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1.
Handb Exp Pharmacol ; 265: 269-301, 2021.
Article in English | MEDLINE | ID: mdl-32548785

ABSTRACT

The landscape of cancer treatment has improved over the past decades, aiming to reduce systemic toxicity and enhance compatibility with the quality of life of the patient. However, at the therapeutic level, metastatic cancer remains hugely challenging, based on the almost inevitable emergence of therapy resistance. A small subpopulation of cells able to survive drug treatment termed the minimal residual disease may either harbor resistance-associated mutations or be phenotypically resistant, allowing them to regrow and become the dominant population in the therapy-resistant tumor. Characterization of the profile of minimal residual disease represents the key to the identification of resistance drivers that underpin cancer evolution. Therapeutic regimens must, therefore, be dynamic and tailored to take into account the emergence of resistance as tumors evolve within a complex microenvironment in vivo. This requires the adoption of new technologies based on the culture of cancer cells in ways that more accurately reflect the intratumor microenvironment, and their analysis using omics and system-based technologies to enable a new era in the diagnostics, classification, and treatment of many cancer types by applying the concept "from the cell plate to the patient." In this chapter, we will present and discuss 3D model building and use, and provide comprehensive information on new genomic techniques that are increasing our understanding of drug action and the emergence of resistance.


Subject(s)
Antineoplastic Agents , Neoplasms , Antineoplastic Agents/pharmacology , Drug Development , Humans , Neoplasms/drug therapy , Quality of Life , Systems Biology , Tumor Microenvironment
2.
Anticancer Agents Med Chem ; 20(9): 1038-1050, 2020.
Article in English | MEDLINE | ID: mdl-32067622

ABSTRACT

BACKGROUND: Melanoma is the most aggressive skin cancer, and BRAF (V600E) is the most frequent mutation that led to the development of BRAF inhibitors (BRAFi). However, patients treated with BRAFi usually present recidivism after 6-9 months. Curcumin is a turmeric substance, and it has been deeply investigated due to its anti-inflammatory and antitumoral effects. Still, the low bioavailability and biodisponibility encouraged the investigation of different analogs. DM-1 is a curcumin analog and has shown an antitumoral impact in previous studies. METHODS: Evaluated DM-1 stability and cytotoxic effects for BRAFi-sensitive and resistant melanomas, as well as the role in the metalloproteinases modulation. RESULTS: DM-1 showed growth inhibitory potential for melanoma cells, demonstrated by reduction of colony formation, migration and endothelial tube formation, and cell cycle arrest. Subtoxic doses were able to downregulate important Metalloproteinases (MMPs) related to invasiveness, such as MMP-1, -2 and -9. Negative modulations of TIMP-2 and MMP-14 reduced MMP-2 and -9 activity; however, the reverse effect is seen when increased TIMP-2 and MMP-14 resulted in raised MMP-2. CONCLUSION: These findings provide essential details into the functional role of DM-1 in melanomas, encouraging further studies in the development of combinatorial treatments for melanomas.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/drug effects , Melanoma/drug therapy , Metalloproteases/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle Checkpoints/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Melanoma/metabolism , Melanoma/pathology , Metalloproteases/metabolism , Molecular Structure , Proto-Oncogene Proteins B-raf/metabolism , Structure-Activity Relationship , Tumor Cells, Cultured
3.
Appl Biochem Biotechnol ; 185(4): 863-874, 2018 Aug.
Article in English | MEDLINE | ID: mdl-29362989

ABSTRACT

Early and accurate detection of primary or metastatic tumors is of great value in staging, treatment management, and prognosis. Tumor angiogenesis plays an essential role in the growth, invasion, and metastatic spread of solid cancers, and so, is a promising approach for tumor imaging. The GX1 (CGNSNPKSC) peptide was identified by phage display library and has been investigated as a marker for human cancers. This study aims to evaluate the 99mTc-HYNIC-PEG4-c (GX1) as a biomarker for tumor imaging. Our results showed that GX1 specifically binds to tumor cells in vitro. SKMEL28 and MDA-MB231 cells achieved total binding peak at 60 min of incubation. For B16F10 and MKN45 cells, the total and specific binding were similar during all time points, while A549 cell line showed rapid cellular total uptake of the tracer at 30 min of incubation. Biodistribution showed low non-specific uptakes and rapid renal excretion. Melanoma tumors showed enhanced GX1 uptake in animal model at 60 min, and it was significantly blocked by cold peptide. The radiotracer showed tumor specificity, especially in melanomas that are highly vascularized tumors. In this sense, it should be considered in future studies, aiming to evaluate degree of angiogenesis, progression, and invasion of tumors.


