-6/STAT3 signaling pathway represent decisive regulatory factors in cellular senescence. The objective of this study was to compare the effects of the STAT3 inhibitors on senescent and proliferative tumour cells. Further, the therapeutic potential of the STAT3 inhibitors was evaluated using murine tumour models.Materials and MethodsIn vitro, as well as in vivo experiments were performed using TC-1 (model for HPV16-associated tumours) TRAMP-C2 (prostate cancer) cell lines. C57Bl/6NCrl mice, 7–8 weeks old, were obtained from Velaz (Prague, Czech Republic). Experimental protocols were approved by the Institutional Animal Care Committee of the Institute of Molecular Genetics (Prague, Czech Republic). STAT3 inhibitors, namely STATTIC, BP-102 (synthesised at the University of Hradec Kralove) and their derivatives were tested for their effects on tumour cells, such as cytotoxicity, ability to inhibit STAT3 phosphorylation, cell proliferation and tumour growth in syngeneic mice.ResultsWe have previously demonstrated that docetaxel-induced senescence in the TC-1 and TRAMP-C2 murine tumour cell lines, which was proved by in vitro (detection of increased p21 expression, positive beta-galactosidase staining, and the typical SASP capable to induce ‘bystander’ senescence), and in vivo experiments, using C57BL/6 mice [1]. Both TC-1 and TRAMP-C2 cells displayed elevated IL-6 secretion and activated STAT3 signaling pathway. Therefore, we tested efficacy of the STAT3 inhibitors on these cell lines. Cytotoxic and STAT3 phosphorylation inhibitory effects of the inhibitors were observed in both proliferating and senescent cells. Antitumor effects of selected inhibitors were evaluated.ConclusionsCollectively, STAT3 is an attractive target for therapeutic approaches in cancer treatment and we can assume that inhibition of the STAT3 pathway can be used for elimination of the pernicious effects of the senescent cells.ReferenceSimova J, Sapega O, Imrichova T, Stepanek I, Kyjacova L, Mikyskova R, Indrova M, Bieblova J, Bubenik J, Bartek J, et al: Tumor growth accelerated by chemotherapy-induced senescent cells is suppressed by treatment with IL-12 producing cellular vaccines. Oncotarget7: 54952–54964, 2016. This work was supported by the research grant No. NV18-05-00562 provided by the Grant Agency of the Ministry of Health of the Czech Republic.Disclosure InformationO. Sapega: None. R. Mikyskova: None. K. Musilek: None. J. Bieblova: None. Z. Hodny: None. M. Reinis: None.

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Dichotomous role of Shp2 for naïve and primed pluripotency maintenance in embryonic stem cells

10.21203/rs.3.rs-727080/v1 ◽

2021 ◽

Author(s):

Seong Min Kim ◽

Eun-Ji Kwon ◽

Yun-Jeong Kim ◽

Young-Hyun Go ◽

Ji-Young Oh ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Embryonic Stem ◽

Erk Signaling ◽

Differentiation Potential ◽

Stat3 Signaling ◽

Stat3 Phosphorylation ◽

Pluripotency Maintenance

Abstract The requirement of the Mek1 inhibitor (iMek1) during naïve pluripotency maintenance results from the activation of the Mek1-Erk1/2 (Mek/Erk) signaling pathway upon leukemia inhibitory factor (LIF) stimulation. Through a meta-analysis of previous genome-wide screening for negative regulators of naïve pluripotency, Ptpn11 (encoding the Shp2 protein, which serves both as a tyrosine phosphatase and putative adapter), was predicted as one of the key factors for the negative modulation of naïve pluripotency through LIF-dependent Jak/Stat3 signaling. Using an isogenic pair of naïve and primed mouse embryonic stem cells (mESCs), we demonstrated the differential role of Shp2 in naïve and primed pluripotency. Loss of Shp2 increased naive pluripotency by promoting Jak/Stat3 signaling and disturbed in vivo differentiation potential. In sharp contrast, Shp2 depletion significantly impeded the self-renewal of ESCs under primed culture conditions, which was concurrent with a reduction in Mek/Erk signaling. Similarly, upon treatment with an allosteric Shp2 inhibitor (iShp2), the cells sustained Stat3 phosphorylation and decoupled Mek/Erk signaling, thus replacing the use of iMek1 not only for maintenance but also for the establishment of naïve ESCs through reprogramming. Taken together, our findings highlight the differential roles of Shp2 in naïve and primed pluripotency and propose the usage of iShp2 instead of iMek1 for the efficient maintenance and establishment of naïve pluripotency.

