RESUMO
Adeno-associated satellite virus type 4 interferes with the replication of its helper adenovirus. No interferon-like soluble substance could be detected in satellite-infected cultures and other DNA- and RNA-containing viruses were not inhibited by coinfection with satellite virus under conditions which reduced adenovirus yields by more than 90% in monkey cells. Altering the concentration of adenovirus in the presence of constant amounts of satellite resulted in a constant degree of interference over a wide range of adenovirus inocula and suggested that adenovirus concentration was not a significant factor in the observed interference. The interference with adenovirus replication was abolished by pretreating satellite preparations with specific antiserum, ultraviolet light or heating at 80 degrees C for 30 min. This suggested that infectious satellite virus mediated the interference. Satellite virus concentration was found to be a determinant of interference and studies indicated that the amount of interference with adenovirus was directly proportional to the concentration of satellite virus. 8 hr after adenovirus infection, the replication of adenovirus was no longer sensitive to satellite interference. This was true even though the satellite virus was enhanced as effectively as if the cells were infected simultaneously with both viruses. Interference with adenovirus infectivity was accompanied by reduced yields of complement-fixing antigen and of virus particles which suggested that satellite virus interfered with the formation and not the function of adenovirus products. When cells were infected either with adenovirus alone or with adenovirus plus satellite, the same proportion of cells plated as adenovirus infectious centers. However, the number of plaque-forming units of adenovirus formed per cell in the satellite-infected cultures was reduced by approximately 90%, the same magnitude of reduction noted in whole cultures coinfected with satellite and adenovirus. This suggested that all cells infected with the two viruses were producing a reduced quantity of adenovirus.
Assuntos
Adenoviridae/imunologia , Adenoviridae/efeitos da radiação , Animais , Centrifugação com Gradiente de Concentração , Efeito Citopatogênico Viral , Haplorrinos , Temperatura Alta , Humanos , Rim/imunologia , Poliovirus/imunologia , Efeitos da Radiação , Simplexvirus/imunologia , Raios Ultravioleta , Vírus da Estomatite Vesicular Indiana/imunologiaRESUMO
Immunoconjugates (BR96-DOX) were prepared between chimeric monoclonal antibody BR96 and the anticancer drug doxorubicin. The monoclonal antibody binds an antigen related to Lewis Y that is abundantly expressed at the surface of cells from many human carcinomas; it has a high degree of tumor selectivity and is internalized after binding. BR96-DOX induced complete regressions and cures of xenografted human lung, breast, and colon carcinomas growing subcutaneously in athymic mice and cured 70 percent of mice bearing extensive metastases of a human lung carcinoma. Also, BR96-DOX cured 94 percent of athymic rats with subcutaneous human lung carcinoma, even though the rats, like humans and in contrast to mice, expressed the BR96 target antigen in normal tissues.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Doxorrubicina/uso terapêutico , Imunotoxinas/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Antígenos de Neoplasias/imunologia , Antígenos de Superfície/imunologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Doxorrubicina/administração & dosagem , Humanos , Imunotoxinas/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Nus , Transplante de Neoplasias , Ratos , Ratos NusRESUMO
BACKGROUND: Although doxorubicin remains one of the most effective agents for the treatment of solid tumors, there is an intensive effort to synthesize doxorubicin analogues (compounds with similar chemical structures) that may have improved antitumor properties. We have synthesized a novel doxorubicin disaccharide analogue (MEN 10755) and have characterized some of its relevant biochemical, biologic, and pharmacologic properties. METHODS: The antitumor activity of this compound (MEN 10755) was studied in a panel of human tumor xenografts, including xenografts of A2780 ovarian tumor cells, MX-1 breast carcinoma cells, and POVD small-cell lung cancer cells. MEN 10755 was compared with doxorubicin according to the optimal dose and schedule for each drug. The drug's cytotoxic effects, induction of DNA damage, and