RESUMO
BACKGROUND: The architectural transcription factor High Mobility Group-A1 (HMGA1) binds to the minor groove of AT-rich DNA and forms transcription factor complexes ("enhanceosomes") that upregulate expression of select genes within the inflammatory cascade during critical illness syndromes such as acute lung injury (ALI). AT-rich regions of DNA surround transcription factor binding sites in genes critical for the inflammatory response. Minor groove binding drugs (MGBs), such as Distamycin A (Dist A), interfere with AT-rich region DNA binding in a sequence and conformation-specific manner, and HMGA1 is one of the few transcription factors whose binding is inhibited by MGBs. OBJECTIVES: To determine whether MGBs exert beneficial effects during endotoxemia through attenuating tissue inflammation via interfering with HMGA1-DNA binding and modulating expression of adhesion molecules. METHODOLOGY/PRINCIPAL FINDINGS: Administration of Dist A significantly decreased lung and liver inflammation during murine endotoxemia. In intravital microscopy studies, Dist A attenuated neutrophil-endothelial interactions in vivo following an inflammatory stimulus. Endotoxin induction of P-selectin expression in lung and liver tissue and promoter activity in endothelial cells was significantly reduced by Dist A, while E-selectin induction was not significantly affected. Moreover, Dist A disrupted formation of an inducible complex containing NF-kappaB that binds an AT-rich region of the P-selectin promoter. Transfection studies demonstrated a critical role for HMGA1 in facilitating cytokine and NF-kappaB induction of P-selectin promoter activity, and Dist A inhibited binding of HMGA1 to this AT-rich region of the P-selectin promoter in vivo. CONCLUSIONS/SIGNIFICANCE: We describe a novel targeted approach in modulating lung and liver inflammation in vivo during murine endotoxemia through decreasing binding of HMGA1 to a distinct AT-rich region of the P-selectin promoter. These studies highlight the ability of MGBs to function as molecular tools for dissecting transcriptional mechanisms in vivo and suggest alternative treatment approaches for critical illness.
Assuntos
Distamicinas/uso terapêutico , Endotoxemia/tratamento farmacológico , Proteína HMGA1a/metabolismo , Fígado/patologia , Pulmão/patologia , Selectina-P/genética , Regiões Promotoras Genéticas , Sequência Rica em At , Animais , Bovinos , Comunicação Celular/efeitos dos fármacos , Citocinas/metabolismo , Distamicinas/farmacologia , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotoxemia/complicações , Endotoxemia/patologia , Endotoxemia/prevenção & controle , Endotoxinas , Humanos , Inflamação/complicações , Inflamação/metabolismo , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Selectina-P/metabolismo , Ligação Proteica/efeitos dos fármacosRESUMO
BACKGROUND: Bladder cancers have different angiogenic pathways distinguishing not only papillary from solid tumours, but even papillary superficial from papillary invasive ones, thus representing selective targets for antiangiogenic drugs. METHODS: The bacterial wall component tecogalan, inhibiting basic fibroblast growth factor (bFGF), the fumagillin derivative TNP-470, inhibiting vascular endothelial growth factor (VEGF), the distamycin A derivative PNU153429, and the tetracycline minocycline were administered to nude mice injected with the human bladder cancer cell lines 639V, causing bFGF-expressing papillary superficial tumours, or T24, causing VEGF-expressing papillary invasive tumours. RESULTS: Tecogalan had no effect even on 639V tumour growth, where bFGF was unaffected. TNP-470 only had an effect on T24 tumours, delaying tumour appearance and growth and lowering VEGF; these effects were augmented by adding minocycline. PNU153429 had no effect on 639V tumours, and a slight effect on T24 tumours. CONCLUSION: TNP-470 may represent a selective drug for the treatment of VEGF-expressing invasive papillary bladder tumours.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Papilar/tratamento farmacológico , Distamicinas/uso terapêutico , Polissacarídeos Bacterianos/uso terapêutico , Sesquiterpenos/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Papilar/patologia , Linhagem Celular Tumoral , Cicloexanos , Distamicinas/farmacologia , Feminino , Fator 2 de Crescimento de Fibroblastos/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Minociclina/administração & dosagem , Minociclina/farmacologia , O-(Cloroacetilcarbamoil)fumagilol , PPAR gama/efeitos dos fármacos , PPAR gama/metabolismo , Polissacarídeos Bacterianos/farmacologia , Sesquiterpenos/farmacologia , Neoplasias da Bexiga Urinária/patologia , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Potent in vivo activity against methicillin-resistant Staphylococcus aureus (MRSA) has been difficult to achieve with previously reported DNA binding antibacterials. Herein, we describe an efficient access to a focused library of new analogues yielding compounds with improved activity in a mouse peritonitis model. The most potent molecules (14 and 19) exhibit efficacy against MRSA at ED50 values of approximately 1 and approximately 5 mg/kg, respectively, and display excellent in vitro activity against vancomycin-resistant S. aureus.
