RESUMO
The organo-osmium complex [OsII(ɳ6-p-cym)(PhAzPy-NMe2)I]+ (FY26) exhibits promising in vitro antitumour activity against mouse hepatocarcinoma Hepa1-6 and other mouse or human cancer cell lines. Here, we drastically enhance water solubility of FY26 through the replacement of the PF6- counter-anion with chloride using a novel synthesis method. FY26â PF6 and FY26â Cl displayed similar in vitro cytotoxicity in two cancer cell models. We then show the moderate and late anticancer efficacy of FY26â PF6 and FY26â Cl in a subcutaneous murine hepatocarcinoma mouse model. Both efficacy and tolerability varied according to FY26 circadian dosing time in hepatocarcinoma tumour-bearing mice. Tumour and liver uptake of the drug were determined over 48 h following FY26â Cl administration at Zeitgeber time 6 (ZT6), when the drug is least toxic (in the middle of the light span when mice are resting). Our studies suggest the need to administer protracted low doses of FY26 at ZT6 in order to optimize its delivery schedule, for example through the use of chrono-releasing nanoparticles.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Complexos de Coordenação/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Complexos de Coordenação/administração & dosagem , Complexos de Coordenação/efeitos adversos , Complexos de Coordenação/farmacocinética , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Distribuição TecidualRESUMO
BACKGROUND: We aimed first to evaluate the early oxidative stress following radionuclide therapy (RNT) with 177Lu-PSMA and 177Lu-DOTATATE and second to evaluate the protective effect of vitamin C on oxidative stress. MATERIALS AND METHODS: Prostate cancer and neuroendocrine tumor (NET) patients referred to therapy with 177Lu-PSMA and 177Lu-DOTATATE, respectively, were enrolled in this study. The patients divided into the control group underwent routine RNT without any intervention and the intervention group was asked to take effervescent tablets (500 mg) of vitamin C for two days prior to the RNT (three tablets per day). To measure oxidative stress, blood samples were taken immediately before treatment and 48 h after treatment, and the serums were separated and frozen. To evaluate oxidative stress, the serum levels of malondialdehyde (MDA) and glutathione (GSH) and the activity of glutathione reductase were measured before and two days after treatment. RESULTS: In total, 61 RNT cycles were evaluated in 34 patients with age of 65 ± 2.83 (median ± SE) years (range of 27-99); this total included 20 (59%) prostate cancer patients [35 cycles (57.4%)] and 14 patients (41%) with NET [26 cycles (42.6%)]. Of the 61 evaluated cycles, 27 cycles were given in the control group and 34 cycles were given in the intervention group. The serum level of MDA was significantly increased after treatment compared to before treatment (P = 0.02) in the control group, while no significant change in the serum level of MDA was observed in the intervention group (P = 0.52). The serum level of GSH was insignificantly decreased after treatment compared to before treatment in the control group and slightly increased after treatment in the intervention group (P > 0.05). The serum level of glutathione reductase was insignificantly increased in all groups of patients after treatment (P > 0.05). CONCLUSION: According to the results of this study, RNT with Lu-PSMA and Lu-DOTATATE may induce oxidative stress via the generation of free radicals and reactive oxygen species. Consumption of vitamin C prior to RNT may ameliorate this oxidative stress. These preliminary results have positive implications for clinical practice. Verification of these noteworthy results is needed and can be conducted with larger randomized controlled trials with longer time points.
Assuntos
Ácido Ascórbico/farmacologia , Complexos de Coordenação/efeitos adversos , Tumores Neuroendócrinos/metabolismo , Octreotida/análogos & derivados , Compostos Organometálicos/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Protetores contra Radiação/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Complexos de Coordenação/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/radioterapia , Octreotida/efeitos adversos , Octreotida/uso terapêutico , Compostos Organometálicos/uso terapêutico , Neoplasias da Próstata/diagnóstico por imagemRESUMO
ABSTRACT: Radiopharmaceutical extravasation is a known nuclear medicine adverse effect, mostly with no complication in case of diagnostic radiopharmaceutical. However, a therapeutic radiopharmaceutical extravasation may have clinical consequences and must be treated quickly and effectively. We report here a case of 177Lu-DOTA0-Tyr3-octreotate extravasation.