intracellular accumulation were studied in A2780 cells. DNA cleavage mediated by the enzyme topoisomerase II was investigated in vitro by incubating fragments of simian virus 40 DNA with the purified enzyme at various drug concentrations and analyzing the DNA cleavage-intensity patterns. Drug-induced apoptosis (programmed cell death) in tumors was determined with the use of MX-1 and POVD tumor-bearing athymic Swiss nude mice. RESULTS: MEN 10755 was more effective than doxorubicin as a topoisomerase II poison and stimulated DNA fragmentation at lower intracellular concentrations. In addition, MEN 10755 exhibited striking antitumor activity in the treatment of human tumor xenografts, including those of the doxorubicin-resistant breast carcinoma cell line MX-1. CONCLUSIONS: The high antitumor activity of MEN 10755 in human tumor xenografts, including doxorubicin-resistant xenografts, and its unique pharmacologic and biologic properties make this disaccharide analogue a promising candidate for clinical evaluation.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , DNA Topoisomerases Tipo II/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Doxorrubicina/análogos & derivados , Neoplasias Experimentais/tratamento farmacológico , Animais , Neoplasias da Mama/tratamento farmacológico , Carcinoma de Células Pequenas/tratamento farmacológico , Dano ao DNA , Dissacarídeos/síntese química , Doxorrubicina/síntese química , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Nus , Neoplasias Experimentais/genética , Neoplasias Ovarianas/tratamento farmacológico , Fatores de Tempo , Transplante HeterólogoRESUMO
The effects of 4'-epi-daunorubicin, 4'-epi-adriamycin, and the corresponding beta anomers on the in vitro activity of Escherichia coli DNA polymerase I and RNA polymerase were determined and compared with the effects of the parent compounds. The observed effects parallel the cytotoxic activities, assayed by inhibition of mouse embryo fibroblast proliferation, and the inhibitory activities on DNA synthesis in cultured cells. The data indicate that the inverted configuration at position 1 of the amino sugar results in a markedly reduced biological activity. This conclusion is also substantiated by the data obtained with the beta anomer of adriamycin. A preliminary investigation on the binding properties of these derivatives suggests that the inverted configuration at C-1' produces a significant decrease in the binding to DNA. In contrast, epimerization at position 4' did not produce any significant change in activity. The relationship between biological and biochemical activity and DNA binding properties of the tested compounds are discussed with particularly reference to antitumor activity.
Assuntos
Daunorrubicina/análogos & derivados , Doxorrubicina/análogos & derivados , Divisão Celular/efeitos dos fármacos , Células Cultivadas , DNA/metabolismo , DNA Nucleotidiltransferases/metabolismo , RNA Polimerases Dirigidas por DNA/metabolismo , Daunorrubicina/farmacologia , Doxorrubicina/farmacologia , Escherichia coli/enzimologia , Fibroblastos/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Four new derivatives of daunorubicin and two new derivatives of Adriamycin characterized by the absence of the methoxyl groups at the C-4 position have been studied in cell cultures in vitro to establish structure-activity relationships. 4-Demethoxydaunorubicin was 27 to 100 times more active than was daunorubicin when inhibiting the cloning efficiency of exponential-phase HeLa cells and, like daunorubicin, was slightly active on early plateau-phase cells. DNA synthesis in mouse embryo fibroblasts stimulated by fetal calf serum was inhibited equally by the two compounds, although 4-Demethoxydaunorubicin was slightly more active than was daunorubicin when inhibiting RNA synthesis. The beta anomer of 4-demethoxydaunorubicin showed a reduced activity on HeLa cells compared to its alpha anomer, but it was equally active on DNA synthesis. The stereoisomers of 4-demethoxydaunorubicin bearing the inverted configuration in positions 7 and 9 were devoid of significant cytotoxic activity and were only slightly active on DNA synthesis at the doses tested. 4-demethoxyadriamycin and 4-demethoxy-4'-epi-adriamycin were 65 to 500 times more active than was Adriamycin on HeLa cell cloning efficiency and about 10 times more active on DNA synthesis in mouse embryo fibroblasts. Cell uptake in mouse embryo fibroblasts was also investigated for all the new derivatives tested.
