Trastuzumab and Liposomal Doxorubicin in the Treatment of MCF-7 Xenograft Tumor-Bearing Mice: Combination Does Not Affect Drug Serum Levels

Abstract Objectives Breast cancer is a common malignant tumor in women with limited treatment options and multiple side effects. Today, the anti-cancer properties of natural compounds have attracted widespread attention from researchers worldwide. Methods In this study, we treated 4T1 tumor-bearing Balb/c mice with intraperitoneal injection of Auraptene, paraffin oil, and saline as two control groups. Body weight and tumor volume were measured before and after treatment. Hematoxylin and eosin (H & E) staining and immunohistochemistry of Ki-67 were used as markers of proliferation. In addition, ELISA assays were performed to assess serum IFN-γ and IL-4 levels. Results There was no significant change in body weight in all animal groups before and after treatment. 10 days after the last treatment, Auraptene showed its anti-cancer effect, which was confirmed by the smaller tumor volume and H & E staining. In addition, Ki-67 expression levels were significantly reduced in tumor samples from the Auraptene-treated group compared to the paraffin oil and saline-treated groups. In addition, in tumor-bearing and normal mice receiving Auraptene treatment, IL-4 serum production levels were reduced, while serum levels of IFN-γ were significantly up-regulated in tumor-bearing mice after Auraptene treatment. Conclusions In the case of inhibition of tumor volume and Ki-67 proliferation markers, Auraptene can effectively inhibit tumor growth in breast cancer animal models. In addition, it might increases Th1 and CD8 + T cell responses after reducing IL-4 serum levels and IFN-γ upregulation, respectively. However, further research is needed to clarify its mechanism of action.

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High expression of manganese superoxide dismutase in 7,12-dimethylbenz[a]anthracene-induced ovarian cancer and increased serum levels in the tumor-bearing rats

Carcinogenesis ◽

10.1093/carcin/13.10.1941 ◽

1992 ◽

Vol 13 (10) ◽

pp. 1941-1943 ◽

Cited By ~ 9

Author(s):

Toshiyuki Nakata ◽

Keiichiro Suzuki ◽

Junichi Fujii ◽

Mutsuo Ishikawa ◽

Haruyuki Tatsumi ◽

...

Keyword(s):

Ovarian Cancer ◽

Superoxide Dismutase ◽

Manganese Superoxide Dismutase ◽

Serum Levels ◽

High Expression ◽

Tumor Bearing ◽

Manganese Superoxide

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CD11b− Donor Dendritic Cells Enhance Donor T-Cells’ Th1 Polarization and Graft Versus Leukemia Activity in Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v112.11.1252.1252 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1252-1252 ◽

Cited By ~ 1

Author(s):

Jian-Ming Li ◽

Kataryna A. Darlak ◽

Ying Lu ◽

Cynthia Giver ◽

Wayne Harris ◽

...

Keyword(s):