Assuntos
Complexos de Coordenação/efeitos adversos , Complexos de Coordenação/metabolismo , Octreotida/análogos & derivados , Humanos , Masculino , Octreotida/efeitos adversos , Octreotida/metabolismo , CintilografiaRESUMO
Functionalized carbon nanotubes are interesting, promising and unique delivery systems for anticancer drugs, which are now in the spotlight of nanomedicine. Connecting nanotubes with anticancer drugs or new compounds with anticancer properties aims at improving their stability, efficiency and reduces the toxic side effects of cancer treatment. In our research, we are interested in connecting functionalized MWCNTs-NH2 with [InH][trans-RuCl4(In)2], (KP1019) which is one of the most promising anticancer ruthenium(iii) drug candidates, known mainly as a cytotoxic agent for the treatment of platinum-resistant colorectal cancers. As a result of the amidation of MWCNTs (1), MWCNTs-NH2 (2) were obtained. Then, they were modified with [InH][RuCl4(In)2] (4) and the nanosystem [MWCNT-NH3+][RuCl4(In)2-] (3) was obtained. The characterization of the resulting products was performed using IR, Raman spectroscopy, thermal gravimetric, XRD, STEM-EDX, ESI-MS, ICP-MS, and XPS analyses. The cytotoxic activity has been tested on human lung carcinoma (A549), chronic myelogenous leukemia (K562) and human cervix carcinoma (HeLa) cells which showed the higher toxicity of the nanosystem than the ruthenium complex.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Indazóis/química , Nanotubos de Carbono/química , Rutênio/química , Células A549 , Antineoplásicos/efeitos adversos , Complexos de Coordenação/efeitos adversos , Células HeLa , HumanosRESUMO
Lu-DOTATATE is an effective treatment for inoperable metastatic well-differentiated pancreatic neuroendocrine tumors. There are no guidelines for patients with terminal renal failure. We present the case of a 74-year-old woman who received different lines of treatment: analogs of somatostatin, chemotherapy, a first series of peptide receptor radionuclide therapy (PRRT), and finally chemoembolization. Because of persistent hepatic progression, a safe and successful administration of 4 cycles of a second series of PRRT under hemodialysis was administered. Patient was in scintigraphic complete remission at 12 months with normal hematological parameters at 12 and 30 months after PRRT.
Assuntos
Complexos de Coordenação/efeitos adversos , Complexos de Coordenação/uso terapêutico , Progressão da Doença , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Neoplasias Pancreáticas/radioterapia , Diálise Renal , Segurança , Idoso , Embolização Terapêutica , Feminino , Humanos , Tumores Neuroendócrinos/patologia , Octreotida/efeitos adversos , Octreotida/uso terapêutico , Neoplasias Pancreáticas/patologia , Resultado do TratamentoRESUMO
There is an urgent need for more effective, less toxic cancer therapy agents. Motivated by this need, we synthesized a small panel of N-heterocyclic carbene (NHC)-coordinated ruthenium(II) arene complexes Ru1-Ru6 with the formula [Ru(p-cymene)(L)Cl]PF6 (L = NHC ligand with varying substituents). Cell-based in vitro studies revealed that despite the structural similarity, Ru1-Ru6 exhibited distinct cytotoxic activities against cancer cells. In particular, Ru4 and Ru6, which bear n-octyl and pentamethylbenzyl motifs, respectively, were the most active at inducing apoptosis. In human ovarian A2780 cancer cells, Ru4 and Ru6 showed the highest cytotoxicities with IC50 values of 2.74 ± 0.15 µM and 1.98 ± 0.10 µM, respectively, and they were approximately 2-fold more potent than cisplatin (IC50 = 5.55 ± 0.37 µM). In addition to the cell killing capacity, inhibition of cell migration was validated by using these two optimized complexes. Mechanistic studies revealed that Ru4 and Ru6 complexes induced apoptosis in a caspase-dependent manner, primarily through intracellular reactive oxygen species (ROS) overproduction and cell cycle arrest at G1 phase. Furthermore, in a preclinical metastatic model of A2780 tumor xenograft, administration of Ru4 and Ru6 (20 µmol/kg) resulted in a marked inhibition of tumor progression and metastasis. Finally, a substantially alleviated systemic toxicity was observed for both complexes in comparison with cisplatin in animals. Overall, this study greatly increases our understanding of NHC-coordinated Ru(II) arene metallodrugs, aiding further investigation of their therapeutic potential in the treatment of metastatic cancers.