Assuntos
Distamicinas/síntese química , Distamicinas/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Animais , DNA/metabolismo , Distamicinas/uso terapêutico , Relação Dose-Resposta a Droga , Resistência a Medicamentos , Cinética , Ligantes , Meticilina , Camundongos , Peritonite/tratamento farmacológico , Peritonite/microbiologia , Relação Estrutura-Atividade , Taxa de Sobrevida , VancomicinaRESUMO
Brostallicin is a bromoacryloyl derivative of distamycin A, which has shown very promising preclinical activity against a variety of human tumors both in vitro and in vivo. The drug has a limited toxicity towards bone marrow precursor cells in vitro resulting in a therapeutic index much higher than those achieved with other distamycin A derivatives. It retains activity against cancer cells resistant to alkylating agents, topoisomerase I inhibitors and cells with mismatch repair deficiency. Brostallicin has a peculiar mechanism of action involving activation upon binding to glutathione (GSH) catalyzed by glutathione-S-transferase (GST). As a consequence, cells expressing relatively high GST/GSH levels are more susceptible to treatment with brostallicin. Considering that increased levels of GST/GSH are often found in human tumors, this could represent an advantage for the drug in the clinic. Initial clinical studies indicate the tolerability of the drug and allow the determination of the optimal dose for subsequent studies. Some partial response were obtained in these initial phase I studies. Altogether, the results suggest brostallicin to be a new promising anticancer agent with a new mechanism of action. It also raises the possibility to use it in combination with other anticancer drugs currently used.
Assuntos
Alquilantes/uso terapêutico , Antineoplásicos/uso terapêutico , Distamicinas/uso terapêutico , Alquilantes/farmacocinética , Alquilantes/toxicidade , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Ensaios Clínicos Fase I como Assunto , DNA/efeitos dos fármacos , Distamicinas/farmacocinética , Distamicinas/toxicidade , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Glutationa/química , Glutationa/metabolismo , Glutationa Transferase/química , Glutationa Transferase/metabolismo , Guanidinas/administração & dosagem , Guanidinas/farmacocinética , Guanidinas/uso terapêutico , Guanidinas/toxicidade , Humanos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Pirróis/administração & dosagem , Pirróis/farmacocinética , Pirróis/uso terapêutico , Pirróis/toxicidadeRESUMO
In this study, we evaluated the potential of the distamycin derivative MEN 10716 as a telomerase inhibitor. Exposure of human melanoma cell extracts to MEN 10716 induced a dose-dependent inhibition of telomerase activity, with an IC50 of 24+/-3 microM. When intact JR8 melanoma cells were chronically exposed to the drug (200 microM every other day for 50 days), a marked inhibition (>80%) of the enzyme's catalytic activity was consistently observed starting from day 1. At later points in time, MEN 10716 inhibited melanoma cell proliferation and induced apoptosis. Cells surviving MEN 10716 exposure were characterised by a higher melanin content and a greater expression of p16(INK4A) protein than control cells. The effects of MEN 10716 were subsequently evaluated in different tumour cell systems. In particular, even in the H460 non-small cell lung cancer cell line, chronic exposure of the cells to the drug (100 microM every other day for 50 days) induced a consistent inhibition (>85%) of telomerase activity, a reduction of cell proliferation potential, and apoptosis. Conversely, MEN 10716 treatment did not appreciably inhibit cell proliferation in the U2-OS telomerase-negative human osteogenic sarcoma cell line. Interestingly, no variation in the mean telomere length was observed in MEN 10716-treated JR8 melanoma cells, whereas an appreciable increase in the mean telomere length was found in H460 lung cancer cells after drug exposure. Overall, the results of the study indicate that MEN 10716 is a possible telomerase inhibitor and suggest that abrogation of telomerase activity can affect cell proliferation even through pathways that are not dependent on telomere erosion.