Subject(s)
Isotope Labeling , Melanoma/diagnostic imaging , Neoplasms, Experimental/diagnostic imaging , Neovascularization, Pathologic/diagnostic imaging , Peptides , Radiopharmaceuticals , A549 Cells , Animals , Humans , Melanoma/metabolism , Mice , Neoplasms, Experimental/metabolism , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Peptides/chemistry , Peptides/pharmacokinetics , Peptides/pharmacology , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/pharmacology
4.
Appl Biochem Biotechnol, v. 185, n. 4, p. 863-874, ago. 2018
Article in English | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: bud-2535

ABSTRACT

Early and accurate detection of primary or metastatic tumors is of great value in staging, treatment management, and prognosis. Tumor angiogenesis plays an essential role in the growth, invasion, and metastatic spread of solid cancers, and so, is a promising approach for tumor imaging. The GX1 (CGNSNPKSC) peptide was identified by phage display library and has been investigated as a marker for human cancers. This study aims to evaluate the 99mTc-HYNIC-PEG4-c (GX1) as a biomarker for tumor imaging. Our results showed that GX1 specifically binds to tumor cells in vitro. SKMEL28 and MDA-MB231 cells achieved total binding peak at 60 min of incubation. For B16F10 and MKN45 cells, the total and specific binding were similar during all time points, while A549 cell line showed rapid cellular total uptake of the tracer at 30 min of incubation. Biodistribution showed low non-specific uptakes and rapid renal excretion. Melanoma tumors showed enhanced GX1 uptake in animal model at 60 min, and it was significantly blocked by cold peptide. The radiotracer showed tumor specificity, especially in melanomas that are highly vascularized tumors. In this sense, it should be considered in future studies, aiming to evaluate degree of angiogenesis, progression, and invasion of tumors.

5.
Appl Biochem Biotechnol ; 183(1): 265-279, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28281182

ABSTRACT

Angiogenesis plays a critical role in progression of malignant gliomas. The development of glioma-specific labeling molecules that can aid detection and visualization of angiogenesis can help surgical planning and improve treatment outcome. The aim of this study was to evaluate if two peptides (GX1 and RGD-GX1) linked to angiogenesis can be used as an MR-imaging markers of angiogenesis. MR imaging was performed in U87 glioblastoma-bearing NOD-SCID mice at different time points between 15 and 120 min post-injection to visualize particle distribution. GX1 and RGD-GX1 exhibited the highest accumulation in U87 glioblastoma at 120 min post i.v. administration. GX1-conjugated agents lead to higher decrease in transverse relaxation time (T 2) (i.e., stronger contrast enhancement) than RGD-GX1-conjugated agents in U87 glioblastoma tumor model. In addition, we tested if U87-IDH1R132 mutated cell line had different pattern of GX1 or RGD-GX1 particle accumulation. Responses in U87-IDH1WT followed a similar pattern with GX1 contrast agents; however, lower contrast enhancement was observed with RGD-GX1 agents. The specific binding of these peptides to human glioblastoma xenograft in the brain was confirmed by magnetic resonance imaging. The contrast enhancement following injection of magnetonanoparticles conjugated to GX1 peptide matched well with CD31 staining and iron staining.


Subject(s)
Brain Neoplasms , Contrast Media , Glioma , Magnetic Resonance Imaging , Magnetite Nanoparticles , Neoplasms, Experimental , Neovascularization, Pathologic , Oligopeptides , Animals , Brain Neoplasms/blood supply , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/metabolism , Cell Line, Tumor , Contrast Media/chemistry , Contrast Media/pharmacology , Glioma/blood supply , Glioma/diagnostic imaging , Glioma/metabolism , Humans , Magnetite Nanoparticles/chemistry , Magnetite Nanoparticles/therapeutic use , Male , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasms, Experimental/blood supply , Neoplasms, Experimental/diagnostic imaging , Neoplasms, Experimental/metabolism , Neovascularization, Pathologic/diagnostic imaging , Neovascularization, Pathologic/metabolism , Oligopeptides/chemistry , Oligopeptides/pharmacology
6.
Curr Radiopharm ; 10(1): 65-72, 2017.
Article in English | MEDLINE | ID: mdl-28164753

ABSTRACT

BACKGROUND AND OBJECTIVE: Radiotracer diagnosis of insulinoma, can be done using somatostatin or glucagon-like peptide 1 (GLP-1). Performance of GLP-1 antagonists tends to be better than of agonists. METHODS: We investigated the uptake of the antagonist exendin (9-39), radiolabeled with technetium- 99m. Two different sites of the biomolecule were selected for chelator attachment. RESULTS: HYNIC-ßAla chelator attached to serine (C- terminus) of exendin, was associated with higher tumor uptake than to aspartate (N- terminus). CONCLUSION: The chelator position in the biomolecule influenced receptor uptake.