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Phytochemical profile, toxicological evaluation of Rhipsalis baccifera (Sol.) Stearn (Cactaceae) extract and their antitumor activity in Ehrlich carcinoma-bearing mice

10.53365/nrfhh/142159 ◽

2021 ◽

Author(s):

Jéssica Alves Cavalcantea ◽

Luiz da Silva Maia Neto ◽

Anna Lígia de Castro Figueiredo ◽

Weslley Oliveira ◽

José Roberto Pimentel Cabral de Seixas ◽

...

Keyword(s):

Antitumor Activity ◽

Therapeutic Potential ◽

Lethal Dose ◽

Artemia Salina ◽

Subsequent Treatment ◽

Ehrlich Carcinoma ◽

Toxicological Evaluation ◽

Phytochemical Profile

Rhipsalis baccifera (Sol.) Stearn is a typical cactus from tropical regions with wide geographic distribution, and its therapeutic potential is not yet fully understood, such as antitumoral property. Thus, this study evaluated the cytotoxic ethanolic extract of R. baccifera (EERB) and its antitumor activity against Erlich's tumor in mice. The EERB was obtained, and its phytochemical profile was filed by thin-layer chromatography. The toxicity was evaluated in vitro and in vivo using the microcrustacean Artemia salina Leach and mice. The lethal dose was determined after implantation of a tumor cell suspension, with subsequent treatment with EERB (200 mg/kg and 100 mg/kg) 48h after implantation. These values represent the tenth part of the DL50 and CL50, respectively. The presence of phenols, tannins and triterpenes were demonstrated in the phytochemical results. Toxicity was dose-dependent, and the tumor inhibition was 84.1% and 75.8% at doses of 200 mg/kg and 100 mg/kg, respectively. We can highlight that the growth of Erlich's carcinoma suffered inhibitory effects against the EERB. EERB was found to have low acute toxicity and a high potential for use in antitumor therapy. Thus, new studies involving pre-clinical and clinical analyses of the extract are essential to determine the safe dose.

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Leonurine-Repressed miR-18a-5p/SOCS5/JAK2/STAT3 Axis Activity Disrupts CML malignancy

Frontiers in Pharmacology ◽

10.3389/fphar.2021.657724 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hui-Min Liu ◽

Chun-Ling Guo ◽

Yao-Fang Zhang ◽

Jian-Fang Chen ◽

Zhi-Peng Liang ◽

...

Keyword(s):

Biological Activity ◽

Chronic Myeloid Leukemia ◽

Anticancer Activity ◽

Colony Formation ◽

Myeloid Leukemia ◽

Xenograft Growth ◽

Stat3 Signaling ◽

Natural Alkaloid ◽

Active Natural

Leonurine, an active natural alkaloid compound isolated from Herba leonuri, has been reported to exhibit promising anticancer activity in solid tumors. The aim of this study was to explore whether leonurine is able to inhibit chronic myeloid leukemia (CML) malignancy. Here, we found that leonurine dose dependently inhibited the proliferation, migration, colony formation and promoted apoptosis of CML cells. Furthermore, leonurine markedly reduced CML xenograft growth in vivo. Mechanically, leonurine upregulated SOCS5 expression, thus leading JAK2/STAT3 signaling suppression. Silencing of SOCS5 by its siRNA abrogated the effect of leonurine on CML cells, demonstrating that SOCS5 mediates the anti-leukemia effect of leonurine. Notably, we observed that miR-18a-5p was remarkably increased in CML cells. Treating CML cells with leonurine significantly decreased miR-18a-5p expression. Moreover, we found miR-18a-5p repressed SOCS5 by directly targeting its 3′-UTR. miR-18a-5p downregulation induced by leonurine reduced the biological activity of CML cells by relieving miR-18a-5p repression of SOCS5 expression. Taken together, leonurine exerts significant anti-leukemia efficacy in CML by regulating miR-18a-5p/SOCS5/JAK2/STAT3 axis.

