Phytolacca decandra 30 CH dilution as an anticancer agent in murine mammary adenocarcinoma model

Homeopathy is an effective and safe therapy that provides better quality of life and reduces the adverse effects of conventional therapy used in different diseases. However, there are few published studies showing effects of homeopathic medicines in cancer models. Considering the principle "like cures like" the Phytolocca decandra causes similar symptoms to those presented in cancer subjects. Therefore, the aim of this study was to evaluate the effects of homeopathic preparations of Phytolacca decandra in the development of murine mammary tumor. For this, 4T1 mammary adenocarcinoma cells were inoculated subcutaneously in the inguinal breast of female BALB/c mice. Then, mice were blind treated with water containing only vehicle (control) or vehicle with Phytolacca decandra dilutions (6CH, 12CH, 30CH or 200cH). Tumor growth was monitored in alternated days during 21 days after tumor cells inoculation. Then, mice were euthanized and tumor, spleen, and lungs were removed to histological analyses. Results showed that animals treated with 30CH when compared with other groups exhibited tumor growth delay and smaller tumor weight, less vascularization and smaller relative weight of the spleen and pulmonary metastases. Together, results obtained in this pilot study demonstrated that treatment with Phytolacca decandra 30CH dilution induces delayed of breast tumor growth suggesting that this dilution may be a promising alternative therapy in the treatment of breast cancer.

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Inhibition of Poly(ADP-Ribose) Polymerase Enhances Cell Death and Improves Tumor Growth Delay in Irradiated Lung Cancer Models

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-06-2872 ◽

2007 ◽

Vol 13 (10) ◽

pp. 3033-3042 ◽

Cited By ~ 187

Author(s):

Jeffrey M. Albert ◽

Carolyn Cao ◽

Kwang Woon Kim ◽

Christopher D. Willey ◽

Ling Geng ◽

...

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Tumor Growth ◽

Growth Delay ◽

Tumor Growth Delay ◽

Cancer Models

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M867, a Novel Selective Inhibitor of Caspase-3 Enhances Cell Death and Extends Tumor Growth Delay in Irradiated Lung Cancer Models

PLoS ONE ◽

10.1371/journal.pone.0002275 ◽

2008 ◽

Vol 3 (5) ◽

pp. e2275 ◽

Cited By ~ 30

Author(s):

Kwang Woon Kim ◽

Luigi Moretti ◽

Bo Lu

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Tumor Growth ◽

Caspase 3 ◽

Selective Inhibitor ◽

Growth Delay ◽

Tumor Growth Delay ◽

Cancer Models

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P3-030: Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models

Journal of Thoracic Oncology ◽

10.1097/01.jto.0000283787.20114.86 ◽

2007 ◽

Vol 2 (8) ◽

pp. S619-S620

Author(s):

Bo Lu

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Tumor Growth ◽

Growth Delay ◽

Tumor Growth Delay ◽

Cancer Models

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Post-Irradiated Tumor-Derived Exosomes Lead to Melanoma Tumor Growth Delay, Potentially Mediated by Death Associated Molecular Pattern (DAMPs) Proteins

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2018.06.374 ◽

2018 ◽

Vol 102 (3) ◽

pp. S155 ◽

Cited By ~ 3

Author(s):

K.K. Jella ◽

T. Nasti ◽

Z. Li ◽

D. Lawson ◽

R. Ahmed ◽

...

Keyword(s):

Tumor Growth ◽

Growth Delay ◽

Tumor Growth Delay ◽

Melanoma Tumor ◽

Molecular Pattern

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Effect of Dose, Timing and Delivery of Tumor Necrosis Factor Alpha as an Adjuvant in Cryosurgery of ELT-3 Uterine Leiomyoma (Fibroid) Tumor

Journal of Medical Devices ◽

10.1115/1.3147380 ◽

2009 ◽

Vol 3 (2) ◽

Author(s):

J. Jiang ◽

J. Bischof

Keyword(s):