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Compostos Heterocíclicos/química , Rutênio/química , Segurança , Animais , Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Benzeno/química , Linhagem Celular Tumoral , Complexos de Coordenação/efeitos adversos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Camundongos , Metástase Neoplásica , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Platinum/S-1 (PS) and platinum/5-fluorouracil (PF) as first-line chemotherapies are extensively used for the treatment of advanced gastric or gastroesophageal junction cancer (AGC); however, there is no definite consensus on which regimen is best. In our meta-analysis, we compared PS with PF in terms of their efficacy and safety in AGC patients. METHODS: PubMed, ScienceDirect, Web of Science, Scopus, Ovid MEDLINE, EMBASE, The Cochrane Library, Google Scholar, and CNKI were systematically searched for pertinent literature. We analyzed overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse effects (AEs) as major end points. RESULTS: A total of 3,225 studies were identified, among which 6 randomized controlled trials, including 1,736 participants, were ultimately included in our analysis. Our results showed that PS and PF were comparable in terms of OS (p = 0.33, 95% confidence interval [CI]: 0.84-1.06), PFS (p = 0.63, 95% CI: 0.87-1.09), ORR (p = 0.38, 95% CI: 0.91-1.28), DCR (p = 0.41, 95% CI: 0.86-1.43), total AEs (p = 0.41, 95% CI: 0.98-1.01), and grade ≥3 AEs (p = 0.58, 95% CI: 0.82-1.41). However, those who received PF had a shorter time to failure (TTF) (p = 0.01, 95% CI: 0.77-0.97), and a significantly higher rate and more severe cases of stomatitis, nausea, and hypokalemia were reported in the PF group. CONCLUSIONS: PF and PS show similar antitumor efficacy (OS, PFS, ORR, and DCR), but patients receiving PS exhibit longer TTF and fewer AEs (stomatitis, nausea, and hypokalemia) than those receiving PF.
Assuntos
Antineoplásicos/uso terapêutico , Complexos de Coordenação/uso terapêutico , Fluoruracila/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Ácido Oxônico/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Tegafur/uso terapêutico , Antineoplásicos/efeitos adversos , Complexos de Coordenação/efeitos adversos , Complexos de Coordenação/química , Intervalo Livre de Doença , Combinação de Medicamentos , Quimioterapia Combinada , Junção Esofagogástrica/patologia , Fluoruracila/efeitos adversos , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Humanos , Estadiamento de Neoplasias , Ácido Oxônico/efeitos adversos , Platina/química , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Tegafur/efeitos adversos , Resultado do TratamentoRESUMO
We report herein three novel complexes whose design was based on the approach that consists of combining commercially available antibiotics with metals to attain different physicochemical properties and promote antimicrobial activity. Thus, new isostructural three-dimensional (3D) hydrogen bonding frameworks of pipemidic acid with manganese (II), zinc (II) and calcium (II) have been synthesised by mechanochemistry and are stable under shelf conditions. Notably, the antimicrobial activity of the compounds is maintained or even increased; in particular, the activity of the complexes is augmented against Escherichia coli, a representative of Gram-negative bacteria that have emerged as a major concern in drug resistance. Moreover, the synthesised compounds display similar general toxicity (Artemia salina model) levels to the original antibiotic, pipemidic acid. The increased antibacterial activity of the synthesised compounds, together with their appropriate toxicity levels, are promising outcomes.