Assuntos
DNA/biossíntese , Daunorrubicina/análogos & derivados , Doxorrubicina/análogos & derivados , RNA/biossíntese , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Daunorrubicina/metabolismo , Daunorrubicina/farmacologia , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Relação Estrutura-Atividade , Timidina/metabolismo , Uridina/metabolismoRESUMO
Stable acquired resistance to etoposide (VP-16) or teniposide (VM-26) in HCT116 human colon carcinoma cells and A549 human lung adenocarcinoma cells, was previously obtained by weekly 1-h exposures to either drug (B. H. Long, Natl. Cancer Inst. Monogr., 4: 123-127, 1987). The purpose of this study was to identify possible mechanisms of resistance present in these cells by using human mdr1 and topoisomerase II DNA probes, antibodies to these gene products, and P4 phage unknotting assay for topoisomerase II activities. HCT116(VP)35 cells were 9-, 7-, and 6-fold resistant to VP-16, VM-26, and Adriamycin, respectively, and showed no cross-resistance to colchicine and actinomycin D. These cells had no differences in mdr1 gene, mdr1 mRNA, or P-glycoprotein levels but displayed decreased levels of topoisomerase II mRNA and enzyme activity without any alteration of drug sensitivity displayed by the enzyme. HCT116(VM)34 cells were 5-, 7-, and 21-fold resistant to VP-16, VM-26, and Adriamycin; were cross-resistant to colchicine (7-fold) and actinomycin D (18-fold); and possessed a 9-fold increase in mdr1 mRNA and increased P-glycoprotein without evidence of mdr1 gene amplification. No alterations in topoisomerase II gene or mRNA levels, enzyme activity, or drug sensitivity were observed. A549(VP)28 and A549(VM)28 cells were 8-fold resistant to VP-16 and VM-26 and 3-fold resistant to Adriamycin. Both lines were not cross-resistant to colchicine or actinomycin D but were hypersensitive to cis-platinum. No alterations in mdr1 gene, mdr1 mRNA, or P-glycoprotein levels, but lower topoisomerase II mRNA levels and decreased enzyme activities, were observed. Of the four acquired resistant cell lines, resistance is likely related to elevated mdr1 expression in one line and to decreased topoisomerase II expression in the other three lines.
Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Etoposídeo/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Teniposídeo/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Sequência de Bases , Linhagem Celular , DNA/análise , DNA/efeitos dos fármacos , Dano ao DNA , Sondas de DNA , DNA Topoisomerases Tipo II/biossíntese , DNA Topoisomerases Tipo II/genética , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Resistência a Medicamentos/genética , Etoposídeo/farmacocinética , Humanos , Immunoblotting , Glicoproteínas de Membrana/biossíntese , Dados de Sequência Molecular , Proteínas de Neoplasias/biossíntese , Porfiromicina/farmacocinética , Porfiromicina/farmacologia , RNA/análiseRESUMO
4'-Iodo-4'-deoxydoxorubicin is a doxorubicin (DXR) analogue with greater lipophilicity and reduced basicity of the amino group. In vitro 4'-iodo-4'-deoxydoxorubicin is more cytotoxic than DXR against a panel of human and murine cell lines and is characterized by a higher and faster uptake. In vivo, the spectrum of activity of 4'-iodo-4'-deoxydoxorubicin is comparable to that of DXR, but the new compound has higher activity against murine P388 leukemia resistant to DXR and against pulmonary metastases from Lewis lung carcinoma. Moreover, the new analogue exhibits antitumor activity also after p.o. administration and shows no cardiotoxicity in experimental systems.