Tumor Growth ◽

Uterine Fibroid ◽

Tumor Size ◽

Uterine Leiomyoma ◽

Mode Of Delivery ◽

Growth Delay ◽

Tumor Growth Delay ◽

Tnf Α ◽

Pre Treatment

Uterine leiomyoma (fibroid or myoma) is the most common indication for hysterectomy in premenopausal women. Cryomyolysis is a uterus sparing procedure in which a myoma is frozen by a cryoprobe, thereby causing tissue necrosis upon thawing and eventual reduction in myoma size. Unfortunately, although the iceball is readily visualized (by ultrasound-US or magnetic resonance-MR), the tissue at the periphery of the iceball is not completely destroyed. One potential solution to this problem is the use of cryosurgical adjuvants that increase cryosurgical image guidance and efficacy. Previous work in our lab has shown that TNF-α (native or as the nanodrug, CYT-6091, Cytimmune Sciences, Inc.) can act synergistically with cryosurgery to destroy all prostate cancer within an iceball. Building on this work, the current study was designed to test TNF-α as an adjuvant in an in vivo model of uterine fibroid (ELT-3) in a nude mouse. The aims of this study are to characterize in vivo: 1) the destruction of the uterine fibroid over time after cryosurgery; 2) the effect of TNF-α pre-treatment on enhancement of cryosurgery; 3) the effect of TNF-α dose, pre-treatment time and mode of delivery on the above and to note any toxicities. ELT–3 rat uterine fibroid cells were grown in the hind limb of female nude mice. TNF-α at various dose (2μg and 5μg) was administered at 1, 2 and 4 hours before cryotreatment in native or CYT-6091. Native TNF-α was injected either intra-tumorally or peri-tumorally. Injecting TNF-α solution into the center of the tumor comprised the intra-tumoral approach. For peri-tumoral injection, TNF-α solution was injected at each one of eight evenly distributed points spanning the circumference of the tumor base. CYT-6091 was administered by i.v. injection only. Cryosurgery was performed with a modified 1 mm diameter cryoprobe tip (−120°C). Freezing was allowed to continue to the visible edge of the tumor. Injury was assessed by measuring tumor-growth delay. Baseline tumor size was measured on day 0; fold-changes in tumor size are reported relative to size at day 0. Toxicity was evaluated by survival rate. Groups were 4–6 animals in each group. The data suggests that pre-treatment with TNF-α before cryosurgery significantly enhances visually guided destruction of uterine leiomyoma, and that the dose, timing and mode of delivery are important variables in optimization of this combination treatment. First, it was observed that at least four hours pretreatment with TNF-α is required to obtain the synergistic effect of TNF-α and cryoinjury. Second, peri-tumoral injection of native TNF-α, was the most effective delivery method to enhance cryoinjury at low dose (2μg), however it was also the most toxic method at high dose (5μg). On the other hand, CYT-6091, although less effective than peri-tumoral injection at 2μg, was the safest delivery mode (0% lethality at 2μg; 33% at 5μg). Finally, CYT-6091 delivery at 5μg with cryosurgery resulted in a dramatic tumor growth delay compared with cryosurgery alone. Therefore, i.v. injection of CYT-6091 followed by cryosurgery allowed the highest dose of TNF-α, the least toxicity and the best overall myoma reduction. Funding: R01 CA075284, American Medical Systems, Inc. TNF-α and CYT-6091: Cytimmune Sciences, Inc.

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TRU-016, An Anti-CD37 SMIP™ Biologic, In Combination with Other Therapeutic Drugs In Models of Non-Hodgkin's Lymphoma

Blood ◽

10.1182/blood.v116.21.3931.3931 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3931-3931 ◽

Cited By ~ 4

Author(s):

Paul A. Algate ◽

Jennifer Wiens ◽

Christy Nilsson ◽

Mien Sho ◽

Debra T. Chao ◽

...

Keyword(s):