Assuntos
Complexos de Coordenação/química , Metais/química , Ácido Pipemídico/química , Animais , Artemia/efeitos dos fármacos , Complexos de Coordenação/efeitos adversos , Complexos de Coordenação/farmacologia , Escherichia coli/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Ligação de Hidrogênio/efeitos dos fármacos , Manganês/química , Testes de Sensibilidade Microbiana , Ácido Pipemídico/efeitos adversos , Ácido Pipemídico/farmacologia , Zinco/químicaRESUMO
Several biologically active bivalent Pd and Pt complexes with two structurally similar cyanoxime ligands abbreviated as H(DECO): 2-oximino-2-cyano-N,N'-diethylacetamide, and H(PyrCO): 2-oximino-2-cyan-N-pyrrolidine acetamide were synthesized and characterized using spectroscopic methods, thermal analysis and X-ray crystallography. Structures revealed planar cis-geometry of studied complexes. Freshly obtained Pt(DECO)2, Pd(DECO)2, Pt(PyrCO)2 and Pd(PyrCO)2 complexes were used in for in vitro cytotoxicity assays using two different etiology human cancer cell lines HeLa and WiDr cells. Investigated compounds showed cytotoxicity levels at or above cisplatin. Pt(DECO)2 was also tested in vivo in healthy C57BL/6 mice. The complex was administered at three different dosage (0, 7.5, 15 mg/kg, i.p. once/week), over a total period of 8 weeks. No changes were observed in the animal weight in the treated mice compared to the control dextrose-treated group. The levels of erythrocytes, leukocytes, and hemoglobin were within the normal level suggesting low myelotoxicity. Negligible cardiotoxicity was observed from the histological evaluation of the hearts from the treated animals. Results from the tail nerve conduction velocity (NCV) and nerve histomorphometry suggested no impact of Pt(DECO)2 on peripheral nerves. The complex, however, induced certain hepatotoxicity and lead to the elevation of IL-6, a pro-inflammatory cytokine. Overall, Pt(DECO)2 showed minimal in vivo toxicity, thus presenting a promising candidate for future testing in animal models of cancer.
Assuntos
Complexos de Coordenação , Citotoxinas , Neoplasias/tratamento farmacológico , Paládio , Platina , Animais , Complexos de Coordenação/efeitos adversos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Citotoxinas/efeitos adversos , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Masculino , Camundongos , Neoplasias/metabolismo , Neoplasias/patologia , Paládio/efeitos adversos , Paládio/química , Paládio/farmacologia , Platina/efeitos adversos , Platina/química , Platina/farmacologiaRESUMO
PRRT (peptide receptor radionuclide therapy) with Lu-DOTATATE for neuroendocrine tumor has some well-known adverse effects, concerning specially the bone marrow and kidneys. Hepatotoxicity has been rarely reported, and there are no data regarding hepatic steatosis secondary to PRRT. We reviewed upper abdomen CT and MRI and applied radiologic criteria for the diagnosis of hepatic steatosis on 62 patients treated between the years of 2010 and 2017. Two patients already showed radiologic signs of steatosis in the middle of the treatment and through follow-up all patients showed improvement of the steatosis.