T Cells ◽

Serum Levels ◽

Hematopoietic Stem ◽

Treatment Groups ◽

Post Transplant ◽

Tumor Bearing ◽

Donor T Cells ◽

Ifn Γ ◽

Th1 Cytokines

Abstract Background: Based on a clinical association of donor plasmacytoid dendritic cell (DC) content with leukemia relapses after allogeneic BMT (Waller, Blood 2001), we have previously reported that CD11b− donor DC added to a graft containing FACS-purified hematopoietic stem cells (HSC) and T-cells enhanced interferon-γ (IFN-γ) production and GvL activity in MHC-mismatched allogeneic transplant mouse models (Li, Blood 2007). Objective: In this study, we studied the mechanisms whereby donor DC in the graft modulate donor T-cell activity and the graft-versus-leukemia (GvL) effect in MiHA (C3H.SW → C57BL/6J)- and MHC (C57BL/6J → B10.BR)- mismatched models of allogeneic hematopoietic stem cell transplantation (HSCT). Methods: Mice irradiated to 11 Gy received 5 × 104 log-phase viable MMB3.19 myeloid lymphoma cells via intraperitoneal injection or intravenous injection of 1 x 105 LBRM T-cell lymphoma cells one day before transplant. Allografts consisted of 5 × 104 FACS-purified donor BM CD11b− DC or CD11b+ DC plus 3 × 103 FACS-purified c-kit+ sca-1+ lineage− hematopoietic stem cells (HSC) in combination with either 3 × 105 T-cells, 3 × 105 CD8+ T-cells or no additional T-cells transplanted via tail vein. Graft-versus-host disease (GvHD) clinical scores (based on body weight loss, posture, skin, fur texture, activity) were recorded twice weekly in non-tumor bearing recipients. In vitro proliferation and cytotoxic activity of donor-derived T-cells against tumor targets was assessed by CFSE staining and a caspase flow cytometry assay (CyToxiLux PLUS) using donor T-cells harvested from recipients on day 34 and day 82 post transplant. Serum and intracellular Th1 cytokines (IFN-γ, IL-2, and TNF-α) and Th2 cytokines (IL-4, IL-5, and IL-10) from recipients’ peripheral blood and spleens day 3 and day 10 post-transplant was measured by ELISA and flow cytometry. IFN-γ direct killing of leukemia cells was tested by in vitro IFN-γ exposure. Results: In non-tumor bearing mice, recipients of all combinations of donor DC subsets, with and without donor T-cells had equivalent survival (75% – 85%) at 3 months post transplant without significant clinical signs of GvHD. Transplantation of tumor cells to recipients of HSC alone, HSC plus donor T-cells, or HSC plus T-cells and CD11b+ DC in the MiHA- and the MHC-mismatched transplant models led to 0% or 5% 3 month survival, respectively. Strikingly, tumor-bearing mice transplanted with CD11b− DC had significantly enhanced 3 month survival (35% in the MiHA-mismatched model and 45% in the MHCmismatched model) without increased GvHD (p<0.001). There was no significant difference in survival between mice that received HSC plus CD11b− DC and a mixture of CD4+ and CD8+ donor T-cells versus mice that received HSC plus CD11b− DC and only CD8+ donor T-cells. Donor T-cells harvested from recipients of CD11b− DC 34 days after transplant in the MiHA-mismatched model as well as 82 days after transplant in the MHC-mismatched model displayed increased cell proliferation following co-culture with irradiated hosttype splenocytes as a source of alloantigen compared with donor T-cells harvested from recipients of CD11b+ DC or recipients of HSC plus T-cells without donor DC. Leukemia cell killing was greater following incubation of purified donor T-cells recovered from recipients of CD11b− DC with tumor targets compared to T-cells recovered from other treatment groups. Recipients of CD11b− DC had higher serum levels of Th1 cytokines IFN-γ and IL-2 and higher number of Th1 positive donor T-cells compared with recipients of other treatment groups. In contrast, recipients of CD11b+ DC had higher serum levels of Th2 cytokines IL-4, IL-5, and IL-10 and higher number of Th2 positive donor T-cells. IFN-γ added to in vitro cultures with MMB3.19, and LBRM, had no direct cell killing effect. Conclusion: CD11b− donor DC enhanced Th1 polarization of donor T-cells and GvL without increasing GvHD. Donor CD8+ T-cells mediated tumor killing effect. CD11b+ donor DC enhanced Th2 polarization of donor CD4+ T-cells and led to limited GvHD and GvL.

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In vitro/ In vivo Electrochemical Detection of Pt(II) Species

10.26434/chemrxiv-2021-dhk4c ◽

2021 ◽

Author(s):

Alexander Vaneev ◽

Petr Gorelkin ◽

Olga Krasnovskaya ◽

Roman Akasov ◽

Daniil Spector ◽

...

Keyword(s):

Electrochemical Detection ◽

Single Cells ◽

Electrochemical Technique ◽

Breast Adenocarcinoma ◽

Tumor Spheroids ◽

Tumor Bearing ◽

Advanced Tumor ◽

Mcf 7

The biodistribution of chemotherapy compounds within tumor tissue is one of the main challenges in the development of antineoplastic drugs, and novel techniques for simple, non-expensive, sensitive, and selective detection of various analytes in tumors are of great importance. In this paper we propose the use of platinized carbon nanoelectrodes (PtNE) for electrochemical detection of platinum-based drugs in various biological models, including single cells and tumor spheroids in vitro, and inside solid tumors in vivo. We have demonstrated quantitative direct detection of Pt(II) in breast adenocarcinoma MCF-7 cells treated with cisplatin and cisplatin-based DNP prodrug. To realize the potential of this technique in advanced tumor models, we measured Pt(II) in 3D tumor spheroids in vitro and tumor-bearing mice in vivo. The concentration gradient of Pt (II) species correlated with the distance from the sample surface in MCF-7 tumor spheroids. We then performed detection of Pt(II) species in tumor-bearing mice treated intravenously with cisplatin and DNP. We found that there was deeper penetration of DNP in comparison to cisplatin. This research demonstrates a novel minimally invasive, real-time electrochemical technique for the study of platinum-based drugs.