Assuntos
Doxorrubicina/análogos & derivados , Neoplasias Experimentais/tratamento farmacológico , Administração Oral , Animais , Cardiomiopatias/induzido quimicamente , Doxorrubicina/síntese química , Doxorrubicina/uso terapêutico , Doxorrubicina/toxicidade , Avaliação Pré-Clínica de Medicamentos , Feminino , Leucemia Experimental/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos , Camundongos Endogâmicos , Relação Estrutura-Atividade , Ensaio Tumoral de Célula-TroncoRESUMO
Eleutherobin is a novel natural product isolated from a marine soft coral that is extremely potent for inducing tubulin polymerization in vitro and is cytotoxic for cancer cells with an IC50 similar to that of paclitaxel. This compound is cross-resistant along with other multidrug-resistant agents against P-glycoprotein-expressing cells and is cross-resistant with paclitaxel against a cell line that has altered tubulin. In mechanistic studies, eleutherobin shares with paclitaxel the ability to induce tubulin polymerization in vitro and is most likely cytotoxic by virtue of this mechanism. Human colon carcinoma cells exposed to eleutherobin contain multiple micronuclei and microtubule bundles, and they arrest in mitosis, depending on concentration, cell line, and length of exposure. These morphological abnormalities appearing in cultured cells are indistinguishable from those induced by paclitaxel. Electron microscopy reveals that eleutherobin induces homogeneous populations of long, rigid microtubules similar to those formed by paclitaxel. Thus, eleutherobin is a new chemotype with a mechanism of action similar to that of paclitaxel and, as such, has promising potential as a new anticancer agent.
Assuntos
Alcaloides/farmacologia , Diterpenos , Microtúbulos/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Sítios de Ligação , Ligação Competitiva , Bovinos , Neoplasias do Colo/patologia , Feminino , Inibidores do Crescimento/farmacologia , Humanos , Neoplasias Ovarianas/patologia , Paclitaxel/farmacologia , Polímeros , Tubulina (Proteína)/metabolismo , Células Tumorais CultivadasRESUMO
The internalizing anti-Le(y) monoclonal antibody (MAb) BR64 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to the DOX and either a disulfide or thioether bond to the MAb. The resulting disulfide (BR64-SS-DOX) and thioether (BR64-S-DOX) conjugates were evaluated for stability, potency, and antigen-specific activity in both in vitro and in vivo model systems. The BR64-SS-DOX conjugates demonstrated antigen-specific activity both in vitro and when evaluated against antigen-expressing, DOX-sensitive human carcinoma xenografts. However, the stability and potency of disulfide conjugates were poor, and in vivo activity superior to unconjugated DOX was seen only at doses approaching the maximum tolerated dose. Furthermore, BR64-SS-DOX conjugates were not active against antigen-expressing, DOX-insensitive colon tumor xenografts. In contrast, the BR64-S-DOX conjugates demonstrated good stability both in vitro and in vivo. The increased stability of the BR64-S-DOX conjugates resulted in the delivery of more biologically active DOX to tumors with a concomitant increase in potency and efficacy over that which could be achieved with either unconjugated DOX or BR64-SS-DOX conjugates. Delivery of DOX by BR64-SS-DOX conjugates resulted in complete regressions and cures of both DOX-sensitive lung xenografts and DOX-intensitive colon tumor xenografts. These results demonstrate the importance of linker stability when delivering drugs such as DOX to carcinomas via internalizing antibodies and are likely to have direct relevance to the clinical utility of MAb-directed delivery.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Anticorpos Monoclonais/farmacologia , Antígenos de Neoplasias/imunologia , Doxorrubicina/farmacologia , Imunoconjugados/farmacologia , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacocinética , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Doxorrubicina/química , Doxorrubicina/farmacocinética , Ensaios de Seleção de Medicamentos Antitumorais , Epitopos/imunologia , Feminino , Humanos , Imunoconjugados/química , Imunoconjugados/farmacocinética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