Assuntos
Complexos de Coordenação/efeitos adversos , Fígado Gorduroso/etiologia , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Compostos Radiofarmacêuticos/efeitos adversos , Complexos de Coordenação/uso terapêutico , Fígado Gorduroso/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico por imagem , Octreotida/efeitos adversos , Octreotida/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/uso terapêuticoRESUMO
Cichoric acid (CA) belongs to the group of polyphenols, which occurs in a variety of plant species and it is characterized by anticancer, antibacterial, and antiviral properties. Selected polyphenols have the ability to combine with metal ions to form chelate complexes that reveal greater biological activity than free compounds. In order to study possible antimicrobial and anticancer effect of CA and its complexes with copper(II)/zinc(II)/nickel(II)/cobalt(II) we decided to conduct cytotoxicity tests to estimate the most effective concentrations of tested compounds. The results of the presented study demonstrated, for the first time, that the treatment with newly synthesized CA-metal complexes has anticancer and antimicrobial effects, which were examined in seven different cell lines: MCF-7, MDA-MB-231, and ZR-75-1 breast cancer cell lines, A375 melanoma cell line, DLD-1 cell line, LN-229 cell line, FN cell line; five bacterial strains: Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, Proteus vulgaris, Lactobacillus rhamnosus, yeast Sacchcaromyces boulardii, and pathogenic yeast-like fungi Candida albicans. The presented study indicates that CA-metal complexes could be considered as a potential supplementary tool in anticancer therapy, however, because of their possible toxic activity on fibroblasts, they should be used with caution. Some of the tested complexes have also preservative properties and positive influence on normal non-pathogenic microorganisms, which was demonstrated in selected microbial strains, therefore they may serve as food preservatives of natural origin with cytoprotective properties.
Assuntos
Anti-Infecciosos/administração & dosagem , Antineoplásicos/administração & dosagem , Bactérias/efeitos dos fármacos , Ácidos Cafeicos/farmacologia , Complexos de Coordenação/administração & dosagem , Extratos Vegetais/farmacologia , Succinatos/farmacologia , Leveduras/efeitos dos fármacos , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ácidos Cafeicos/uso terapêutico , Candida albicans/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/efeitos adversos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Fibroblastos/efeitos dos fármacos , Humanos , Íons , Metais/farmacologia , Metais/uso terapêutico , Testes de Sensibilidade Microbiana , Neoplasias/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Saccharomyces boulardii/efeitos dos fármacos , Succinatos/uso terapêuticoRESUMO
BACKGROUND: NETTER-1 trial demonstrated high efficacy and low toxicity of four cycles of Peptide Receptor Radionuclide Therapy (PRRT) in patients with metastasized NET. The present study evaluates the outcome of further PRRT cycles in the so called salvage setting in patients after initial response to four therapy cycles and later progression. METHODS: Thirty five patients (pat.) (25 male, 10 female, 63 ± 9 years) with progressive, metastasized NET (23 small intestinal, 5 lung, 4 CUP, 1 rectal, 1 gastric and 1 paraganglioma) were included. All patients previously received 4 PRRT cycles with 177Lu-DOTATATE and showed initial response. SPECT based dosimetry was applied to determine kidney and tumor doses. Therapy response was evaluated using 68Ga-DOTATATE PET/CT (with high dose CT), CT alone or MRI (RECIST 1.1), toxicity was defined using CTCAE 5.0 criteria. 99mTc99-MAG3 scintigraphy was used to assess potential renal tubular damage. Progression free survival (PFS) and Overall survival (OS) analysis was performed with the Kaplan-Meier-method. RESULTS: The median PFS after initial PRRT was 33 months (95% CI: 30-36). The mean cumulative dose for including salvage PRRT was 44 GBq (range 33.5-47). One pat. (2.9%) showed grade 3 hematotoxicity. Kidney dosimetry revealed a mean cumulative kidney dose after a median of 6 PRRT cycles of 23.8 Gy. No grade 3 / 4 nephrotoxicity or relevant decrease in renal function was observed. Follow-up imaging was available in 32 patients after salvage therapy. Best response according to RECIST 1.1. was PR in one patient (3.1%), SD in 26 patients (81.3%) and PD in 5 patients (15.6%). PFS after salvage therapy was 6 months (95% CI: 0-16; 8 patients censored). Mean OS after initial PRRT was 105 months (95% CI: 92-119) and 51 months (95% CI: 41-61) after start of salvage therapy. Median OS was not reached within a follow-up of 71 months after initial PRRT and 25 months after start of salvage PRRT, respectively. CONCLUSIONS: Salvage therapy with 177Lu-DOTATATE is safe and effective even in patients with extensive previous multimodal therapies during disease progression and represents a feasible and valuable therapy option for progressive NET.
