Colorectal cancer neoadjuvant therapy

Advanced Therapy of Surgical Oncology


Student Project abstract The investigation of platinum-based drug effect on tumor stem cells responsible for tumor generation and propagation is a novel and expanding field, and in the colorectal cancer casuistry they are many features uncovered. Studies concerning the action of platinum compounds against immune mechanisms focusing activated lymphocytes involved could bring novelties in the field of cancer cell biochemistry and function.

Our aim is to perform a multidisciplinary and translational study that impact patient care in colorectal carcinoma. The project objective is to evaluate the platinum-containing drugs effect on stem cells in colorectal carcinoma, this population being responsible for the resistance against chemotherapy treatment.

It is feasible to assess the platinum-treated stem cells, with accent on apoptosis, multidrug resistance, metabolism and cell signaling.

Biopsy and FNAC are invasive procedures, especially in the case of deeply located tumors, and may present severe complications such as infection, bleeding, or inflammation. More importantly, they also carry the risk of seeding tumor cells around the sampling area. Indeed, detached cells can be cleared by interstitial fluids to lymph nodes, or into the veins draining the tissue, thus entering the circulation.

The project intends to investigate the percent of stem cells having genetic mutations, and the effect of platinum-based compounds on cell populations which display chemoresistance versus targeted anti-EGFR therapy.

We propose also to examine the lymphocyte populations implicated in antitumoral immune response, in colorectal cancer neoadjuvant therapy to establish the magnitude of immunomodulation following the platinum condiloamele faringelui action. General objectives of the project A multidisciplinary assessment is proposed, which is capable to merge the scientific achievements of basic and clinical studies and to improve the results quality.

Our aim is to perform a basic and translational study that impact patient care in colorectal carcinoma.

colorectal cancer neoadjuvant therapy

The project main objective is to evaluate the platinum-containing drugs impact on stem cells, these population being responsible for the tumoral dissemination and resistance against chemotherapy treatment. The clue of the treatment resides in the proportion of stem cells inhibited by the drug in the whole tumoral population, and the project proposes to identify and characterize the changes which occur in colon carcinoma stem cells during platinum chemotherapy.

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It is feasible to compare using functional genomic colorectal cancer neoadjuvant therapy the platinum-treated stem and non-stem in the tumoral mass with accent on cells apoptosis, multidrug resistance, metabolism and cell signaling.

The project intends to investigate the percent of stem cells having genetic mutations, and the effect of platinum-based compounds on EGFR-chemoresistant cell populations. One of our objectives is to scan the lymphocyte populations implicated in antitumoral immune response, emphasizing the CD8 positive T lymphocytes and the natural killer cells, in hpv to herpes to establish the magnitude of the changes in human body immune response potential following the platinum compounds action.

Lymphocytes from both peripheral blood and lymph nodes will be evaluated. The proposed objectives were completed, bringing new, significant results in biochemistry of the platinum compounds, the most important metal involved in chemotherapy, but also the platinum-group metals PGMother metal complexes and their ligands showing therapeutic potential.

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We revealed multiple aspects of platinum-based chemotherapy, which join the outcomes of colorectal cancer neoadjuvant therapy biochemical, genomic, proteomic and immune methods in order to improve the therapeutically benefits. After accomplishing all phases of the project, the final results of the project are: Scientific publications which acknowledges the project, indexed on Web of Science Thomson Reuters ISI: 1.

IF 0,; influency score 0, Synthesis of structural analogues of hexadecylphosphocholine and their antineoplastic, antimicrobial and amoebicidal activity. European Journal of Medicinal Chemistry, Imunomodulatory potential of palladium II complexes with 1E,6E -1,7-bis 3,4-dimethoxyphenyl hepta-1,6-diene-3,5-dione. Notulae Botanicae Horti Agrobotanici,43 2 : Platinum derivatives: generic brands vs.

Journal: Inorganic Chemistry Communications Elsevier, — Papers in journals indexed by international databases: Clujul Medical,88 3 : Ferdinand Devinsky from the Comenius University in Bratislava. Gregory S. Virag, M. Perde-Schrepler, C. Tatomir, Hpv oireet naisella. Decean, E.

Fischer-Fodor: UVB-activated signaling pathways and their modulation with Vitis vinifera seeds extract in human skin cells, Abstract Book, pages Virag, E. Improved oxygen-carrying blood substitutes in vitro effect on hematopoietic and endothelial cells. Poster presentation. Virag, O. Balacescu, E. Fischer-Fodor, M. Perde Schrepler, C. Tatomir, L.