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Anticancer Activity Of Plant Genus Clerodendrum (Lamiaceae): A Review

Majalah Obat Tradisional ◽

10.22146/mot.31554 ◽

2017 ◽

Vol 22 (3) ◽

pp. 182

Author(s):

Donald Emilio Kalonio ◽

Rini Hendriani ◽

Elisabeth N. Barung

Keyword(s):

Molecular Docking ◽

Anticancer Activity ◽

Docking Simulation ◽

Scientific Data ◽

Anticancer Effect ◽

Literature Study ◽

Molecular Docking Simulation ◽

Chemical Content

Plants of the genus Clerodendrum (Lamiaceae) is widespread in tropical and subtropical regions. Plants of this genus are used both empirically and scientifically as anti-inflammatory, antidiabetic, antimalarial, antiviral, antihypertensive, hypolipidemic, antioxidant, and antitumor. Results of the molecular docking simulation of chemical content of these plants could potentially provide an anticancer effect. This paper aims to review the anticancer activity of plant genus Clerodendrum based on scientific data. The method used in this study is the literature study. Searches were conducted online (in the database PubMed, Science Direct and Google Scholar) and on various books (Farmakope Herbal Indonesia and PROSEA). A total 12 plants of the genus Clerodendrum have anticancer activity in vitro and in vivo, thus potentially to be developed as a source of new active compounds with anticancer activity.

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STAT3 Activation Promotes NK Cell Proliferation, NKG2D Expression, and NK Cell Antitumor Activity

Blood ◽

10.1182/blood.v116.21.105.105 ◽

2010 ◽

Vol 116 (21) ◽

pp. 105-105

Author(s):

Prasad Phatarpekar ◽

Shiguo Zhu ◽

Cecele J. Denman ◽

Nam Nguyen-Jackson ◽

Stephanie S. Watowich ◽

...

Keyword(s):

Cell Proliferation ◽

Antitumor Activity ◽

Nk Cells ◽

Nk Cell ◽

Stat3 Signaling ◽

Nkg2d Expression ◽

Stat3 Phosphorylation ◽

Phosphorylated Stat3 ◽

Stat3 Inhibition

Abstract Abstract 105 Background: Signal Transducer and Activator of Transcription 3 (STAT3) activation plays an important role in carcinogenesis, and is recognized as a therapeutic target in many human malignancies. STAT3 was also found to be an important negative regulator in cellular immunity, and in some animal models inhibition of STAT3 has been effective in improving NK antitumor efficacy. However, there has been little direct assessment for the role of STAT3 signaling in human NK cells. We previously described robust ex vivo expansion and activation of NK cells by cocultivation with K562-based artificial antigen presenting cells (aAPC) genetically modified to express membrane bound IL-21 (mIL21). We found that mIL21 results in greater proliferation, longer telomere length, and less senescence than NK cells expanded with mIL15. Since STAT3 is predominantly activated by IL-21 whereas IL-15 predominantly activates STAT5, we hypothesized that activation of STAT3 plays a critical role in NK cell expansion and anti-tumor activity. We also found that the histone deacetylase (HDAC) inhibitor MS275 upregulates NKG2D expression, whereas the HDAC inhibitor valproic acid downregulates NKG2D expression. We found that STAT3 is constitutively phosphorylated in NK cells, and valproic acid, but not MS275, efficiently inhibits STAT3 tyrosine phosphorylation. This led us to hypothesize that constitutive STAT3 phosphorylation is required for NKG2D expression and NK cell antitumor activity. Objective: To assess the role of STAT3 phosphorylation in NK cell proliferation, NKG2D expression, and antitumor activity. Methods: In human NK cells, small molecule STAT3 inhibitors JSI-124 and S3I-201 were applied to block STAT3 phosphorylation. In mice, floxed STAT3 was deleted in hematopoietic cells by Cre expression under the Tie2 promoter. NK cell proliferation was induced by K562 aAPCs expressing mIL21. IL10 and IL21 were applied to induce STAT3 phosphorylation. STAT3 phosphorylation was detected by western blot and phospho-flow. NKG2D expression and NK cell cytoxicity were evaluated by flow cytometry and Calcein release assay. STAT3 binding to DNA upstream of NKG2D was assessed by ChIP assay. Statistical comparison was performed by paired Student's t test using GraphPad Prism. Results: Analysis of phosphorylated STAT3 in NK cells by phospho-flow showed increased levels of activated STAT3 in NK cells stimulated with mIL-21 compared to mIL-15. We found that inhibition of STAT3 strongly suppressed the expansion of NK cells and significantly reduced cytotoxicity of expanded NK cells. We found that NKG2D surface expression on NK cells was significantly downregulated by STAT3 inhibitors, and accordingly, NK cell mediated killing activity was decreased. Conversely, STAT3 activation in primary NK cells by IL10 and IL21 upregulated NKG2D expression, resulting in increased NK cell mediated tumor lysis that could be reversed by small molecule STAT3 inhibition. We then analyzed NKG2D expression on NK cells in mice, and found that NKG2D expression in STAT3 knockouts was significantly lower than on wild type mice. By ChIP assay, we found that phosphorylated STAT3 directly binds upstream of NKG2D. IL10 and IL21 increased this binding, and STAT3 inhibition decreased this binding. Conclusions: Our finding of an immune-activating role for STAT3 in NK cells differs from previous reports, and is for the first to show that NK cell proliferation, NKG2D expression, and cytotoxicity is regulated by STAT3 phosphorylation. This novel role for STAT3 signaling may be important in the application of targeted STAT3 therapies and in improving NK cell therapeutic efficacy for patients with cancer. Work is in progress to delineate downstream signaling of STAT3 in NK cells. Disclosures: No relevant conflicts of interest to declare.