Assuntos
Antineoplásicos/uso terapêutico , Antivirais/farmacologia , Distamicinas/farmacologia , Distamicinas/uso terapêutico , Telomerase/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Melanoma/tratamento farmacológico , Melanoma/enzimologia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/enzimologia , Células Tumorais CultivadasRESUMO
Human leukaemic K562 cells can be induced in vitro to erythroid differentiation by a variety of chemical compounds, including haemin, butyric acid, 5-azacytidine, cytosine arabinoside, mithramycin and chromomycin, cisplatin and cisplatin analogues. Differentiation of K562 cells is associated with an increase of expression of embryo-fetal globin genes, such as the zeta-, epsilon- and gamma-globin genes. The K562 cell line has been proposed as a very useful in vitro model system to determine the therapeutic potential of new differentiating compounds as well as to study the molecular mechanism(s) regulating changes in the expression of embryonic and fetal human globin genes. Inducers of erythroid differentiation stimulating gamma-globin synthesis could be considered for possible use in the therapy of haematological diseases associated with a failure in the expression of normal beta-globin genes. We have analysed the effects of tallimustine and distamycin on cell growth and differentiation of K562 cells. The results demonstrated that tallimustine is a potent inducer, while distamycin is a weak inducer, of K562 cell erythroid differentiation. Erythroid differentiation was associated with an increase of accumulation of gamma-globin mRNA and of production of both haemoglobin (Hb) Gower 1 and Hb Portland. In addition, tallimustine-mediated erythroid induction occurred in the presence of activation of the apoptotic pathway. The reasons for proposing tallimustine as an inducer of gamma-globin gene expression are strongly sustained by the finding that this compound stimulates fetal haemoglobin production in human erythroid precursor cells from normal subjects.
Assuntos
Proteínas de Ligação a DNA/uso terapêutico , Distamicinas/uso terapêutico , Eritrócitos/fisiologia , Globinas/genética , Compostos de Mostarda Nitrogenada/uso terapêutico , RNA Mensageiro/metabolismo , Apoptose , Northern Blotting/métodos , Diferenciação Celular/efeitos dos fármacos , Divisão Celular , Citarabina/uso terapêutico , Distamicinas/química , Hemoglobina Fetal/biossíntese , Células-Tronco Hematopoéticas/efeitos dos fármacos , Hemoglobinas/biossíntese , Humanos , Hidroxiureia/farmacologia , Células K562 , Compostos de Mostarda Nitrogenada/química , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The relatively low therapeutic index of the clinically used alkylating agents is probably related to the fact that these compounds cause DNA damage in a relatively unspecific manner, mainly involving guanine-cytosine rich stretches of DNA present in virtually all genes, therefore inducing unselective growth inhibition and death, both in neoplastic and in highly proliferative normal tissues. These considerations explain why in the last twenty years there has been an increasing interest in the identification of compounds which can target DNA with a much higher degree of sequence specificity than that of conventional alkylators. Minor groove binders (MGBs) are one of the most widely studied class of alkylating agents characterised by a high level of sequence specificity. The prototype of this class of drugs is distamycin A which is an antiviral compound able to interact, non-covalently, in theminor groove of DNA in A-T rich regions. It is not cytotoxic against tumour cells and thus has been used as a carrier for targeting cytotoxic alkylating moieties in theminor groove of DNA. The benzoyl mustard derivative of distamycin A, tallimustine, was found to be able to alkylate the N(3) of adenine in theminor groove of DNA only in the target hexamer 5'-TTTTGA or 5'-TTTTAA. Tallimustine was investigated in the clinic and was not successful because it causes severe bone marrow toxicity. The screening of other distamycin derivatives, which maintain antitumour activity and exhibit much lower toxicity against human bone marrow cells than tallimustine led to the identification of brostallicin (PNU-166196) which is currently under early clinical investigation. Although MGBs which bind DNA in A-T rich regions have not fulfilled the expectations, it is too early to draw definitive conclusions on this class of compounds. The peculiar bone-marrow toxicity observed in the clinic both with tallimustine or with CC-1065 derivatives is not necessarily a feature of all MGBs, as indicated by recent evidence obtained with brostallicin and other structurally unrelated MGBs (e.g., ET-743).
