RESUMO
BACKGROUND: Treatment options for sarcoma are limited. Histone deacetylase inhibitors increase the efficacy of topoisomerase II inhibitors by promoting access to chromatin and by down-regulating DNA repair. Thus, combined panobinostat and epirubicin therapy was evaluated to treat refractory sarcoma. PATIENTS AND METHODS: Patients with advanced solid tumors were enrolled in a 3 + 3 dose-escalation phase I trial of panobinostat given on days 1, 3, and 5 followed by 75 mg/m(2) of epirubicin on day 5 in 21-day cycles, with a dose expansion at maximum tolerated dose (MTD) in 20 sarcoma patients. Peripheral blood mononucleocyte histone acetylation was also evaluated. RESULTS: Forty patients received 20-60 mg panobinostat. Dose-limiting toxicities included thrombocytopenia, febrile neutropenia, and fatigue at 60 mg, defining a panobinostat MTD at 50 mg. Four responses were seen in 37 assessable patients, all after progression on prior topoisomerase II inhibitors. For those with sarcoma, 12 of 20 derived clinical benefit (1 partial response and 11 stable disease, median overall survival 8.3 months), including 8 of 14 previously progressed on topoisomerase II therapy. Treatment benefits correlated with increased histone acetylation and decreased neutrophil count on day 5. CONCLUSIONS: Panobinostat and epirubicin treatment is well tolerated and may reverse anthracycline resistance. Changes in histone acetylation and associated decrease in neutrophil count correlated with clinical benefit and warrant investigation as predictive biomarkers. CLINICAL TRIAL: This trial is registered at www.Clinicaltrials.gov, Identifier: NCT00878904.
Assuntos
Quimioterapia Combinada , Epirubicina/administração & dosagem , Ácidos Hidroxâmicos/administração & dosagem , Indóis/administração & dosagem , Sarcoma/tratamento farmacológico , Adulto , Idoso , Cromatina/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Epirubicina/efeitos adversos , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Indóis/efeitos adversos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Panobinostat , Sarcoma/genética , Sarcoma/patologia , Inibidores da Topoisomerase II/administração & dosagemAssuntos
Linfoma Intraocular , Linfoma , Humanos , Lenalidomida , Recidiva Local de Neoplasia , Estudos Prospectivos , RituximabRESUMO
BACKGROUND: Based upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with incurable HCC and Child Pugh score ≤B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD. RESULTS: Twenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alpha-fetoprotein (AFP) declined ≥50% in 60% assessable patients. CONCLUSION: The MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , alfa-Fetoproteínas/metabolismo , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Biomarcadores/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Células Neoplásicas Circulantes , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Precursores de Proteínas/sangue , Protrombina , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Sorafenibe , Resultado do TratamentoRESUMO
BACKGROUND: Src inhibitors sensitise melanoma cells to chemotherapy in preclinical models. The combination of dasatinib and dacarbazine was tested in a phase I trial in melanoma. METHODS: Patients had ECOG performance status 0-2 and normal organ function. Dacarbazine was administered on day 1 and dasatinib on day 2 through 19 of each 21-day cycle. Both were escalated from 50 mg b.i.d. of dasatinib and 800 mg m(-2) of dacarbazine. Available pre-treatment biopsies were sequenced for BRAF, NRAS, and C-Kit mutations. RESULTS: Dose-limiting toxicity was reached at dasatinib 70 mg b.i.d./dacarbazine 1000 mg m(-2), and was predominantly haematological. In 29 patients receiving dasatinib 70 mg b.i.d., the objective response rate (ORR) was 13.8%, the clinical benefit rate (ORR+SD) was 72.4%, the 6-month progression-free survival (PFS) was 20.7%, and the 12-month overall survival (OS) was 34.5%. Two out of three patients who were wild type for BRAF, NRAS, and c-KIT mutations had confirmed partial responses, and one had a minor response. CONCLUSION: The recommended phase II dose is dasatinib 70 mg b.i.d with dacarbazine 800 mg m(-2). PFS and OS data for dasatinib at 70 mg b.i.d. with dacarbazine compared favourably with historical controls. Preliminary data support evaluating tumour mutation status further as a biomarker of response.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Metástase Neoplásica , Quinases da Família src/antagonistas & inibidores , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dacarbazina/efeitos adversos , Dasatinibe , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Análise de Sobrevida , Tiazóis/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: This phase II study evaluated single-agent bosutinib in pretreated patients with locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Patients received oral bosutinib 400 mg/day. The primary end point was the progression-free survival (PFS) rate at 16 weeks. Secondary end points included objective response rate, clinical benefit rate, 2-year overall survival rate, safety, and changes in levels of bone resorption/formation biomarkers. RESULTS: Seventy-three patients were enrolled and treated. Median time from diagnosis of metastatic disease to initiation of bosutinib treatment was 24.5 months. For the intent-to-treat population, the PFS rate at 16 weeks was 39.6%. Unexpectedly, all responding patients (n = 4) were hormone receptor positive. The clinical benefit rate was 27.4%. The 2-year overall survival rate was 26.4%. The main toxic effects were diarrhea (66%), nausea (55%), and vomiting (47%). Grade 3-4 laboratory aminotransferase elevations occurred in 14 (19%) patients. Myelosuppression was minimal. No consistent changes in the levels of bone resorption/formation biomarkers were seen. CONCLUSIONS: Bosutinib showed promising efficacy in prolonging time to progression in chemotherapy-pretreated patients with locally advanced or metastatic breast cancer. Bosutinib was generally well tolerated, with a safety profile different from that of the Src/Abl tyrosine kinase inhibitor dasatinib in a similar patient population.
Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Nitrilas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Terapia de Salvação/métodos , Adulto , Idoso , Remodelação Óssea/efeitos dos fármacos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Estadiamento de Neoplasias , Proteínas Tirosina Quinases/antagonistas & inibidoresRESUMO
BACKGROUND: Histone deacetylases (HDACs) are crucial components of the oestrogen receptor (ER) transcriptional complex. Preclinically, HDAC inhibitors can reverse tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer. This concept was examined in a phase II combination trial with correlative end points. METHODS: Patients with ER-positive metastatic breast cancer progressing on endocrine therapy were treated with 400 mg of vorinostat daily for 3 of 4 weeks and 20 mg tamoxifen daily, continuously. Histone acetylation and HDAC2 expression in peripheral blood mononuclear cells were also evaluated. RESULTS: In all, 43 patients (median age 56 years (31-71)) were treated, 25 (58%) received prior adjuvant tamoxifen, 29 (67%) failed one prior chemotherapy regimen, 42 (98%) progressed after one, and 23 (54%) after two aromatase inhibitors. The objective response rate by Response Evaluation Criteria in Solid Tumours criteria was 19% and the clinical benefit rate (response or stable disease >24 weeks) was 40%. The median response duration was 10.3 months (confidence interval: 8.1-12.4). Histone hyperacetylation and higher baseline HDAC2 levels correlated with response. CONCLUSION: The combination of vorinostat and tamoxifen is well tolerated and exhibits encouraging activity in reversing hormone resistance. Correlative studies suggest that HDAC2 expression is a predictive marker and histone hyperacetylation is a useful pharmacodynamic marker for the efficacy of this combination.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Antagonistas de Estrogênios/administração & dosagem , Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Tamoxifeno/uso terapêutico , Acetilação , Adulto , Idoso , Neoplasias da Mama/mortalidade , Feminino , Histona Desacetilase 2/análise , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Pessoa de Meia-Idade , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , VorinostatRESUMO
BACKGROUND: Histone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA. METHODS: This phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin. RESULTS: In total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day(-1) on days 1-3, followed by doxorubicin (20 mg m(-2)) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day(-1) of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day(-1). Non-dose-limiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for > or =8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression. CONCLUSION: These findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day(-1). The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Histona Desacetilases , Neoplasias/tratamento farmacológico , Acetilação , Adulto , Idoso , Idoso de 80 Anos ou mais , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Coração/efeitos dos fármacos , Histona Desacetilases/análise , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , VorinostatRESUMO
17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is an ansamycin antibiotic that binds to a conserved pocket in Hsp90 and induces the degradation of proteins that require this chaperone for conformational maturation. 17-AAG causes a retinoblastoma (RB)-dependent G1 block in cancer cells and is now in clinical trial. In breast cancer cells, G1 block is accompanied by differentiation and followed by apoptosis. The differentiation is characterized by specific changes in morphology and induction of milk fat proteins and lipid droplets. In cells lacking RB, neither G1 arrest nor differentiation occurs; instead, they undergo apoptosis in mitosis. Introduction of RB into these cells restores the differentiation response to 17-AAG. Inhibitors of the ras, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase pathways cause accumulation of milk fat proteins and induction of lipid droplets when associated with G1 arrest but do not cause morphological changes. Thus, regulation of Hsp90 function by 17-AAG in breast cancer cells induces RB-dependent morphological and functional mammary differentiation. G1 arrest is sufficient for some but not all aspects of the phenotype. Induction of differentiation may be responsible for some of the antitumor effects of this drug.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Quinonas/farmacologia , Rifabutina/farmacologia , Apoptose/efeitos dos fármacos , Benzoquinonas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Divisão Celular/efeitos dos fármacos , Divisão Celular/fisiologia , Fase G1/efeitos dos fármacos , Glicolipídeos/metabolismo , Glicoproteínas/metabolismo , Proteínas de Choque Térmico HSP90/fisiologia , Lactamas Macrocíclicas , Gotículas Lipídicas , Proteínas do Leite/metabolismo , Fenótipo , Fosforilação , Proteína do Retinoblastoma/metabolismo , Proteína do Retinoblastoma/fisiologia , Rifabutina/análogos & derivados , Células Tumorais CultivadasRESUMO
