RESUMO
Triple-negative breast cancer (TNBC) represents aggressive phenotype with limited treatment options due to the lack of drug targets. Natural compounds are extensively studied regarding their potential to alter the efficacy of cancer treatment Among them sulforaphane - an isothiocyanate of natural origin, was shown to be a hormetic compound, that may exert divergent effects: cytoprotective or cytotoxic depending on its concentrations. Thus, the aim of this study was to determine the effect of its low, dietary concentrations on the proliferation and migration of the TNBC cells in the in vivo and in vitro 2D and 3D model. Results of the in vivo experiment showed up to 31% tumor growth inhibition after sulforaphane treatment associated with lowered proliferating potential of cancer cells, reduced areas of necrosis, and changed immune cell type infiltration, showing less malignant type of tumor in contrast to the non-treated group. Also, the study revealed that sulforaphane decreased the number of lung metastases. The in vitro study confirmed that SFN inhibited cell migration, but only in cells derived from 3D spheroids, not from 2D in vitro cultures. The results show a specific role of sulforaphane in the case of cells released from the TNBC primary tumor and its environment.
Assuntos
Movimento Celular , Proliferação de Células , Isotiocianatos , Sulfóxidos , Neoplasias de Mama Triplo Negativas , Isotiocianatos/farmacologia , Isotiocianatos/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Sulfóxidos/farmacologia , Feminino , Humanos , Movimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Animais , Proliferação de Células/efeitos dos fármacos , Camundongos , Anticarcinógenos/farmacologia , Anticarcinógenos/administração & dosagem , Anticarcinógenos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide isomerase (PDI, EC 5.3.4.1) inhibitors. The inhibitory activity on PDI was determined against recombinant human PDIA1 and PDIA3 proteins using an insulin reduction assay. These compounds in low micromolar to low nanomolar concentrations showed the effective in vitro inhibitory properties of PDIA1 with weaker effects on PDIA3. Complexes of 15N- and 15N,13C- uniformly labelled recombinant human PDIA1a with two PDIA1 inhibitors were produced and investigated by a protein nuclear magnetic resonance (NMR) spectroscopy. It was found that both C53 and C56 of the PDIA1 enzyme were involved in covalent binding. Finally, in a range of pharmacological studies, we demonstrated that investigated compounds displayed anti-cancer and anti-thrombotic activity. These findings demonstrate that sulphonamides of Az-COOH derivatives are promising candidates for the development of novel anti-cancer and anti-thrombotic agents.
Assuntos
Aziridinas , Isomerases de Dissulfetos de Proteínas , Sulfonamidas , Humanos , Aziridinas/farmacologia , Isomerases de Dissulfetos de Proteínas/antagonistas & inibidores , Isomerases de Dissulfetos de Proteínas/química , Sulfonamidas/farmacologiaRESUMO
BACKGROUND: Patients with cancer develop endothelial dysfunction and subsequently display a higher risk of cardiovascular events. The aim of the present work was to examine changes in nitric oxide (NO)- and prostacyclin (PGI2)-dependent endothelial function in the systemic conduit artery (aorta), in relation to the formation of lung metastases and to local and systemic inflammation in a murine orthotopic model of metastatic breast cancer. METHODS: BALB/c female mice were orthotopically inoculated with 4T1 breast cancer cells. Development of lung metastases, lung inflammation, changes in blood count, systemic inflammatory response (e.g. SAA, SAP and IL-6), as well as changes in NO- and PGI2-dependent endothelial function in the aorta, were examined 2, 4, 5 and 6 weeks following cancer cell transplantation. RESULTS: As early as 2 weeks following transplantation of breast cancer cells, in the early metastatic stage, lungs displayed histopathological signs of inflammation, NO production was impaired and nitrosylhemoglobin concentration in plasma was decreased. After 4 to 6 weeks, along with metastatic development, progressive leukocytosis and systemic inflammation (as seen through increased SAA, SAP, haptoglobin and IL-6 plasma concentrations) were observed. Six weeks following cancer cell inoculation, but not earlier, endothelial dysfunction in aorta was detected; this involved a decrease in basal NO production and a decrease in NO-dependent vasodilatation, that was associated with a compensatory increase in cyclooxygenase-2 (COX-2)- derived PGI2 production. CONCLUSIONS: In 4 T1 metastatic breast cancer in mice early pulmonary metastasis was correlated with lung inflammation, with an early decrease in pulmonary as well as systemic NO availability. Late metastasis was associated with robust, cancer-related, systemic inflammation and impairment of NO-dependent endothelial function in the aorta that was associated with compensatory upregulation of the COX-2-derived PGI2 pathway.