The effect of paclitaxel on the adhesive and motility properties of human ovarian carcinoma cell lines was investigated. Paclitaxel significantly inhibited the motility of OVCAR 5, SK-OV-3, and HOC-1OTC ovarian carcinoma cell lines (IC50 = 2.1 x 10(-8), 2 x 10(-9), and 1.9 x 10(-8) m, respectively) but did not affect the adhesion of these cells to the subendothelial matrix. The association between inhibition of motility and cytotoxic activity was investigated using an A2780 subclone (1A9) and three paclitaxel-resistant variants (designated 1A9/PTX22, 1A9/PTX10, and 1A9/PTX18). Although paclitaxel did not significantly affect the adhesion to subendothelial matrix of the sublines, it completely inhibited their migration. Inhibition of migration was similar in 1A9 cells and the resistant sublines, with an IC50 of 1 x 10(-8) for 1A9 cells and 5.4 x 10(-9), 1.1 x 10(-8), and 5.2 x 10(-9) m for 1A9/PTX22, 1A9/PTX10, and 1A9/PTX18, respectively. Paclitaxel inhibited motility induced by soluble attractant (chemotaxis) and immobilized attractant (haptotaxis). Inhibition of cell motility occurred in the absence of an antiproliferative effect, because higher concentrations of paclitaxel were required to inhibit tumor cell proliferation (IC50 = 1.9 x 10(-7) and 4.6 x 10(-6), 1 x 10(-5), and 3.1 x 10(-6) m for 1A9 and 1A9/PTX22, 1A9/PTX10, and 1A9/PTX18, respectively). These data show that paclitaxel is a potent inhibitor of ovarian carcinoma cell motility and that this activity is independent of its cytotoxic activity.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Movimento Celular/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/farmacologia , Adesão Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Neoplasias Ovarianas/patologia , Células Tumorais CultivadasRESUMO
Matrix metalloproteinases (MMPs) have been implicated in tumor cell invasion, metastasis, and angiogenesis. BAY 12-9566, a novel, non-peptidic biphenyl MMP inhibitor, has shown preclinical activity on a broad range of tumor models and is currently in clinical development. The purpose of this study was to investigate the antiangiogenic activity of BAY 12-9566. In vitro, BAY 12-9566 prevented matrix invasion by endothelial cells in a concentration-dependent manner (IC50 = 8.4x10(-7) M), without affecting cell proliferation. In vivo, oral daily administration of BAY 12-9566 (50-200 mg/kg) inhibited angiogenesis induced by basic fibroblast growth factor in the Matrigel plug assay, reducing the hemoglobin content of the pellets. Histological analysis showed a reduction in the amount of functional vessels within the Matrigel. We conclude that the MMP inhibitor BAY 12-9566 inhibits angiogenesis, a property that further supports its clinical development as an antimetastatic agent.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Endotélio Vascular/fisiologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Inibidores de Metaloproteinases de Matriz , Neovascularização Patológica/prevenção & controle , Neovascularização Fisiológica/efeitos dos fármacos , Compostos Orgânicos , Animais , Compostos de Bifenilo , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Colágeno , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Humanos , Laminina , Camundongos , Camundongos Endogâmicos C57BL , Fenilbutiratos , Proteoglicanas , Veias UmbilicaisRESUMO
The known 2-aminoimidazole alkaloid naamidine A (1) was isolated from a Fijian Leucetta sp. sponge as an inhibitor of the epidermal growth factor (EGF) receptor. The compound exhibited potent ability to inhibit the EGF signaling pathway and is more specific for the EGF-mediated mitogenic response than for the insulin-mediated mitogenic response. Evaluation in an A431 xenograft tumor model in athymic mice indicated that naamidine A exhibited at least 85% growth inhibition at the maximal tolerated dose of 25 mg/kg. Preliminary mechanism of action studies indicate that the alkaloid fails to inhibit the binding of EGF to the receptor and has no effect on the catalytic activity of purified c-src tyrosine kinase.
Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Imidazóis/farmacologia , Células 3T3 , Alcaloides/isolamento & purificação , Animais , Antineoplásicos/isolamento & purificação , Proteína Tirosina Quinase CSK , Carcinoma de Células Escamosas/patologia , Divisão Celular/efeitos dos fármacos , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Imidazóis/isolamento & purificação , Camundongos , Camundongos Nus , Transplante de Neoplasias , Poríferos/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Transplante Heterólogo , Quinases da Família srcRESUMO
The synthesis of 4'-epi-daunorubicin and of 4'-epi-adriamycin was performed by condensation of 2,3,6-trideoxy-3-trifluoroacetamido-4-O-trifluoroacetyl-alpha-L-arabino-hexopyranosyl chloride with daunomycinone or the protected adriamycinone derivative 17, respectively. Both the alpha and beta anomers were obtained and characterized. All new compounds are biologically active in cultured cells and the alpha anomers display noticeable activity in experimental tumors in mice. Interestingly, 4'-epi-adriamycin (4) appears nontoxic to cultured heart cells up to a concentration of 5 mug/ml.