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Erythropoietin regulates POMC expression via STAT3 and potentiates leptin response

Journal of Molecular Endocrinology ◽

10.1530/jme-15-0171 ◽

2015 ◽

Vol 56 (2) ◽

pp. 55-67 ◽

Cited By ~ 8

Author(s):

Soumyadeep Dey ◽

Xiaoxia Li ◽

Ruifeng Teng ◽

Mawadda Alnaeeli ◽

ZhiYong Chen ◽

...

Keyword(s):

Energy Expenditure ◽

Culture System ◽

Arcuate Nucleus ◽

Ex Vivo ◽

High Dose ◽

Reduced Body ◽

Stat3 Signaling ◽

Stat3 Phosphorylation ◽

Neural Cultures

The arcuate nucleus of the hypothalamus is essential for metabolic homeostasis and responds to leptin by producing several neuropeptides including proopiomelanocortin (POMC). We previously reported that high-dose erythropoietin (Epo) treatment in mice while increasing hematocrit reduced body weight, fat mass, and food intake and increased energy expenditure. Moreover, we showed that mice with Epo receptor (EpoR) restricted to erythroid cells (ΔEpoRE) became obese and exhibited decreased energy expenditure. Epo/EpoR signaling was found to promote hypothalamus POMC expression independently from leptin. Herein we used WT and ΔEpoREmice and hypothalamus-derived neural culture system to study the signaling pathways activated by Epo in POMC neurons. We show that Epo stimulation activated STAT3 signaling and upregulated POMC expression in WT neural cultures. ΔEpoREmice hypothalamus showed reduced POMC levels and lower STAT3 phosphorylation, with and without leptin treatment, compared toin vivoandex vivoWT controls. Collectively, these data show that Epo regulates hypothalamus POMC expression via STAT3 activation, and provide a previously unrecognized link between Epo and leptin response.

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In the Search for New Anticancer Drugs, IV+ Antitumor Activity of Seleno-TEPA

Zeitschrift für Naturforschung B ◽

10.1515/znb-1983-0917 ◽

1983 ◽

Vol 38 (9) ◽

pp. 1138-1141 ◽

Cited By ~ 3

Author(s):

Maria Konieczny ◽

Peter L. Gutierrez ◽

George Sosnovsky

Keyword(s):

Antitumor Activity ◽

Anticancer Activity ◽

Anticancer Drugs ◽

Human Cell ◽

Human Cell Lines ◽

Colony Assay ◽

Selenium Analog ◽

New Anticancer Drugs ◽

Cell Colony

Abstract In order to test the effect of selenium on the anticancer activity of alkylating drugs, Seleno-TEPA (4), the selenium analog of the clinically used Thio-TEPA (1) was tested in vivo against the lymphocytic P 388 and lymphoid L1210 murine leukemias. Compound 4 is more active against P 388 leukemia than against L1210, and appears to be active over a narrower concentration range than Thio-TEPA (1). Compound 4 is less active against P 388 leukemia than 1, as evidenced by the T/C values of 164 for 4 and 239 for 1 at a dose of 4.2 mg/kg. The activity of 4 was also evaluated on the HL60 and K 562 human cell lines. Under the conditions of the cell colony assay technique, Seleno-TEPA (4) is less effective than Thio-TEPA (1).

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