Assuntos
Antineoplásicos/metabolismo , DNA/metabolismo , Distamicinas/metabolismo , Animais , Antineoplásicos/uso terapêutico , Antivirais/metabolismo , Antivirais/uso terapêutico , Sítios de Ligação , Distamicinas/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Ensaios de Seleção de Medicamentos Antitumorais/estatística & dados numéricos , HumanosRESUMO
The problem of estimating parameters in the drift coefficient when a diffusion process is observed continuously requires some specific assumptions. In this paper, we consider a stochastic version of the Gompertzian model that describes in vivo tumor growth and its sensitivity to treatment with antiangiogenic drugs. An explicit likelihood function is obtained, and we discuss some properties of the maximum likelihood estimator for the intrinsic growth rate of the stochastic Gompertzian model. Furthermore, we show some simulation results on the behavior of the corresponding discrete estimator. Finally, an application is given to illustrate the estimate of the model parameters using real data.
Assuntos
Modelos Estatísticos , Processos Estocásticos , Inibidores da Angiogênese/uso terapêutico , Animais , Antibióticos Antineoplásicos/uso terapêutico , Biometria/métodos , Divisão Celular , Distamicinas/uso terapêutico , Humanos , Camundongos , Camundongos Nus , Sarcoma de Kaposi/tratamento farmacológico , Sarcoma de Kaposi/patologia , Transplante HeterólogoAssuntos
Antibióticos Antineoplásicos/isolamento & purificação , Antibióticos Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pirróis/isolamento & purificação , Pirróis/uso terapêutico , Sarcoma 180/tratamento farmacológico , Animais , Antivirais/uso terapêutico , Distamicinas/uso terapêutico , Fermentação , Humanos , Camundongos , Camundongos Nus , Testes de Sensibilidade Microbiana , Streptomyces , Relação Estrutura-AtividadeRESUMO
The antiangiogenic, antitumoural and antimetastatic effects of two novel sulphonic derivatives of distamycin A, PNU145156E and PNU153429, were studied in a Kaposi's sarcoma-like tumour model obtained by injecting nude mice with cells releasing extracellular HIV-Tat protein, derived from a tumour which developed in a BK virus/tat transgenic mouse. Both PNU145156E and PNU153429 were administered intraperitoneally every fourth day for three weeks at doses of 100 or 50 mg/kg of body weight respectively, starting one day after injecting the tumour cells. Both drugs delayed tumour growth in nude mice, preventing neovascularization induced by the Tat protein. PNU153429 also significantly reduced the number and size of spontaneous tumour metastases. Both effects on tumour growth and metastases were augmented by treating simultaneously nude mice with 7.5 mg/kg of body weight of minocycline given per os daily for four weeks starting four days after injecting the tumour cells. Neither acute nor chronic toxic side-effects were observed during the life span of treated nude mice. Due to their antiangiogenic and anti-Tat effects, these drugs are promising for the treatment of Kaposi's sarcoma in AIDS patients.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Distamicinas/uso terapêutico , Produtos do Gene tat/antagonistas & inibidores , HIV-1/genética , Metástase Neoplásica/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Neovascularização Patológica/tratamento farmacológico , Sarcoma de Kaposi/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/toxicidade , Animais , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Distamicinas/administração & dosagem , Distamicinas/farmacologia , Distamicinas/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Genes tat , Masculino , Camundongos , Camundongos Nus , Camundongos Transgênicos , Minociclina/administração & dosagem , Transplante de Neoplasias , Sarcoma de Kaposi/etiologia , Sarcoma de Kaposi/patologia , Transfecção , Produtos do Gene tat do Vírus da Imunodeficiência HumanaRESUMO
We investigated whether recombinant human (rHu-IFN-beta) (IFN-beta) could counteract the inhibition of natural killer (NK) activity caused by antitumor agents. Peripheral blood lymphocytes (PBL) were incubated with different antitumor agents alone or in combination with IFN-beta for 3 days and then tested in a cytotoxicity assay against the K562 cell line. The following drugs were used, all of which caused a dose-dependent inhibition of NK activity: etoposide, camptothecin, doxorubicin, cis-DDP, tallimustine, and L-PAM. Concomitant treatment with (1000 U/ml) IFN-beta counteracted the inhibitory effect of etoposide and camptothecin but had no consistent effect on the inhibition mediated by the other drugs. Mean values of inhibition of NK activity at 1 microM camptothecin was 48%+/-3.4% and with IFN-beta was 10%+/-4.9%. With 100 microM etoposide, mean value of inhibition was 78%+/-3.3%, and with IFN-beta, it was 18%+/-1.5%. Cell viability, assessed by vital dye exclusion, and drug uptake, assessed with radiolabeled