Tumor Growth ◽

Follicular Lymphoma ◽

B Cell ◽

Cell Lymphoma ◽

Combination Index ◽

Growth Delay ◽

Tumor Growth Delay ◽

B Cell Malignancies

Abstract Abstract 3931 Background: CD37 is a 50–55 kDa heavily glycosylated member of the tetraspanin superfamily of molecules. This cell surface protein is expressed on normal and transformed B-cells, and has been implicated in diverse processes including cellular activation and proliferation, cell motility, and cell-cell adhesion. TRU-016 is a novel humanized anti-CD37 SMIP™ protein. Pre-clinical studies have demonstrated that anti-CD37 SMIP™ protein mediates caspase-independent direct killing of normal and malignant B-cells, a mechanism of action that appears to be different than CD20 therapies. In addition, TRU-016 results in indirect killing through NK cell mediated SMIP-protein directed cellular cytotoxicity (SDCC). The therapeutic potential of TRU-016 against several subsets of B-cell malignancies is currently being investigated in the clinic. Methods: The ability of TRU-016 to interact and increase cell killing with established therapeutics rituximab (anti-CD20 antibody), bendamustine (bi-functional alkylating agent/nucleoside analog), LY294002 (PI3K inhibitor) and temsirolimus (mTOR inhibitor) was investigated in vitro using the Rec-1 (mantle cell lymphoma) and SU-DHL-6 (diffuse large B cell lymphoma) cell lines. Individual drugs were tested in combination with TRU-016 as well as in a multiple drug cocktail. Combination index analyses were performed for drug combinations over the 20–90% effect levels. To determine whether in vitro synergy could be recapitulated in vivo, DoHH-2 (follicular lymphoma) xenografts were treated with TRU-016, bendamustine, and the combination of TRU-016 and bendamustine with or without rituximab. Furthermore, the effect of the dosing schedule with the combination of TRU-016 and rituximab was explored by comparing the treatment over a short time period to an extended (maintenance) dosing regimen. CD37 expression on the tumor xenografts was evaluated post different treatment by immunohistochemistry. Results: Combination index analyses determined that the killing effects of TRU-016 was synergistic with rituximab, bendamustine and temsirolimus in NHL models. Furthermore, TRU-016 provided additional efficacy when added to the combination of rituximab and bendamustine. In vivo results demonstrated that the in vitro synergy results were applicable to a more complex in vivo disease model. The combination of TRU-016 with bendamustine or rituximab resulted in increased tumor growth delay compared to that attained with the individual drugs. The addition of TRU-016 to the combination of bendamustine and rituximab resulted in increased tumor growth delay compared to the two drugs alone. The observed efficacy of the combination of TRU-016 and rituximab could be extended with repeated (maintenance) dosing with tumor free survival being observed beyond the 35 days of dosing. The combination of TRU-016 with temsirolimus also resulted in a reduction of tumor growth compared to either molecule alone. CD37 target expression was detected in the xenograft tumors post-treatment with all drugs tested. Conclusions: TRU-016 in combination with rituximab, bendamustine or temsirolimus increased cell killing of NHL cells in vitro over that observed for each agent alone. Furthermore, the triple combination of TRU-016 with rituximab, bendamustine or temsirolimus displayed greater anti-tumor activity in vivo than each of the agents alone against a follicular lymphoma tumor model. The addition of TRU-016 to a combination of rituximab and bendamustine resulted in increased killing in vitro and in vivo. The combinatorial activity of TRU-016 and rituximab in vivo was increased when the drugs were administered over a longer period. These results provide preclinical rationale for the potential different combinations of TRU-016 with several established therapeutics for the treatment of NHL and related B-cell malignancies. Disclosures: Algate: Trubion Pharmaceuticals: Employment. Wiens:Trubion Pharmaceuticals: Employment. Nilsson:Trubion Pharmaceuticals: Employment. Sho:Facet/Abbott: Employment. Chao:Facet/Abbott: Employment. Starling:Facet/Abbott: Employment. Gordon:Trubion Pharmaceuticals: Employment.

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An engineered immunotherapy (NKTR-214) with altered selectivity toward the IL2 receptor: Efficacy and tolerability in a murine tumor model.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3060 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3060-3060

Author(s):

Deborah H. Charych ◽

Murali Addepalli ◽

Steve Lee ◽

Thomas Chang ◽

Xiaofeng Liu ◽

...

Keyword(s):

T Cells ◽

Tumor Growth ◽

Immune Cells ◽

Tumor Model ◽

Optimal Dose ◽

Growth Delay ◽

Blue Dye ◽

Tumor Localization ◽

Tumor Growth Delay ◽

Polymer Conjugation

3060 Background: Cytokine-based immunotherapy has been successful for the treatment of cancer, with potential for durable responses in multiple indications. One approach towards stimulating the immune system is to target the heterotrimeric interleukin2 receptor, IL2R. NKTR-214 uses polymer technology to alter receptor subunit selectivity to favor expansion of CD8+ memory effector T cells (CD8T) in the tumor over CD4+ regulatory T cells (Treg). In addition, polymer conjugation is designed to improve exposure and enhance tumor localization, significantly improving efficacy, modulating vascular leak syndrome (VLS) and allowing flexible dosing regimens. Methods: C57BL/6 mice bearing established subcutaneous B16F10 melanoma were treated with NKTR-214 at a variety of doses (0.25-4.0 mg/kg) and schedules (q5dx3 to q14dx2). Mice treated with clinically validated IL2 were administered 3mg/kg, bidx5 for 2 cycles. Efficacy was measured by monitoring tumor volumes. Tolerability was evaluated by survival. VLS was measured by injection of Evans Blue dye followed by colorimetry in lungs. Tumor immunotyping, by flow cytometry. Results: Tumors from mice receiving NKTR-214 had a CD8/Treg ratio of over 1,000 versus 14 for IL2. NKTR-214 administered at 2 mg/kg, q9dx3 was identified as the optimal regimen and showed tumor growth delay of 26 days compared to 9 days for optimally dosed IL2. 90% of NKTR-214 treated mice tolerated treatment compared to 67% for IL2. VLS was completely resolved prior to administration of the next dose of NKTR-214, unlike IL2. NKTR-214 was well tolerated in rats at two schedules, at MTD. Conclusions: NKTR-214 is a highly differentiated cytokine with a new mechanism of action that may provide options for cancer immunotherapy. Polymer conjugation of a clinically validated cytokine alters the IL2R selectivity to favor expansion of tumor killing immune cells (CD8T) over regulatory immune cells (Treg) in the tumor. The conjugate is also designed to improve exposure and enhance tumor localization, offering more options of dose and schedule. The optimal dose and schedule is cytokine-sparing, provides substantial tumor growth delay, and reduces toxicity.

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