Assuntos
Aorta/patologia , Neoplasias da Mama/patologia , Epoprostenol/metabolismo , Neoplasias Pulmonares/patologia , Óxido Nítrico/metabolismo , Animais , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Endotélio Vascular/patologia , Feminino , Inflamação , Pulmão/irrigação sanguínea , Pulmão/patologia , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We established a new B-cell leukaemia cell line CLB70 from a dog with chronic lymphocytic leukaemia. This cell line is positive for CD20, CD45, CD79a, MHC class II, IgG, IgM; weakly positive for CD21; and negative for CD3, CD4, CD5, CD8, CD14, CD34, CD117. PCR for antigen receptor gene rearrangement (PARR) analysis revealed a biclonal immunoglobulin heavy chain (IgH) gene rearrangement and negative result for TCRγ. Western blot analysis of anti- and pro-apoptotic proteins showed increased expression of Bcl-2, Mcl-1, NF-kB, and Ras, and decreased expression of p53. CLB70 cells grow rapidly in vitro and are tumourigenic in nude mice. The CLB70 line is highly sensitive to doxorubicin, less sensitive to etoposide and imatinib, and resistant to piroxicam, celecoxib and dexamethasone. Our results indicate that CLB70 cells are derived from mature B-cells and they may be a useful tool for the development of new therapeutic strategies for both dogs and humans.
Assuntos
Antineoplásicos/uso terapêutico , Doenças do Cão/patologia , Leucemia de Células B/veterinária , Animais , Biomarcadores Tumorais/metabolismo , Western Blotting , Celecoxib/uso terapêutico , Linhagem Celular Tumoral , Dexametasona/uso terapêutico , Doenças do Cão/tratamento farmacológico , Cães , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/uso terapêutico , Feminino , Mesilato de Imatinib/uso terapêutico , Leucemia de Células B/tratamento farmacológico , Leucemia de Células B/patologia , Camundongos , Transplante de Neoplasias/veterinária , Piroxicam/uso terapêuticoRESUMO
At present, effective anticancer therapy remains one of the most challenging tasks facing the scientific community. A major limitation to most conventional low-molecular weight anticancer chemotherapeutics is their unfavourable uptake by healthy tissue, fast metabolism and lack of tumour cell selectivity. One way to solve this problem is the application of hybrid nanoparticles containing widely known therapeutic substances. This study was performed with the aim of investigating the potential of use hydroxyethyl starch (HES) as a high-molecular weight carrier for anticancer drug (methotrexate, MTX). HES-MTX conjugates were characterized in terms of MTX content, hydrodynamic size, zeta potential, and drug release kinetics. In vitro biological characteristics were determined using different cancer cell lines. The antitumor effect in vivo was tested in NOD/SCID mice subcutaneously inoculated with MV-4-11 human leukaemia cells and CDF1 mice intraperitoneally inoculated with P388 murine leukaemia cells. The in vivo experiments revealed the considerably higher antitumor efficacy of HES-MTX conjugates in comparison to unconjugated drug. The results presented in this article demonstrate that the application of HES as an anticancer drug carrier can improve the treatment efficacy and have significant implications for the future design and implementation of drug-carrier conjugates. The study should help create new opportunities in the design of HES-based innovative drug-carrier conjugates.