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Role of isothiocyanate conjugate of pterostilbene on the inhibition of MCF-7 cell proliferation and tumor growth in Ehrlich ascitic cell induced tumor bearing mice

Experimental Cell Research ◽

10.1016/j.yexcr.2013.10.015 ◽

2014 ◽

Vol 320 (2) ◽

pp. 311-328 ◽

Cited By ~ 19

Author(s):

Kumar Nikhil ◽

Shruti Sharan ◽

Ajanta Chakraborty ◽

Naganjaneyulu Bodipati ◽

Rama Krishna Peddinti ◽

...

Keyword(s):

Cell Proliferation ◽

Tumor Growth ◽

Tumor Bearing ◽

Ascitic Cell ◽

Mcf 7

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Researches for the Effects and Mechanisms of Recombinant Human Erythropoietin Administrated in BALB/c Murine Models with Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.4929.4929 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4929-4929

Author(s):

Caigang Xu ◽

Yu Liu ◽

Juan Xu ◽

Meiyu Zhou

Keyword(s):

Multiple Myeloma ◽

Placebo Group ◽

Tumor Size ◽

Serum Levels ◽

Monoclonal Immunoglobulin ◽

Treatment Groups ◽

Tumor Bearing ◽

Spearman's Rho ◽

Tnf Α ◽

Individual Survival

Abstract Abstract 4929 Background Multiple myeloma myeloma accounts for approximately 1 percent of all cancers and 10 percent of hematologic cancers. It is incurable with conventional chemotherapy. Recent studies suggest that rHuEpo has additional biological effects which significantly prolonged the expected survival of six end-stage multiple myeloma (MM) patients and led to hypothesize that Epo might have an anti-neoplastic or anti-myeloma effect. This latter observation was further supported by studies. Objective Based on the myeloma models which established in BALB/c murine with MPC-11 myeloma cell line, our study is to verify the true effects, to research the suitable dose and administration way of recombinant human erythropietin(rHuEPO) for individuals with MM, as well as the possible antitumor mechanism in BALB/c murine myeloma models. Methods 550 healthful BALB/c mice were injected s.c. with 6×105 MPC-11 cells to establish the multiple myeloma models. When small palpable tumors were observed, the tumor-bearing mice were randomizedly divided into five groups which were respectively administrated the various rHuEPO doses (10,20,30,40 and 50 units per injection) and a placebo group with the saline. In the study, rHuEPO treatment was strated in 5 days after the initial MPC-11 cells injection, daily s.c. injections of rHuEPO for 30 consecutive days, followed by one injection per week for 4 weeks with a same dose as before. Hemoglobin, serum IL-6 and TNF-α were monitored before the start of rHuEPO administration and in 15 days, 30 days and 60 days after the start of rHuEPO administration. Immunofixation electrophoresis(IFE) was performed to detect the existence of the serum monoclonal immunoglobulin before the rHuEPO treatment and in 60 days after the rHuEPO-treatment. In the second part of the study, microvessel density(MVD) and TdT-mediated dUTP nick end labeling (TUNEL) techniques were performed to evaluate the tumor proliferation burden and tumor cell apoptosis respectively. Tumor volume change was monitored twice a week and weight change of tumour-bearing mice was measured once a week for every individual mouse during the whole study. Results The serum monoclonal immunoglobulin appeared in 12 days after the initial MPC-11 cells injection. There wasn't a significant decrease in tumor size of bearing cancer mice after administration of rHuEPO, and there was no significant difference among each dosage group. rHuEPO can obviously increase Hb levels in bearing cancer mice. The mice with a smaller tumor size had a higher Hb level, which resulting in a longer survival. Individual survival showed a significant positive correlation with Hb level (Spearman's rho 0.821, p=0.000), and in contrast, it had a negative correlation with tumor size (Spearman's rho 0.475, p=0.009). The serum levels of IL-6 showed no significant differences between the each rHuEPO treatment group and the placebo group, and the result was the same in the serum levels of TNF-α. Also, there is no difference in MVD between the treatment groups and placebo group. The apoptotic index of the treatment groups with rHuEPO seemed a little higher than that of the placebo group. Conclusion rHuEPO administration to the tumor-bearing mice seemed to prolong their individual survival. Insufficient evidence was found for the anti-MM therapeutic role of rHuEPO in our study. Disclosures No relevant conflicts of interest to declare.