Colorectal cancer neoadjuvant therapy

Balacescu, I. Biochemical aspects of apoptosis and immunomodulation as a consequence of the treatment with platinum complexes and other metal-based compounds with antitumor therapeutic potential Through two main activities: 6. Evaluation of the molecules implicated in apoptotic signaling pathways in colorectal cells treated with metal complexes 6. Assessment of the metal compounds effect on lymphocyte subsets and cellular adhesion molecules The final phase of the project, PHASE VI December 10th December 31st was implemented by completing the following objective: 6.

Evaluation of the molecules implicated in apoptotic signaling pathways in colorectal cells treated with metal complexes In order to identify new biomarkers connected to the apoptotic processes induced by metal compounds, the biologic colorectal cancer neoadjuvant therapy of a new class of dysprosium complexes was studied; the antiproliferative effect of the Dy compounds was compared with that of standard platinum-based drugs.

The complex and its ligand toxicity were and we proved the decisive role of the central metal in the colorectal cancer neoadjuvant therapy biologic activity and in early apoptosis triggering. The treated tumor cell populations were exposed to a uniform magnetic filed, with an intensity which does not affected the cells viability, and we observed that unlike to the ligand or the platinum drugs, the magnetic field applied concomittant with in Dy III Na ampy 4]n treatment induced a stronger growth inhibitory hpv virus treatment uk on tumor populations.

The cancer cells drug resistance was impeded by the simultaneous application of the Dy complex and the magnetic field; this phenomenon was monitored through the evaluation of the MDR-1 biomarker of drug efflux in the cell, and a statistic significance was proved. The results of the research were published in the manuscript entitled: Multifunctional applications of a dysprosium-based metal—organic chain with single-ion magnet condiloame în deschiderea externă a uretrei, Belén Fernández, Itziar Oyarzabal, Eva Fischer-Fodor, Sergiu Macavei, Ignacio Sánchez, José M.

CrystEngComm,18, Under the frame of the 6. The compounds were synthesized and fully characterized by the team of Prof. Smith from the University of Cape Town, and published in J. Chem, The complexes were tested in vitro in order to elucidate their biologic activity against human colon cells in vitro. The inhibitory effect against the tumor cell populations was tested by MTT method and the degree of the toxicity was quantified using the IC50 half inhibitory concentration parameter, which revealed a colorectal cancer neoadjuvant therapy toxicity colorectal cancer neoadjuvant therapy the invasive, mutant colon cancer cells.

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The compounds potential to induce the programmed cell death was evaluated through the identification by Annexin V binding of phosphatidyl-serine translocated to the cell outer membrane during apoptosis.

In parallel, the number of necrotic cells was evaluated. This data are well correlated with the iron cellular uptake, measured with atomic absorption spectrometry. A manuscript was elaborated jointly with the research partners from South Africa.

Assessment of the metal compounds effect on lymphocyte subsets and cellular adhesion molecules The activity colorectal cancer neoadjuvant therapy to achieve the phase VI objective was the study of two complexes of the Platinum Group Metals PGMsteric isomers, having as central metal Pd II and the ligand 1e,6e -1,7-bis 4-dimethylamino phenyl hepta-1,6-diene-3,5 dione, in two different conformations.

Their antiproliferative effect was tested with colorimetric viability methods; the ligand was inactive, while the two complexes half inhibitory concentrations were significant lower was of ligand, proving a structure-activity relationship.

More, the dose-response correlation was found in both complexes; the colorectal cancer neoadjuvant therapy conformer A being more active against colon tumor cells.

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The compounds inclusion inside the tumor cells was evaluated based on their autofluorescence; a higher accumulation was observed in k-ras mutant DLD-1 cells. The second research direction was to elucidate the role of A si B, on cellular adhesion molecules. In this purpose we studied the effect of the metal complexes A and B against the peripheral blood mononuclear cells Colorectal cancer neoadjuvant therapy on the compounds modulator effect on the neural cell adhesion molecule NCAM or CD56 biomarker, which characterizes the cytotoxic natural killer cell subset.

In the antitumor immune response an important role is of adhesion and activation marker CD11a ITGAL and of tumor necrosis factor CD27; their expression was quantified using the flow cytometry and a statistic significant correlation was found with the presence of CD56 markers on the PBMC cell membrane.

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The expression of these membrane markers was significantly different in untreated cells versus the cells treated with A and B, in CD56 pisotive NK cells and in CD14 positive monocytes. The research results were published in Studia Universitatis UBB Chemia,61, 3 I :with the title: Cytotoxic activity of palladium II complexes of 1e,6e -1,7-bis 4-dimethylamino phenyl hepta-1,6-diene-3,5-dione against human colon carcinoma, authors: N.

Miklasova, R. Miklas, P. Virag, C. Tatomir, C.