Assuntos
Complexos de Coordenação/uso terapêutico , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Compostos Radiofarmacêuticos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Complexos de Coordenação/administração & dosagem , Complexos de Coordenação/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/mortalidade , Octreotida/administração & dosagem , Octreotida/efeitos adversos , Octreotida/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Doses de Radiação , Radiometria , Compostos Radiofarmacêuticos/efeitos adversos , Receptores de Peptídeos/metabolismo , Retratamento , Terapia de Salvação , Resultado do TratamentoAssuntos
Complexos de Coordenação/química , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/efeitos adversos , Antioxidantes/química , Antioxidantes/farmacologia , Meios de Contraste/química , Complexos de Coordenação/efeitos adversos , Complexos de Coordenação/farmacologia , Humanos , Íons/química , LigantesRESUMO
BACKGROUND: Ruthenium complexes have been extensively investigated for their prospective value as alternatives to cisplatin. Recently, we reported the in vitro anticancer properties of a family of organometallic ruthenium( II)-cyclopentadienyl complexes and have explored their mechanism of action. OBJECTIVE: The purpose of this study was to evaluate the in vivo antitumour efficacy and toxicity of one of these Ru(II) compounds, [RuCp(mTPPMSNa)(2,2'-bipy)][CF3SO2] (TM85) which displayed an interesting spectrum of activity against several cancer cells. METHODS: Studies to assess the antitumour activity and toxicity were performed in a metastatic prostate (PC3) mice model using ICP-MS, nuclear microscopy, elemental analysis and Transmission Electron Microscopy (TEM). RESULTS: TM85 showed low systemic toxicity but no significant tumour reduction, when administered at tolerated dose (20mg/kg) over 10 days. Ru was mainly retained in the liver and less in kidneys, with low accumulation in tumour. Increased bilirubin levels, anomalous Ca and Fe concentrations in liver and mitochondria alterations were indicative of liver injury. The hepatotoxicity observed was less severe than that of cisplatin and no nephrotoxicity was found. CONCLUSION: Under the experimental conditions of this study, TM85 is less toxic than cisplatin, induces similar tumour reduction and avoids the formation of metastatic foci. No renal toxicity was observed by the analysis of creatinine levels and the effective renal plasma flow by 99mTc-MAG3 clearance. Hence, it can be considered a valuable compound for further studies in the field of Ru-based anticancer drugs.
Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Ciclopentanos/química , Neoplasias da Próstata/tratamento farmacológico , Rutênio/química , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/efeitos adversos , Cisplatino/farmacologia , Complexos de Coordenação/efeitos adversos , Complexos de Coordenação/farmacologia , Relação Dose-Resposta a Droga , Humanos , Fígado/metabolismo , Masculino , Neoplasias da Próstata/patologiaRESUMO
AIM: Preclinical evaluation of a cytotoxic copper (II) complex formulated in long circulating nanoliposomes for melanoma treatment. MATERIALS & METHODS: Liposomal nanoformulations of the copper complex were characterized in terms of thermodynamic behavior (differential scanning calorimeter), pH-sensitivity (spectrophotometry) and antiproliferative effects against murine melanoma B16F10 cells in vitro. Preclinical studies were performed in a C57BL/6 syngeneic melanoma model. RESULTS: Nanoformulations were thermodynamically stable, and CHEMS-containing nanoliposomes were pH-sensitive and preserved the antiproliferative properties of the copper compound. These nanoformulations significantly impaired tumor progression in vivo, devoid of toxic side effects, compared with control mice or mice treated with the free metallodrug. CONCLUSION: Copper complex-containing nanoliposomes demonstrate high anticancer efficacy and safety, constituting a step forward to the development of more effective therapeutic strategies against melanoma.