etoposide, were similar in cells treated with or without IFN-beta. The protective effect of IFN-beta on NK function was rather selective, as IFN-beta did not counteract the drug-mediated inhibition of PBL proliferation when stimulated by phytohemagglutinin (PHA). Other cytokines, IFN-alpha, IFN-gamma, and interleukin-2 (IL-2), had similar protective effect, although IFN-beta, was slightly more potent. On the other hand, IL-6, a cytokine sharing some properties with IFNs was ineffective. Camptothecin inhibited the expression of mRNA for granzyme B, a lytic protein involved in lymphoid-mediated cytotoxicity. Combined treatment with IFN-beta restored-at least in part-the transcription of granzyme B mRNA. These results show that the immunosuppressive effect of some antitumor agents could be partly counteracted by treatment with IFN-beta.
Assuntos
Antineoplásicos/uso terapêutico , Camptotecina/antagonistas & inibidores , Etoposídeo/antagonistas & inibidores , Imunossupressores/antagonistas & inibidores , Interferon beta/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Cisplatino/uso terapêutico , Testes Imunológicos de Citotoxicidade , Distamicinas/uso terapêutico , Doxorrubicina/uso terapêutico , Melfalan/uso terapêutico , Compostos de Mostarda Nitrogenada/uso terapêutico , Proteínas Recombinantes/uso terapêuticoRESUMO
MEN 10710 is a new synthetic distamycin derivative possessing four pyrrole rings and a bis-(2-chloroethyl)aminophenyl moiety linked to the oligopyrrole backbone by a flexible butanamido chain. Its biological properties have been investigated in comparison with the structurally related compound, tallimustine (FCE24517), and the classical alkylating agent, melphalan (L-PAM). Cytotoxic potency of MEN 10710 was increased from 10- to 100-fold, as compared to tallimustine or L-PAM in murine L1210, human LoVo and MCF7 tumor cell lines. MEN 10710 was still active against L1210/L-PAM leukemic cells, while a partial cross-resistance was observed in LoVo/DX and in MCF7/DX cells selected for resistance to doxorubicin and expressing a MDR phenotype. Treatment with verapamil (VRP) reduced the resistance to tallimustine, but not to MEN 10710, in MCF7/DX cells. The cytotoxic effects reflect in vivo antitumor potency and toxicity in the treatment of human tumor xenografts. MEN 10710 was more effective in A2780/DDP, an ovarian carcinoma selected for resistance to cisplatin. On the other hand, the IC30 for inhibiting murine granulocyte/macrophage colony formation was 50 times higher for MEN 10710 than for tallimustine, suggesting a lower myelotoxic potential. In conclusion, the particular biological profile of MEN 10710 characterized by a marked cytotoxic potency, an interesting antitumor efficacy and a reduced in vitro myelosuppressive action may represent a further improvement in the rational design of a novel distamycin-related alkylating compound.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Distamicinas/farmacologia , Distamicinas/farmacocinética , Compostos de Mostarda Nitrogenada/farmacologia , Compostos de Mostarda Nitrogenada/farmacocinética , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos Alquilantes/farmacocinética , Bloqueadores dos Canais de Cálcio/farmacologia , Sobrevivência Celular , Distamicinas/uso terapêutico , Humanos , Leucemia L1210/tratamento farmacológico , Melfalan/farmacocinética , Melfalan/farmacologia , Camundongos , Transplante de Neoplasias , Neoplasias Experimentais/tratamento farmacológico , Células-Tronco Neoplásicas , Compostos de Mostarda Nitrogenada/uso terapêutico , Tamanho do Órgão/efeitos dos fármacos , Células Tumorais Cultivadas , Verapamil/farmacologiaRESUMO
Malaria, one of the most serious diseases transmitted by arthropods, is largely present in tropical and even temperate zones in endemic or epidemic form. More than 40% of the world's population lives in areas at risk for exposure, and the World Health Organization reports that approximately 300 million people are affected by the infection (mostly caused by the species Plasmodium falciparum), with 1-2 million deaths per year. These data, and the fact that malaria is becoming increasingly refractory to treatment through resistance of the parasite to antimalarial agents currently in use, e.g., chloroquine, emphasize the need to develop new drugs. The well-known antiparasitic activity of oligopyrrolamidine natural products, such as distamycin and netropsin, suggested the antimalarial evaluation of related compounds obtained by new chemical modifications. Besides possessing antiviral and antitumoural properties, distamycin exhibits interesting in vitro activity against P. falciparum. Unfortunately, the high toxicity associated with this product precludes its development as a drug. However, some synthetic analogues of distamycin proved to be highly active against chloroquine-sensitive and -resistant strains of P. falciparum, besides showing low toxicity in vitro.