Subject(s)
Chelating Agents/pharmacology , Glucagon-Like Peptide 1/antagonists & inhibitors , Insulinoma/diagnostic imaging , Pancreatic Neoplasms/diagnostic imaging , Peptide Fragments/pharmacology , Radiopharmaceuticals/pharmacology , Animals , Cell Line, Tumor , Chromatography, High Pressure Liquid , Male , Mice , Mice, SCID , Radionuclide Imaging , Sensitivity and Specificity , Technetium/pharmacology , Tissue Distribution
7.
Amino Acids ; 48(3): 821-831, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26592499

ABSTRACT

Gliomas are the most common type among all central nervous system tumors. The aggressiveness of gliomas is correlated with the level of angiogenesis and is often associated with prognosis. The aim of this study is to evaluate the novel GX1 peptide and the heterodimer RGD-GX1 radiolabeled with technetium-99m, for angiogenesis detection in glioma models. Radiolabeling and radiochemical controls were assessed for both radioconjugates. In vitro binding studies in glioma tumor cells were performed, as well as biodistribution in SCID mice bearing tumor cells, in order to evaluate the biological behavior and tumor uptake of the radiocomplexes. Blocking and imaging studies were also conducted. MicroSPECT/CT images were acquired in animals with experimentally implanted intracranial tumor. Open field activity was performed to evaluate behavior, as well as perfusion and histology analysis. The radiochemical purity of both radiotracers was greater than 96 %. In vitro binding studies revealed rather similar binding profi le for each molecule. The highest binding was for RGD-GX1 peptide at 120 min in U87MG cells (1.14 ± 0.35 %). Tumor uptake was also favorable for RGD-GX1 peptide in U87MG cells, reaching 2.96 ± 0.70 % at 1 h p.i. with 47 % of blocking. Imaging studies also indicated better visualization for RGD-GX1 peptide in U87MG cells. Behavior evaluation pointed brain damage and histology studies confirmed actual tumor in the uptake site. The results with the angiogenesis seeking molecule (99m)Tc-HYNIC-E-[c(RGDfk)-c(GX1)] were successful, and better than with (99m)Tc-HYNIC-PEG4-c(GX1). Future studies targeting angiogenesis in other glioma and nonglioma tumor models are recommended.


Subject(s)
Glioma/diagnostic imaging , Neovascularization, Pathologic/diagnostic imaging , Oligopeptides/administration & dosage , Radiopharmaceuticals/administration & dosage , Animals , Cell Line, Tumor , Disease Models, Animal , Glioma/diagnosis , Glioma/metabolism , Humans , Mice , Mice, SCID , Neovascularization, Pathologic/metabolism , Oligopeptides/chemistry , Oligopeptides/metabolism , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/metabolism , Technetium/administration & dosage , Technetium/chemistry , Technetium/metabolism , Tomography, Emission-Computed, Single-Photon
8.
Nucl Med Biol ; 39(1): 145-53, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22079036

ABSTRACT

INTRODUCTION: The aim of this work was to quantify the effects of injection volume at different technetium-99m specific radiotracer doses on its lymphatic movement in animal model. PROCEDURES: Effects of injection volume (50, 100 µl) at different doses (0.05, 0.135, 0.22 nmol) on popliteal node (PN) detection were studied in rats. The radiotracer under study was (99m)Technetium-cysteine-mannose-dextran conjugate (30 kDa). RESULTS: At 0.05 nmol dose, higher PN uptake was observed at 50 µl injection volume (2.6 fold increase). Conversely, at 0.135 nmol dose, an increase of radiotracer retention in PN was achieved at 100 µl volume, 78% higher than 50 µl. However, at 0.22 nmol dose, the injection volume changes did not influence on the PN uptake. Considering as suitable radiotracer performance: high PN uptake and extraction, better combinations were 0.05 nmol/50 µl, 0.135 nmol/100 µl, 0.22/50 µl. CONCLUSION: Suitable performances could be reached by proper combinations of dose, injection volume and concentration for a specific radiotracer used in sentinel lymph node detection.


Subject(s)
Cysteine/analogs & derivatives , Dextrans/pharmacokinetics , Lymph Nodes/metabolism , Mannose/pharmacokinetics , Organotechnetium Compounds/pharmacokinetics , Radiopharmaceuticals/pharmacokinetics , Animals , Cysteine/administration & dosage , Cysteine/pharmacokinetics , Dextrans/administration & dosage , Female , Lymph Nodes/diagnostic imaging , Mannose/administration & dosage , Organotechnetium Compounds/administration & dosage , Radionuclide Imaging , Radiopharmaceuticals/administration & dosage , Rats , Rats, Wistar , Sentinel Lymph Node Biopsy/methods , Tissue Distribution
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