Assuntos
Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , Melanoma Experimental/tratamento farmacológico , Nanopartículas/química , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/efeitos adversos , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Lipossomos/química , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
PURPOSE: Peptide receptor radionuclide therapy (PRRT) with the radiolabeled somatostatin analogue [Lutetium-177-DOTA0-Tyr3]octreotate (177Lu-DOTATATE) is widely applied for inoperable metastatic small intestinal and nonfunctioning pancreatic neuroendocrine tumors (pNETs). The aim of this study is to describe the safety and efficacy of the treatment of functioning pNETs. METHODS: Patients were treated with up to four cycles of 177Lu-DOTATATE with an intended dose of 7.4 Gbq per cycle. Radiological (Response Evaluation Criteria in Solid Tumors 1.1), symptomatic, and biochemical response were analyzed retrospectively for all patients with a functioning pNET (insulinoma, gastrinoma, VIPoma, and glucagonoma) treated with 177Lu-DOTATATE. Quality of life (QOL) was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Module questionnaire. RESULTS: Thirty-four patients with a metastatic functioning pNET (European Neuroendocrine Tumor Society grade 1 or 2) were included: 14 insulinomas, 5 VIPomas, 7 gastrinomas, and 8 glucagonomas. Subacute hematological toxicity, grade 3 or 4 occurred in 4 patients (12%) and a hormonal crisis in 3 patients (9%). PRRT resulted in partial or complete response in 59% of patients and the disease control rate was 78% in patients with baseline progression. 71% of patients with uncontrolled symptoms had a reduction of symptoms and a more than 80% decrease of circulating hormone levels was measured during follow-up. After PRRT, median progression-free survival was 18.1 months (interquartile range: 3.3 to 35.7) with a concurrent increase in QOL. CONCLUSION: Treatment with 177Lu-DOTATATE is a safe and effective therapy resulting in radiological, symptomatic and biochemical response in a high percentage of patients with metastatic functioning pNETs. Hormonal crises occur relatively frequent and preventive therapy should be considered before and/or during PRRT.
Assuntos
Complexos de Coordenação/administração & dosagem , Lutécio/administração & dosagem , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Neoplasias Pancreáticas/radioterapia , Radioisótopos/administração & dosagem , Adulto , Idoso , Complexos de Coordenação/efeitos adversos , Feminino , Gastrinas/sangue , Gastrinas/metabolismo , Glucagon/sangue , Glucagon/metabolismo , Humanos , Insulina/sangue , Insulina/metabolismo , Lutécio/efeitos adversos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/patologia , Octreotida/administração & dosagem , Octreotida/efeitos adversos , Pâncreas/metabolismo , Pâncreas/patologia , Pâncreas/efeitos da radiação , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/patologia , Qualidade de Vida , Doses de Radiação , Radioisótopos/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Peptídeo Intestinal Vasoativo/sangue , Peptídeo Intestinal Vasoativo/metabolismoRESUMO
Biospeciation of essential and toxic metal ions, metal complexes with biological or medicinal activity are discussed in the paper in order to emphasize the importance of the distribution of metal ions in biological milieu. The exact knowledge of the chemical species present in the different organs/compartments/fluids/cells may provide essential information about the pharmacokinetic properties and the biological effect of the metal ion or the drug candidate metal complex. The transport of essential and toxic metal ions in the blood serum is discussed first, which is followed by the description of biodistribution of several important metal complexes with medicinal interest such as (i) anticancer, (ii) insulin-enhancing and (iii) MRI contrast agents in biological fluids.