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Competition Between Heparin and Polyethylene Glycol as Biofunctionalization for Improving Stability of Liposomal Doxorubicin

Advanced Science Engineering and Medicine ◽

10.1166/asem.2020.2496 ◽

2020 ◽

Vol 12 (2) ◽

pp. 271-277

Author(s):

Eman R. Abbase ◽

Medhat W. Shafaa ◽

Mohsen M. Mady

Keyword(s):

Polyethylene Glycol ◽

Drug Release ◽

Zeta Potential ◽

Release Rate ◽

Liposomal Doxorubicin ◽

Entrapment Efficiency ◽

Drug Release Rate ◽

Pegylated Liposomes ◽

Positively Charged ◽

Mcf 7

In order to improve liposomal doxorubicin stability, differentiation between Heparin and Polyethylene Glycol (PEG) as biofunctionalization for liposomal doxorubicin has been investigated by measuring the entrapment efficiency, size distribution, zeta potential, evaluating the in vitro potential cytotoxicity against MCF-7 (Breast cancer cell) and stability in serum by measuring the drug release rate. We synthesized Four liposomal formulations: (A) Conventional liposomes; DPPC:DOX, (B) Positively charged PEGylated liposomes; DPPC:CHOL:SA:PEG:DOX (C) Negatively charged PEGylated liposomes: DPPC:CHOl:DCP:PEG:DOX (D) positively charged liposomes to conjugate heparin; DPPC:CHOL:SA:DOX. Entrapment efficiency of doxorubicin dramatically increased after PEGylation and conjugation with heparin. In addition, zeta potential was changed upon the encapsulation of doxorubicin into conventional and PEGylated liposomes which indicates that DOX encapsulated completely into liposomes. For heparin conjugated liposomes, zeta potential was slightly changed. Sulphorhodamine-B (SRB) assay showed a greater cytotoxic effect of the liposomal doxorubicin formulations at different concentrations with respect to free drug against MCF-7 cell lines. The anticancer activity order was observed between the various liposome formulations, especially those observed with conjugated heparin liposomes. Slower drug release rate showed an order of D > C > B > A that means stability showed an order of D > C > B > A. From above results, the most stable liposomal doxorubicin formulation was the liposomal formulation D. The results optimized using heparin than PEG as biofunctionalization. Further studies are suggested for better understanding why heparin improves the stability of liposomal doxorubicin.

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Platelets actively sequester angiogenesis regulators

Blood ◽

10.1182/blood-2008-06-159541 ◽

2009 ◽

Vol 113 (12) ◽

pp. 2835-2842 ◽

Cited By ~ 195

Author(s):

Giannoula Lakka Klement ◽

Tai-Tung Yip ◽

Flavia Cassiola ◽

Lena Kikuchi ◽

David Cervi ◽

...

Keyword(s):

Growth Factor ◽

Plasma Proteins ◽

Therapeutic Response ◽

Malignant Tumors ◽

Serum Levels ◽

Regulatory Proteins ◽

Antiangiogenic Agents ◽

Tumor Bearing ◽

Antiangiogenic Therapies

AbstractClinical trials with antiangiogenic agents have not been able to validate plasma or serum levels of angiogenesis regulators as reliable markers of cancer presence or therapeutic response. We recently reported that platelets contain numerous proteins that regulate angiogenesis. We now show that accumulation of angiogenesis regulators in platelets of animals bearing malignant tumors exceeds significantly their concentration in plasma or serum, as well as their levels in platelets from non–tumor-bearing animals. This process is selective, as platelets do not take up a proportional amount of other plasma proteins (eg, albumin), even though these may be present at higher concentrations. We also find that VEGF-enriched Matrigel pellets implanted subcutaneously into mice or the minute quantities of VEGF secreted by microscopic subcutaneous tumors (0.5-1 mm3) result in an elevation of VEGF levels in platelets, without any changes in its plasma levels. The profile of other angiogenesis regulatory proteins (eg, platelet-derived growth factor, basic fibroblast growth factor) sequestered by platelets also reflects the presence of tumors in vivo before they can be macroscopically evident. The ability of platelets to selectively take up angiogenesis regulators in cancer-bearing hosts may have implications for the diagnosis and management of many angiogenesis-related diseases and provide a guide for antiangiogenic therapies.

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