RESUMO
Geometric isomers (5E,7E) of major active metabolites of vitamin D3 [1alpha,25(OH)2D3 and (24R)-1,24(OH)2D3] were synthesized by a new convenient procedure. Vitamin D triene system of the metabolites was first derivatized as a Diels-Alder adduct. Removal of the triene protecting group, in a key synthetic step, yielded the title compounds PRI-2208 and PRI-2209, respectively. The analogs were examined for their antiproliferative activity in vitro against human breast cancer cells (MCF-7) and promyelocytic leukemia (HL-60) cells. The activity was compared with one of the parent compounds. Both analogs examined revealed similar or higher antiproliferative activity compared to 1alpha,25(OH)2D3 or to (24R)-1,24(OH)2D3. The studies of calcemic activity in vivo showed that analogs PRI-2208 and PRI-2209 did not influence the serum calcium level in doses, in which 1alpha,25(OH)2D3 or (24R)-1,24(OH)2D3 significantly increased this level. The antitumor activity of these analogs in the LLC mice tumor model was studied. Analog PRI-2208 was found to be more active in inhibiting LLC tumor growth than 1alpha,25(OH)2D3, as well as than PRI-2191 and PRI-2209.
Assuntos
Antineoplásicos/farmacologia , Colecalciferol/análogos & derivados , Colecalciferol/química , Animais , Antineoplásicos/síntese química , Cálcio/metabolismo , Proliferação de Células , Química Farmacêutica/métodos , Colecalciferol/síntese química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HL-60 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , EstereoisomerismoRESUMO
The series of new acetylenic thioquinolines containing propargyl, 2-butynyl, 4-bromo-2-butynyl, and 4-hydroxy-2-butynyl groups has been prepared and tested for antiproliferative activity in vitro against human [SW707 (colorectal adenocarcinoma), CCRF/CEM (leukemia)] and murine [P388 (leukemia), B16 (melanoma)] cancer lines. All the compounds obtained exhibited antiproliferative activity. The most active compounds 7, 16, 17, and 19 have the ID(50) values ranging from 0.2 to 4.6 microg/ml comparable to that of cisplatin used as reference compounds.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Leucemia Experimental/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Quinolinas/farmacologia , Sulfetos/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Estereoisomerismo , Relação Estrutura-Atividade , Sulfetos/síntese química , Sulfetos/químicaRESUMO
The structure-activity relationships of new quinoline based compounds were investigated. Quinoline-5,8-dione and styrylquinoline scaffolds were used for the design of potentially active compounds. The novel analogues had comparable antiproliferative activity to cisplatin when evaluated in a bioassay against the P388 leukemia cell line. However, these compounds appeared far less efficient against SK-N-MC neuroepithelioma cells. Analogues without the 5,8-dione structure but containing the 8-carboxylic acid group were also found to induce antiproliferative activity. Hydrophobicity as measured by HPLC did not correlate with antiproliferative activity.
Assuntos
Antineoplásicos/farmacologia , Ácidos Carboxílicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
A series of new acetylenic thioquinolines containing propargyl, 2-butynyl, or 4-bromo-2-butynyl groups has been prepared and tested for antiproliferative activity in vitro against the cells of human [SW707 (colon cancer), CCRF/CEM (leukemia)] and murine [P388 (leukemia), B16 (melanoma)] cancer lines. All the compounds obtained exhibited antiproliferative activity. The most active compounds 4h and 41-m have ID50 values ranging from 0.2 to 3.6 microg/ml, comparable to that of the reference compound cisplatin.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Animais , Linhagem Celular Tumoral , Cisplatino/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Camundongos , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Ultravioleta , Sais de Tetrazólio , TiazóisRESUMO
Bacteriophages (phages) as bacterial viruses are generally believed to have no intrinsic tropism for mammalian cells. In this study the interactions between phages and various eukaryotic cells were investigated. Binding of phages to the membranes of cancer and normal blood cells was observed. Moreover, it was shown that the wild-type phage T4 (wtT4) and its substrain HAP1 with enhanced affinity for melanoma cells inhibit markedly and significantly experimental lung metastasis of murine B16 melanoma cells by 47% and 80%, respectively. A possible molecular mechanism of these effects, namely a specific interaction between the Lys-Gly-Asp motif of the phage protein 24 and beta3-integrin receptors on target cells is proposed. It was also shown that anti-beta3 antibodies and synthetic peptides mimicking natural beta3 ligands inhibit the phage binding to cancer cells. This is in line with the well-described beta3 integrin-dependent mechanism of tumor metastasis. It is concluded that the blocking of beta3 integrins by phage preparations results in a significant decrease in tumor invasiveness.