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Szalontai, D. Cenariu, F. Devinsky, E. Analogous structures of PGM metal complexes Pd 1 and Pt 2 with the ligand 1e,6e -1,7-bis 4-dimethylamino phenyl hepta,5 dione were tested for their immunomudulator effects. The testing was performed o CD4 positive helper and CD8 positive cytotoxic T lymphocyte subpopulations, involved in antitumor respeonse of the cellular immune system.

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The ligand alone has a slight effect on the studied membrane markers, and complex 1 strongly interfere with the costimulatory prcesses in the cellular immune system. Using proteomic methods, a quantitatively evaluation was performed on the intracellular and extracellular production of interleukines IL-2, IL-6, IL-8 andIL, and the date were correlated with the adhesion and activation markers expression.

We concluded that these group of metal complexes exhibited in vitro a significant immune modulator potential, besides the cytotoxic effect, through the main signalling pathways CDCDIL 2 and GITR-T regulator cells. Previous activities: The objective of Phase V December 10th December 31st of the project was: 5.

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Based on the hypothesis that the platinum-based drugs and other metal compounds action modify the tumor microenvironment and these modifications conduct to the tumor cells suppression or contrary, to the development of drug resistance, we examined the ex vivo modulation of different cell types, the principal components of the tumor stroma, and we evaluated as well the lymphocyte infiltration in lymph nodes, emphasizing on CD8 positive cytotoxic T cell subset.

The histological type of the tumors was adenocarcinoma, and all the lymphatic nodes have had tumoral infiltrations; primary cell cultures were carried out, treated in vitro with eliminarea parazitilor antitumor drug oxaliplatin, and than the cell subpopulations were analyzed using the flow cytometry.

Neoadjuvant treatment's tumor response in rectal cancer - Jurnalul de ...

The CD8 positive lymphocytes were detected using the standard fluorescence labeling, the endothelial cells were characterized using the surface marker CD and the anti-fibroblast antibodies enabled the quantification of fibroblast expression in tumor mass.

The percent of the stem-like CD positive cells and EpCAM CD positive tumor cells presence was detected in the lymphatic tissue samples, which confirmed the tumor infiltration, the marker being a specific hpv causes weight loss of epithelial tumor cells.

As a colorectal cancer neoadjuvant therapy of the platinum drug therapy, a raise in the fibroblast and a decrease in the endothelial cells proportion, which can influence the proliferation indirectly, acting on tumor microenvironment.

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Two directions were approached; one of them analyzed the implications of platinum-based neoadjuvant chemotherapy treatment on lymphocyte subsets involved in antitumor immune response in colorectal cancers, the activation processes in cells obtained from lymphatic nodes resection. The testing was conducted in vitro, they sintomi del papilloma virus alla bocca studied the effector T cells isolated from tissue samples, activated through CD25, CD69 and CD27 molecules; the expression of these surface markers was assessed through flow-cytometry, and an experimental validation was made using molecular techniques qT PCR Elisa testing for the soluble form of the molecules.

The conclusions of the study point towards a good preservation of the activated effector lymphocyte subset during the oxaliplatin-based treatment in colorectal cancers. The second line of the study was to elucidate the colorectal cancer neoadjuvant therapy vitro effect exerted by the metal compounds having a central metal from the platinum group, against the cells implicated in antitumor immune response, and the validation of this outcome by measuring the soluble form of the involved molecules, especially interleukins.

Two novel synthesized Palladium II compounds were studied, having a curcuminoid ligand: 1E,6E -1,7-bis 3,4-dimethoxypenyl hepta-1,6-diene-3,5-dione, which showed limited toxicity against the normal peripheral blood mononuclear cells PBMC.

Advanced Therapy of Surgical Oncology

The ligand suppressed the CD8 positive T cells expression, but induced the overexpression of CD4, and has no effect on other markers. Despite the fact that complex 1 slightly inhibited the CD8 expression, it has a benefic effect on other cellular subpopulations implicated in the immune response.

Complex 2 has had an inhibitory effect not only on CD8 positive lymphocytes, but also against CD19 positive B cells and induced reduction in GITR positive cell population, which predicts a moderate immune suppression.

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Overall, the compounds exhibit applicability potential for antitumor prodrugs development. Evaluation of the metal-based compounds in vitro effect on colorectal tumor stem-like cells; having the activities: - Comparison between original versus generic platinum drugs, emphasizing on stem cell proliferation and multidrug resistance There were assessed the differences between the generic and original platinum-based drugs, in order to elucidate some of the reasons why the patients respond differently to the treatment when generic or original drugs are used, an aspect which concern the scientific colorectal cancer neoadjuvant therapy and the clinicians as well.

Under the frame of this activity an evaluation of the in vitro cytotoxicity was made for the original and generic versions of oxaliplatin and carboplatin on tumor cell lines DLD-1, HT and A

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