Assuntos
Antineoplásicos/química , Meios de Contraste/química , Complexos de Coordenação/química , Metais/química , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Complexos de Coordenação/administração & dosagem , Complexos de Coordenação/efeitos adversos , Complexos de Coordenação/farmacologia , Descoberta de Drogas/métodos , Humanos , Insulina/metabolismo , Íons/química , Imageamento por Ressonância Magnética/métodos , Estrutura Molecular , Ligação Proteica , Albumina Sérica Humana/metabolismo , Solubilidade , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
BACKGROUND: Since the serendipitous discovery of the antitumor activity of cisplatin there has been a continuous surge in studies aimed at the development of new cytotoxic metal complexes. While the majority of these complexes have been designed to interact with nuclear DNA, other targets for anticancer metallodrugs attract increasing interest. In cancer cells the mitochondrial metabolism is deregulated. Impaired apoptosis, insensitivity to antigrowth signals and unlimited proliferation have been linked to mitochondrial dysfunction. It is therefore not surprising that mitochondria have emerged as a major target for cancer therapy. Mitochondria-targeting agents are able to bypass resistance mechanisms and to (re-) activate cell-death programs. METHODS: Web-based literature searching tools such as SciFinder were used to search for reports on cytotoxic metal complexes that are taken up by the mitochondria and interact with mitochondrial DNA or mitochondrial proteins, disrupt the mitochondrial membrane potential, facilitate mitochondrial membrane permeabilization or activate mitochondria-dependent celldeath signaling by unbalancing the cellular redox state. Included in the search were publications investigating strategies to selectively accumulate metallodrugs in the mitochondria. RESULTS: This review includes 241 references on antimitochondrial metal complexes, the use of mitochondria-targeting carrier ligands and the formation of lipophilic cationic complexes. CONCLUSION: Recent developments in the design, cytotoxic potency, and mechanistic understanding of antimitochondrial metal complexes, in particular of cyclometalated Au, Ru, Ir and Pt complexes, Ru polypyridine complexes and Au-N-heterocyclic carbene and phosphine complexes are summarized and discussed.
Assuntos
Antineoplásicos/síntese química , Complexos de Coordenação/síntese química , Metais/química , Mitocôndrias/metabolismo , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Apoptose , Complexos de Coordenação/efeitos adversos , Complexos de Coordenação/farmacologia , DNA/química , Descoberta de Drogas/métodos , Humanos , Íons/química , Ligantes , Potencial da Membrana Mitocondrial/fisiologia , Metano/análogos & derivados , Metano/química , Proteínas Mitocondriais/metabolismo , Estrutura Molecular , Fosfinas/química , Piridinas/química , Relação Estrutura-Atividade , Tiorredoxina Dissulfeto Redutase/metabolismoRESUMO
Tumor cell chemoresistance is a major challenge in cancer therapeutics. Major select metal-based drugs are potent anticancer mediators yet they exhibit adverse sideeffects and are efficient against limited types of malignancies. A need, therefore, arises for novel metallodrugs with improved efficacy and decreased toxicity. Enhancement of antitumor drugs based on anticancer metals is currently a very active research field, with considerable efforts having been made toward elucidating the mechanisms of immune action of complex metalloforms and optimizing their immunoregulatory bioactivity through appropriate synthetic structural modification(s) and encapsulation in suitable nanocarriers, thereby enhancing their selectivity, specificity, stability, and bioactivity. In that respect, comprehending the molecular factors involved in drug resistance and immune response may help us develop new approaches toward more promising chemotherapies, reducing the rate of relapse and overcoming chemoresistance. In this review, a) molecular immunerelated mechanisms in the tumor microenvironment, responsible for lower drug sensitivity and tumor relapse, along with b) strategies for reversing drug resistance and targeting immunosuppressive tumor networks, while concurrently optimizing the design of complex metalloforms bearing anti-tumor activity, are discussed in an effort to identify and overcome chemoresistance mechanisms for effective tumor immunotherapeutic approaches.
Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Imunossupressores/química , Metais/química , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Complexos de Coordenação/efeitos adversos , Complexos de Coordenação/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacologia , Estrutura Molecular , Terapia de Alvo Molecular/métodos , Nanopartículas/química , Transdução de Sinais , Relação Estrutura-Atividade , Microambiente TumoralRESUMO
Silver is a non-essential element with promising antimicrobial and anticancer properties. This work is a detailed summary of the newest findings on the bioinorganic chemistry of silver, with a special focus on the applications of Ag+ complexes and nanoparticles. The coordination chemistry of silver is given a reasonable amount of attention, summarizing the most common silver binding sites and giving examples of such binding motifs in biologically important proteins. Possible applications of this metal and its complexes in medicine, particularly as antibacterial and antifungal agents and in cancer therapy, are discussed in detail. The most recent data on silver nanoparticles are also summarized.