Assuntos
Bacteriófago T4/fisiologia , Integrina beta3/fisiologia , Melanoma Experimental/terapia , Transdução de Sinais , Animais , Humanos , Melanoma Experimental/patologia , Melanoma Experimental/secundário , CamundongosRESUMO
The series of new 3,4-disubstituted thioquinolines which possess one or two O, S, Se-propargyl groups has been synthesized on the basis of the reaction of thioquinanthrene with alkoxides. All the compounds obtained were tested for their antiproliferative activity in vitro against the cells of three human cancer cell lines: SW707 (colon cancer), T47D (breast cancer), and HCV29T (bladder cancer). Two compounds, 4-(3-hydroxypropoxy)-3'-propargylthio-3,4'-diquinolinyl sulfide (3) and 3-methylthio-4-propargylselenoquinoline (13) exhibited significant cytostatic activity (ID50 < 4 micrograms/ml) against the cells of all the human cancer lines used and are good candidates for further anticancer activity studies in vitro using a broad panel of human and murine cell lines and for in vivo preclinical screening in different mouse transplantable tumor models.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Cisplatino/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indicadores e Reagentes , Camundongos , Rodaminas , Células Tumorais CultivadasRESUMO
The series of the propargyl thioquinolines has been prepared on the basis of the reaction of thioquinanthrene (1) (1,4-dithiino[2,3-c:5,6-c']-diquinoline) with sodium alkoxides. Some of these compounds have revealed good antiproliferative activity in vitro against the cells of human and murine cancer lines. 13C NMR spectra were measured for the studied compounds to examine the electronic properties-activity relationships. A regression study on 10 compounds showed a linear correlation of antiproliferative activity with electronic properties, expressed as the 13C NMR chemical shift for C-4 carbon atom (R2 = 0.97). It was found that compounds with chemical shift for C-4 value falling in the range of 135-140 ppm exhibited significant antiproliferative activity, while compounds which possess moderate or low activity are located in the range 140-165 ppm. This finding leads to the expectation that the antiproliferative activity of propargyl thioquinolines can be predicted using the 13C NMR chemical shift value of their C-4 carbon atom.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Animais , Cisplatino/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Eritrócitos/efeitos dos fármacos , Humanos , Análise de Regressão , Ovinos/imunologia , Relação Estrutura-Atividade , Sais de Tetrazólio , Tiazóis , Células Tumorais CultivadasRESUMO
The synthesis of several new pyrazolo[3,4-b]pyridine, pyrido[2',3':3,4]-pyrazolo[1,5-a]pyrimidine and imidazo[1',2':1,5]pyrazolo[3,4-b]pyridine derivatives is described. The obtained compounds were tested for their antiproliferative activity in vitro. One of them, 4-phenyl-2-(3,4,5-trimethoxy-beta-styrylo)pyrido- [2',3':3,4]pyrazolo[1,5-a]pyrimidine (9), revealed cytotoxic properties against the cells of all three human cancer cell lines applied. Another one, 2,4-dimethyl-pyrido[2',3':3,4]pyrazolo[1,5-a]-pyrimidine (2), revealed weak cytotoxic activity only against the cells of human bladder cancer cell line HCV29T. All other compounds tested did not reveal any cytotoxic activity.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Humanos , Cetonas/síntese química , Cetonas/farmacologia , Espectroscopia de Ressonância Magnética , Ovinos , Células Tumorais CultivadasRESUMO
Numerous vitamin D3 analogues have been synthesised in recent years in order to obtain compounds with a favourable biological and therapeutic (antipsoriatic and/or antitumour) activity. Our results showed that pre-treatment for 72 hours of HL-60 human promyelocytic leukaemia cells with calcitriol or its new analogues significantly potentiated their sensitivity to the antiproliferative effect in vitro of cisplatin, doxorubicin or genistein. Moreover, for all cytotoxic agents tested a synergistic antiproliferative effect was observed. This effect was expressed as a significant decrease of the ID50 (inhibitory dose 50%) values for each cytotoxic agent applied after pretreatment with calcitriol or its analogues of HL-60 cells in comparison with the effect of cytotoxic agent applied alone. The observed in vitro potentiated antiproliferative effect of cytotoxic drugs used in combination with vitamin D or its analogues may raise the question as to whether such an effect could be expected in the in vivo situation.
Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/farmacologia , Doxorrubicina/farmacologia , Genisteína/farmacologia , Vitamina D/análogos & derivados , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Células HL-60 , HumanosRESUMO
The role of angiogenesis in tumor growth and metastasis is discussed. The endogenous activators and inhibitors of tumor angiogenesis are presented and their mechanisms of action are reviewed. An overview on angiogenesis as a new potential target of antitumor therapy is described. The clinical trials of various antiangiogenic agents are briefly summarized and their differential mechanisms of action are discussed.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Animais , Substâncias de Crescimento/metabolismo , Humanos , Metástase Neoplásica , Neoplasias/fisiopatologia , Indução de Remissão , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The reaction of 2,2,4-trimethyl-1H-2,3-dihydro-1,5-benzodiazepine (1) with cinnamoyl chloride leading to the formation of 1-cinnamoyl derivative 2 is described. Two novel benzodiazepines, 2,2,4-trimethyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepine (3) and 1-cinnamoyl-2,2,4-trimethyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepine (4), were synthesized by the reduction of 1 and 2 using NaBH4 in i-PrOH and two other derivatives 5 and 6 were obtained by reaction of 4 with equimolar and dimolar quantity of cinnamoyl chloride, respectively. The structures of 1-6 were confirmed by analytical and spectral data (IR, 1H NMR, and MS). 7-Carboxy-2,2,4-trimethyl-1H-2,3-dihydro-1,5-benzodiazepine (7) was synthesized and its crystals were subjected to X-ray analysis. Benzodiazepines 1-6 were evaluated for antiproliferative activity in vitro. Among the compounds tested, 4-6 exhibited cytotoxic activity against human cancer cell lines, namely SW707 (colon cancer), MCF-7 (breast cancer), A549 (lung cancer), and HCV29T (bladder cancer).
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzodiazepinas/síntese química , Benzodiazepinas/farmacologia , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Células Tumorais CultivadasRESUMO
Complexes of 2-(4-thiazolyi)benzimidazole (thiabendazole, THBD) with Co(II), Ni(II), Cu(ll) of general formula ML(2)(NO(3))(2) H(2)O and complexes of Pd(II) and Pt(II) of general formula ML2Cl(2) H(2)O have been obtained and characterized by elemental analyses, IR and far IR spectroscopy and magnetic measurements. The X-ray crystal structure of the copper(II) complex has been determined. The in vitro cell proliferation inhibitory activity of these compounds was examined against human cancer cell lines A 549 (lung carcinoma), HCV-29 T (urinary bladder carcinoma), MCF-7 (breast cancer), T47D (breast cancer), MES-SA (uterine carcinoma) and HL-60 (promyelocytic leukemia). Pt-THBD has been found to exhibit an antileukemic activity of the HL-60 line cells matching that of an arbitrary criterion.