Assuntos
Antibacterianos/química , Antimaláricos/síntese química , Distamicinas/química , Animais , Antibacterianos/uso terapêutico , Antimaláricos/uso terapêutico , Distamicinas/uso terapêutico , Desenho de Fármacos , Humanos , Malária/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Tallimustine binds to the minor groove of DNA where it alkylates the N3 position of adenine and may interfere with gene transcription. We conducted a phase II trial of Tallimustine given at a dose of 750 micrograms/m2 intravenously every 4 weeks in patients with small cell lung cancer progressing or relapsing following cisplatin or carboplatin-based chemotherapy. We treated 14 eligible patients with a performance status 0, 1 or 2, bi-dimensionally measurable disease and adequate end-organ function. The main toxicity was neutropenia with a median granulocyte count of 0.1 x 10(9) per liter (range 0-3.9) and four patients (27%) developing febrile neutropenia. In addition, most patients (93%) experienced lethargy. No objective responses were seen. A mixed response was seen in one patient and three others had stable disease for a median of 3.7 months. We conclude that Tallimustine is an ineffective agent in previously treated small cell lung cancer.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Distamicinas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Compostos de Mostarda Nitrogenada/uso terapêutico , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Canadá , Carcinoma de Células Pequenas/mortalidade , Carcinoma de Células Pequenas/patologia , Progressão da Doença , Distamicinas/administração & dosagem , Distamicinas/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Contagem de Leucócitos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neutropenia/sangue , Neutropenia/induzido quimicamente , Compostos de Mostarda Nitrogenada/administração & dosagem , Compostos de Mostarda Nitrogenada/efeitos adversosRESUMO
Tallimustine is a novel benzoyl mustard derivative from distamycin A with a unique mode of action. It is a DNA minor groove binder and produces highly sequence-specific alkylations. Previous studies have shown significant anti-tumour effects in animal models. We performed a phase II study in previously untreated patients with advanced colorectal cancer, using a schedule of i.v. bolus infusions of 900 microgram m-2 once every 4 weeks. Seventeen patients were enrolled, and no responses were documented in 14 evaluable patients. Toxicity mainly consisted a highly selective neutropenia, which warrants further investigation of this agent in combination with myeloid growth factors.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Distamicinas/uso terapêutico , Compostos de Mostarda Nitrogenada/uso terapêutico , Adulto , Idoso , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
FCE 27266, 2,2,'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole carbonyl-imino¿N-methyl-4,2-pyrrole¿carbonylimino])-bis- (1,5-naphthalene) disulfonic acid, is a noncytotoxic compound able to complex bFGF, PDGF beta, IL-8, VEGF and IL-1 beta and to inhibit the binding to their receptors. A single intravenous treatment 48 h prior to intravenous injection with tumor cells was associated with 60% inhibition of lung metastasis from B16F10 murine melanoma and 82% inhibition of liver metastasis from M5076 murine reticulosarcoma. Marginal inhibition was observed in the latter model, administering the drug 24 h after tumor cell injection. Efficacy was maintained in athymic mice, with 95 and 100% inhibition of lung metastasis from B16F10 melanoma and A375 human melanoma. The antimetastatic activity was confirmed in two models of spontaneous metastasis: in Lewis lung carcinoma implanted intramuscularly, daily intraperitoneal treatment from day 1 to 17 was associated with 77% inhibition of lung metastasis; on M5076 reticulosarcoma implanted intramuscularly, daily intraperitoneal treatment from day 1 to 14 prior to amputation of the tumor was associated with significant inhibition of liver metastasis (79%); conversely, daily intraperitoneal treatment from day 15 to 28 starting 1 day after amputation was marginally effective. The administered doses did not inhibit the growth of the primary tumor in both models. It is concluded that FCE 27266 is a novel, promising molecule, with significant efficacy on lung and liver metastases of murine and human origin; its mode of action is still under study and is probably exerted through inhibition of growth factors and cytokines influencing the different steps of angiogenesis and metastasis.