Assuntos
Aminoglicosídeos/síntese química , Antineoplásicos/síntese química , Daunorrubicina/análogos & derivados , Doxorrubicina/análogos & derivados , Aminoglicosídeos/farmacologia , Aminoglicosídeos/uso terapêutico , Animais , Antineoplásicos/farmacologia , Células Cultivadas , Daunorrubicina/síntese química , Daunorrubicina/uso terapêutico , Doxorrubicina/síntese química , Doxorrubicina/uso terapêutico , Células HeLa/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Leucemia Experimental/tratamento farmacológico , Camundongos , Vírus da Leucemia Murina de Moloney/efeitos dos fármacos , Sarcoma 180/tratamento farmacológico , Vírus do Sarcoma Murino/efeitos dos fármacos , EstereoisomerismoRESUMO
A total of 27 selected analogues of VP-16 and VM-26 were compared with VP-16 and VM-26 for their relative abilities to stabilize the enzyme-substrate intermediate normally formed between eukaryote topoisomerase II and DNA. This activity was compared with cytotoxicity results obtained using the human colon HCT116 cell line and antitumor results obtained after intraperitoneal injection of mice with murine leukemia P388. The most potent analogues were those containing OH groups (demethyl) in either the 3' and 4' or the 3', 4', and 5' positions, the latter being twice as potent as VP-16. VM-26 was only 40% more potent than VP-16 in this assay. It was generally found that the 4'-esters had little activity in vitro, yet were cytotoxic and had antitumor activities. All other analogues with little in vitro activity were not very cytotoxic and had little if any antitumor activity. A very good correlation exists between stabilization of topoisomerase II-DNA intermediates, cytotoxicity, and antitumor activity.
Assuntos
Etoposídeo/análogos & derivados , Etoposídeo/toxicidade , Inibidores da Topoisomerase II , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo , DNA Topoisomerases Tipo II/isolamento & purificação , DNA Viral/isolamento & purificação , DNA Viral/metabolismo , Etoposídeo/química , Humanos , Cinética , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Ten anthracyclines, including doxorubicin (DX) and daunorubicin (DNR), and eight analogs with modifications in structure or stereochemistry of the aglycone and/or the aminosugar moiety were simultaneously tested in serial vitro titration studies against human adenocarcinomas in the human tumor stem cell assay. More than a two-log range in cytotoxicity of the various anthracyclines was observed with the tumors tested. Marked individual differences in sensitivity of specific tumors (breast, lung, peritoneal) were observed for the various analogs. By assessing average effects on survival of tumor colony-forming units (TCFU) in the tumors tested, the three compounds lacking the methoxyl group in position 4 of the aglycone (4-demethoxyDX, 4-demethoxy-4'-epiDX, 4-demethoxyDNR) all proved to be more cytotoxic than their parent compounds. Compounds modified in position 4' of the aminosugar were on average either as toxic (4' epiDX) or more toxic (4'-deoxyDX and 4'-0-methylDX) to TCFU than the parent compound DX. On average, 11-deoxyDX was less toxic than DX or the other eight anthracyclines tested. The results obtained are also in good general agreement with those previously reported for anthracyclines with human tumors in xenografts or cancer patients. These antitumor results viewed in concert with toxicology studies in normal mice (including evidence of a lack of cardiac toxicity) suggest that 4'deoxyDX may prove to be a clinically useful anthracycline analog. We also conclude that use of this clinically predictive in vitro soft agar assay provides a rapid and relatively inexpensive means of simultaneously testing a large number of analogs of a parent compound against a spectrum of human tumors.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Ensaio de Unidades Formadoras de Colônias , Neoplasias Experimentais/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Células Cultivadas , Células HeLa , Humanos , Naftacenos/farmacologiaRESUMO
Previous studies on structure-activity relationships of anthracycline antitumor antibiotics have shown that removal of the methoxyl group at position 4 of the aglycone causes a marked increase in the potency of the compounds: 4-demethoxydaunorubicin and 4-demethoxyadriamycin had an antitumor effect similar to that of the parent compound at doses five to eight times lower, and they were active even when administered orally. This paper reports the effects of further substitutions at positions 1, 2, 3, and 4 of 4-demethoxy aglycone. The introduction of methyl groups at positions 2 and 3, or 1 and 4 resulted in decreased cytotoxicity and biological activity. The addition of a benzoyl ring at positions 2 and 3 decreased the activity further. 1,4-Dichloro-4-demethoxydaunorubicin and 2,3-dichloro-4-demethoxydaunorubicin were respectively as active and 2.5 times less active than was daunorubicin against HeLa cells in vitro while they were inactive against P388 and L1210 leukemias in vivo. 2,3-Dimethyl-4-demethoxyadriamycin showed an antitumor activity against mouse leukemias that was slightly higher than was that of adriamycin.