RESUMO
The antitumour and antiangiogenic effects in vivo of genistein, applied alone or in combined therapy with cyclophosphamide, in the Lewis lung carcinoma (LL2) and B16 melanoma mouse tumour models, were analysed. Our own new method, allowing quantification of the volume of blood present in tumour tissue, enabled estimation of the degree of vascularization. Tumour cells entrapped in alginate beads were injected subcutaneously into mice. The quantification of alginate implant vascularization was performed with 125I-labeled mouse albumin injected intravenously. In mice bearing transplantable Lewis lung cancer the additive antiangiogenic, but not cytostatic, effect of genistein combined with cyclophosphamide (CY) was observed, since the treatment with genistein alone reduced tumour blood supply in 35% (tumour weight in 36%), with CY in 38% (tumour weight in 70%) and with both compounds in 61% (tumour weight in 75%). In the B16 melanoma model the respective values were: 60 and 44% for genistein, 83 and 79% for CY and 76 and 74% for combined treatment. These results indicate a higher antiangiogenic rather than cytostatic effect of genistein in both mouse tumour models applied.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Genisteína/farmacologia , Neovascularização Patológica/tratamento farmacológico , Inibidores da Angiogênese/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Lewis/irrigação sanguínea , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/patologia , Divisão Celular/efeitos dos fármacos , Cicloexanos , Ciclofosfamida/administração & dosagem , Feminino , Genisteína/administração & dosagem , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , O-(Cloroacetilcarbamoil)fumagilol , Sesquiterpenos/farmacologiaRESUMO
The results of studies on antiproliferative activity in vitro of nine new platinum(II) complexes against cells of eight human and six murine neoplastic cell lines are described. New complexes with the anionic rest originating from enantiomeric forms of hydroxydicarboxylic malic acid were synthesized to obtain agents with increased water solubility and decreased toxicity. Three compounds, coded 1-3, with ethylenediamine as a neutral ligand, showed cytotoxic activity against 12 out of 14 target cell lines. Their cytotoxic activity was similar or even slightly higher than that of the reference carboplatin. The remaining six compounds, coded 4-9, with 1-alkylimidazole as a neutral ligand, revealed rather low cytotoxic activity, and only against the cells of the human bladder cancer cell line Hu1703He, ovarian cancer cell line OAW-42 and mouse leukemia P388. Most of them appeared to be negative against all other cell lines. No compounds, including reference carboplatin, showed any cytotoxicity against the cells of the T47D human breast cancer cell line or B16F-10 mouse melanoma cell line. The results obtained are in accordance with common opinion, i.e. that the presence of neutral amine ligands with NH groups is required for the cytotoxic activity of platinum complexes. Compounds with a primary amine (ethylenediamine) showed higher cytotoxic activity in vitro than complexes with a tertiary amine (1alkylimidazole).
Assuntos
Antineoplásicos/farmacologia , Compostos Organoplatínicos/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Animais , Carboplatina/farmacologia , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Técnicas In Vitro , Leucemia Experimental/tratamento farmacológico , Camundongos , Estrutura Molecular , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
The results of our studies on the biological activity of side-chain modified analogues of vitamin D are reviewed. These analogues appeared to be effective in induction of cell differentiation, inhibition of tumour cell proliferation in vitro and in increasing of antitumour effect of cytostatics. On the other hand, inhibition of cytostatic-induced apoptosis by these compounds was observed. The mechanism of the antiproliferative effect of calcitriol analogues in vitro is discussed. The induction of antigens CD14 and CD11b expression and phagocytic activity of HL-60 cells after exposure to these compounds is related to their effect on cell differentiation. The differentiation of the HL-60 leukaemia cells induced by side-chain modified analogues of calcitriol increases their sensitivity to the antiproliferative effect of cisplatin, doxorubicin and genistein, despite of that this pretreatment causes resistance of these cells to cytostatics-induced apoptosis. We observed a synergistic antiproliferative effect of the combined therapy using analogues of calcitriol with subsequent treatment with the above-mentioned cytostatics. This effect was measured as a significant decrease of the ID50 values for each cytostatic applied after pretreatment of the tumour cells with the calcitriol analogues. The results presented suggest that the improved therapeutic effect may be achieved also in vivo by the combined application of the analogues (without calcemic activity) of calcitriol with antitumour agents.