Assuntos
Antineoplásicos/farmacologia , Distamicinas/farmacologia , Distamicinas/uso terapêutico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Melanoma/patologia , Receptores de Fatores de Crescimento/metabolismo , Células 3T3 , Animais , Antineoplásicos/uso terapêutico , Ligação Competitiva , Linhagem Celular , Fatores de Crescimento Endotelial/metabolismo , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Células HL-60 , Humanos , Interleucina-1/metabolismo , Interleucina-8/metabolismo , Cinética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/prevenção & controle , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/prevenção & controle , Linfocinas/metabolismo , Linfoma Difuso de Grandes Células B , Masculino , Melanoma/tratamento farmacológico , Melanoma/secundário , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Melanoma Experimental/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Metástase Neoplásica/prevenção & controle , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Fatores de Crescimento/antagonistas & inibidores , Transplante Heterólogo , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
FCE 26644, or 7,7'-(carbonyl-bis[imino-N-methyl-4, 2 pyrrole carbonyl-imino(N-methyl-4,2-pyrrole)carbonyl-imino])-bis-(1,3- naphthalene)disulfonic acid, belongs to the newly synthesized class of sulfonated derivatives of distamycin A. FCE 26644 is a noncytotoxic molecule capable of inhibiting the binding of basic fibreblast growth factor (bFGF), platelet-derived growth factor (PDGF beta) and interleukin 1 (IL-7) to their receptors and to block bFGF-induced vascularization in vivo as well as neovascularization in the chorioallantoic membrane. FCE 26644 and suramin, a compound possessing the same terminal half-life (t1/2) in mice and, presumably, the same mode of action, inhibit the growth of solid murine tumors, M5076 reticulosarcoma, and MXT and S180 fibrosarcoma and are inactive against B16F10 melanoma. The activity of FCE 26644 was constantly observed at nontoxic doses, at variance with suramin. FCE 26644 was also found to maintain activity against M5076 resistant to cyclophosphamide and to be equally active against UV 2237 and UV 2237/ADR fibrosarcoma.
Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Distamicinas/farmacocinética , Distamicinas/uso terapêutico , Fibrossarcoma/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Animais , Ciclofosfamida/uso terapêutico , Esquema de Medicação , Resistência a Medicamentos , Feminino , Fator 2 de Crescimento de Fibroblastos/antagonistas & inibidores , Meia-Vida , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Suramina/farmacocinética , Suramina/uso terapêuticoRESUMO
BACKGROUND: Tallimustine, a benzoyl nitrogen mustard derivative of the antiviral agent distamycin A, is a new alkylating agent which binds to A-T rich regions of DNA in the minor groove producing highly sequence-specific alkylations. Its main preclinical features are a significant antitumor activity in animal models and a lack of cross-resistance in vitro and in vivo with L-PAM. Myelotoxicity was dose-limiting in animals, with a more than 100-fold difference in bone marrow sensitivity between mice and dogs. PATIENTS AND METHODS: Forty adult patients (pts) with solid malignancies were entered in the study. The drug was administered as an IV bolus every 4 weeks. CBC was repeated twice a week and serial assessments of renal function were performed in the week following the first cycle. From the starting dose of 50 micrograms/m2, corresponding to 1/3 of the highest non-toxic dose (HNTD) in dogs, there were increases through 10 dose levels, with reliance only on the features of the myelotoxicity observed. RESULTS: The main toxic effect was neutropenia which was dose-limiting, selective and short-lasting. Only previously-untreated pts received doses of 750 micrograms/m2 or more, with grade 4 neutropenia occurring in > or = 75% of the cycles. The maximally tolerable dose (MTD) was defined as 1250 micrograms/m2, with 3 of 3 pts developing febrile neutropenia requiring IV antibiotics. A platelet count of < 100 x 10(3)/microliters was observed in only one pt. Bone marrow aspiration performed in selected pts on days 8 and 15 confirmed a highly selective impairment by tallimustine of the myeloid lineage, with rapid recovery of the proliferative compartment. Pharmacokinetic studies performed at 1000 micrograms/m2 and 1250 micrograms/m2 showed a rapid fall of the plasma levels within the first 2 hours with drug concentrations between 100 ng/ml and 400 ng/ml within the first hour. A partial response of 4 months' duration was reported in one previously-untreated pt with cutaneous recurrences of malignant mesothelioma. CONCLUSIONS: The report of some antitumour efficacy, the high selectivity of neutropenia, the lack of significant non-hematological toxic effects and the occurrence of detectable but still low plasma drug concentrations suggest that further clinical evaluation of higher doses of tallimustine in combination with colony-stimulating factors would be justified.