Assuntos
Antineoplásicos , Daunorrubicina/análogos & derivados , Doxorrubicina/análogos & derivados , Animais , Daunorrubicina/farmacologia , Doxorrubicina/farmacologia , Células HeLa , Humanos , Leucemia L1210/tratamento farmacológico , Leucemia Experimental/tratamento farmacológico , Camundongos , Relação Estrutura-AtividadeRESUMO
Several novel platinum (IV) mixed ammine/amine dicarboxylate dichlorides of general structure [Pt(IV)Cl2(OCOY)2NH3(XNH2)], where Y is aliphatic or aromatic and X is alicyclic or aliphatic, known to be particularly well absorbed following oral administration, were evaluated by that route for their antitumor activity. Testing of the Pt(IV) derivatives took place concomitantly with i.v. administered cisplatin and carboplatin in two s.c. staged tumor models, the murine M5076 sarcoma and human A2780 ovarian carcinoma. Based upon repetitive experiments which included an evaluation of different vehicles and treatment schedules, each of the orally administered Pt(IV) dicarboxylates was reproducibly active in the M5076 tumor, producing mean maximum gross log cell kill (LCK) values of between 1.5 and 2.0, and lifespan increases, reflected by mean maximum treated/control median survival (T/C) values, of 139-151%. Cisplatin and carboplatin given i.v. yielded mean maximum LCK of 3.5 and 2.5, respectively, as well as mean maximum T/C values of 166% and 164%, respectively, in the same tumor model. The best of the derivatives in the M5076 experiments, JM-216 [ammine/cyclohexylamine diacetato dichloride Pt(IV)], produced LCK values that averaged only 0.5 lower than that of carboplatin, and increases in lifespan not significantly different than that of carboplatin. Against the A2780 tumor, the Pt(IV) dicarboxylates produced individual best effects of between 0.8-1.1 LCK, based on data from two or three experiments. The mean maximum LCK values for cisplatin and carboplatin were 1.8 and 2.2 LCK, respectively. JM-225, ammine/cyclopentylamine diacetato dichloride Pt(IV), was active in two of three experiments, including one result comparable to that of carboplatin. The Pt(IV) mixed ammine/amine dicarboxylate dichlorides represent a novel class of Pt derivative capable of expressing oral antitumor activity in both murine and human tumor models.
Assuntos
Antineoplásicos/farmacologia , Compostos Organoplatínicos/farmacologia , Administração Oral , Animais , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Carboplatina/farmacologia , Cisplatino/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Nus , Transplante de Neoplasias , Compostos Organoplatínicos/farmacocinética , Sarcoma Experimental/tratamento farmacológicoRESUMO
The antitumor activity of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes was evaluated in P388 ascitic leukemia, disseminated Gross leukemia, and advanced mammary carcinoma. In P388 leukemia, free drug and drug entrapped in liposomes demonstrated equivalent antitumor activity at doses of 2.2 and 4.4 mg/kg, demonstrating 52% and 69% ILS (increase in life-span), respectively. Free doxorubicin at a dose of 10 mg/kg was superior, producing a 185% ILS against 82% with liposomal doxorubicin. With an increase in administered dose the antitumor response with liposomal doxorubicin was much more pronounced; at doses of 20 and 25 mg/kg the ILS was in excess of 376%, with five of ten mice surviving tumor-free. In Gross leukemia, the optimum dose of free doxorubicin, 10 mg/kg, brought about 186% T/C (median survival in treated mice over that in controls, X 100), whereas with liposomal doxorubicin the optimum dose was 16.9 mg/kg, which yielded 214% T/C. In advanced mammary carcinoma, the maximum tumor regression with free doxorubicin was at a dose of 7.5 mg/kg, with two of six mice dying of toxicity. Liposomal doxorubicin caused maximum tumor regression at 10.8 mg/kg dose with no toxic deaths. Doxorubicin entrapped in cardiolipin liposomes was much less toxic than free drug at high doses in normal mice.