Assuntos
Antineoplásicos/uso terapêutico , Distamicinas/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos de Mostarda Nitrogenada/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Distamicinas/efeitos adversos , Distamicinas/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neutropenia/induzido quimicamente , Compostos de Mostarda Nitrogenada/efeitos adversos , Compostos de Mostarda Nitrogenada/farmacocinética , Indução de RemissãoRESUMO
Solid tumor growth can be modulated through inhibition of vascularization elicited by angiogenic factors. With the objective to complex these factors, new derivatives of distamycin A were synthesized and evaluated in vitro [1] and in vivo for their ability, after i.v. administration, to inhibit bFGF-induced vascularization and the growth of M5076 murine reticulosarcoma implanted i.m. The tested compounds were able to block angiogenesis with inhibition values ranging between 70-100%. Moreover, they were found to be capable of inducing tumor inhibition with values ranging between 40% and 95% at non-toxic doses.
Assuntos
Antineoplásicos/uso terapêutico , Distamicinas/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Animais , Colágeno , Feminino , Fator 2 de Crescimento de Fibroblastos/farmacologia , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Neovascularização Patológica/patologia , Próteses e Implantes , Relação Estrutura-Atividade , Ácidos Sulfônicos/uso terapêuticoRESUMO
FCE 24157 (chemically (beta-[1-methyl-4-(1-methyl-4--[1-methyl-4-(4-N,N- bis(2-chloroethyl) amino-benzene-1-carboxy-amido) pyrrole-2-carboxiamido]pyrrole-2-carboxyamido)pyrrole-2-c arboxyamido]) propionamidine, hydrochloride) is a distamycin A (Dista A) derivative bearing a benzoyl mustard moiety instead of the formyl group at the N-terminal. Contrary to Dista A, FCE 24517 has been found to display potent cytotoxic activity on human and murine tumour cell lines. The compound maintains activity on melphalan (L-PAM)-resistant cells, whereas cross-resistance is observed on doxorubicin-(DX)-resistant cells. In vivo, FCE 24517 was found to possess evident antineoplastic activity on a series of murine transplanted solid tumours and human tumour xenografts. The following neoplasms were in fact found to be sensitive to FCE 24517 treatment: M14 human melanoma xenograft, N592 human small cell lung carcinoma, MTV murine mammary carcinoma, Colon 38 murine carcinoma, PO2 murine pancreatic carcinoma and M5076 murine reticulosarcoma. Lower effectiveness was observed against the murine P388 and Gross leukaemia, Lewis lung murine carcinoma, LoVo human colon carcinoma xenografts and A459 human lung adenocarcinoma. Against the murine L1210 leukaemia, FCE 24517 displayed a clear activity only when the tumour was transplanted i.p. and treatment was given i.p., whereas only marginal activity was seen against this leukaemia if transplanted i.v. and the drug was given i.v. As true also in vitro, FCE 24517 was effective against i.p. implanted L1210 leukaemia resistant to L-PAM. The mode(s) of action of this new compound is under active investigation.