Assuntos
Doxorrubicina/administração & dosagem , Leucemia Experimental/tratamento farmacológico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Vírus AKR da Leucemia Murina , Animais , Cardiolipinas , Doxorrubicina/toxicidade , Leucemia P388/tratamento farmacológico , Lipossomos , Camundongos , Camundongos EndogâmicosRESUMO
PURPOSE: Five water-soluble paclitaxel derivatives were extensively evaluated for their antitumor activities relative to the parent drug. METHODS: Both subcutaneous (s.c.) murine (M109 lung) and human (A2780 ovarian, L2987 lung) tumor models were used for this purpose. RESULTS: Consecutive daily intravenous (i.v.) paclitaxel therapy of mice bearing s.c. M109, beginning on day 4 or 5 posttumor implant and continuing for 5 days, resulted in a range of maximum gross log cell kill (LCK) values (reflective of delays in tumor growth) and maximum relative median survival time (% T/C) values (reflective of increases in lifespan) of 1.0-2.1 and 132-162% (and one outlying result of 235%), respectively. Against the same tumor model, using the same treatment schedule, each of the water-soluble derivatives was active, with maximum LCK of 1.3-2.5 and T/C of 124-254%. These LCK and %T/C values were always within 0.5 LCK and 15%, respectively, of the concomitantly obtained maximum effects of paclitaxel. When tested in several experiments against staged (50-100 mg) s.c. A2780 tumors, using various i.v. treatment schedules, the water-soluble derivatives achieved a maximum LCK of 1.4-3.8. Evaluated in parallel, paclitaxel achieved a maximum LCK of 2.1-4.5 following every other day x 5 i.v. therapy. When paclitaxel was assayed in several experiments using the staged (50-100 mg) s.c. L2987 tumor model, maximum LCK of 0.9->4.1 were produced following every other day x 5 i.v. therapy. Concomitant testing of the water-soluble derivatives, using the same i.v. treatment schedule, resulted in maximum LCK of 0.2->4.1. In each of the tumor models used, the consistently active, and usually the most active, water-soluble derivative was BMS-185660. The levels of activity observed were comparable (within 1 LCK) to those achieved concomitantly using paclitaxel, and its potency was only slightly inferior to the parent drug. CONCLUSIONS: Based on the evaluations performed in three distal site tumor models, we conclude that BMS-185660 is a water-soluble paclitaxel derivative with preclinical antitumor activity comparable to that of the parent drug.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Paclitaxel/farmacologia , Taxoides , Animais , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Paclitaxel/análogos & derivados , Células Tumorais CultivadasRESUMO
MA is an orally active PG derivative with an excellent safety profile that is used primarily for the treatment of carcinomas of the breast and endometrium. We investigated the potential application of MA as an MDR-reversal agent using cell culture and human tumor xenograft models. The reversing activity of MA in vitro was compared with that of PG and VER in two human MDR cell lines, the colon carcinoma HCT-116/VM46 and the breast carcinoma MCF-7/ADR, and in a murine cell line, J774.2. At concentrations as low as 3 microM, MA was capable of partially restoring sensitivity to Act D in the HCT-116/VM46 cells and sensitivity to DOX in the MCF-7/ADR cells. Although less effective than VER, MA was about 2.5 times more potent than PG in reversing MDR at equimolar concentrations. Increased accumulation of DOX in drug-resistant cells that were treated simultaneously with MA was observed by flow cytometry. In vivo, using established human colon and breast carcinoma xenografts implanted s.c. in athymic mice, the combined therapy with MA and DOX resulted in enhanced antitumor activity relative to that of DOX alone in the MDR sublines. These results suggest that MA may be a promising clinical MDR-reversing agent.