Histone deacetylase (HDACs) regulate histone acetylation by catalyzing the removal of acetyl groups on the NH(2)-terminal lysine residues of the core nucleosomal histones. Modulation of the acetylation status of core histones is involved in the regulation of the transcriptional activity of certain genes. HDAC activity is generally associated with transcriptional repression. Aberrant recruitment of HDAC activity has been associated with the development of certain human cancers. We have developed a class of HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), that were initially identified based on their ability to induce differentiation of cultured murine erythroleukemia cells. Additional studies have demonstrated that SAHA inhibits the growth of tumors in rodents. In this study we have examined the effects of SAHA on MCF-7 human breast cancer cells. We found that SAHA causes the inhibition of proliferation, accumulation of cells in a dose-dependent manner in G(1) then G(2)-M phase of the cell cycle, and induction of milk fat globule protein, milk fat membrane globule protein, and lipid droplets. Growth inhibition was associated with morphological changes including the flattening and enlargement of the cytoplasm, and a decrease in the nuclear:cytoplasmic ratio. Withdrawal of SAHA led to reentry of cells into the cell cycle and reversal to a less differentiated phenotype. SAHA induced differentiation in the estrogen receptor-negative cell line SKBr-3 and the retinoblastoma-negative cell line MDA-468. We propose that SAHA has profound antiproliferative activity by causing these cells to undergo cell cycle arrest and differentiation that is dependent on the presence of SAHA. SAHA and other HDAC inhibitors are currently in Phase I clinical trials. These findings may impact the clinical use of these drugs.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Inibidores Enzimáticos/farmacologia , Ácidos Hidroxâmicos/farmacologia , Neoplasias da Mama/metabolismo , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Transformada , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Inibidores de Histona Desacetilases , Humanos , Lipídeos/biossíntese , Proteínas do Leite/biossíntese , Receptor ErbB-2/biossíntese , Receptor ErbB-2/fisiologia , Receptores de Estrogênio/biossíntese , Receptores de Estrogênio/fisiologia , Proteína do Retinoblastoma/biossíntese , Proteína do Retinoblastoma/fisiologia , VorinostatRESUMO
Geldanamycin (GM) is a natural antibiotic that binds Hsp90 and induces the degradation of receptor tyrosine kinases, steroid receptors, and Raf. It is a potent inhibitor of cancer cells that overexpress HER-kinases, but its effects on other important proteins may cause significant toxicity and limit its clinical use. We report the synthesis and identification of a GM dimer, GMD-4c, which had selective activity against HER-kinases. Selectivity was a function of linker length and required two intact GM moieties. GMD-4c is a potent inducer of G1 block and apoptosis of breast cancer cell lines that overexpress HER2, but does not appreciably inhibit the growth of 32D cells that lack HER-kinases. GMD-4c could be useful in the treatment of carcinomas dependent on HER-kinases.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/enzimologia , Quinonas/farmacologia , Receptor ErbB-2/metabolismo , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/uso terapêutico , Benzoquinonas , Western Blotting , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Divisão Celular/efeitos dos fármacos , Dimerização , Regulação para Baixo/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Concentração Inibidora 50 , Lactamas Macrocíclicas , Proteínas Proto-Oncogênicas c-raf/metabolismo , Quinonas/química , Quinonas/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/biossíntese , Receptor IGF Tipo 1/metabolismo , Receptores de Estrogênio/metabolismo , Especificidade por Substrato , Células Tumorais CultivadasRESUMO
PURPOSE: We conducted this phase I trial to determine the safety and toxicity profile of LY353381.HCl-a novel, potent, third-generation selective estrogen receptor modulator (SERM)-because this benzothiophene derivative demonstrated an SERM profile in preclinical studies. PATIENTS AND METHODS: We studied 32 patients with recurrent or metastatic breast cancer. Patients were treated in four cohorts with oral daily doses of 10, 20, 50, and 100 mg. Pharmacokinetic sampling was performed during the first 72 hours following the first dose on day 1 and during the 24 hours after the day 57 dose. Eligibility criteria included Eastern Cooperative Oncology Group performance status of 0 to 2; no significant major organ dysfunction; and at least 3 weeks elapsed since most recent hormonal therapy, chemotherapy, and estrogen replacement therapy. RESULTS: The median patient age was 56 years (range, 30 years to 76 years). The median number of prior chemotherapies for metastatic disease was one (range, zero to four), while the median number of prior hormone regimens for metastatic disease was two (range, zero to five). Receptor status was estrogen receptor (ER) positive and progesterone receptor (PR) positive, 19 patients; ER positive and PR negative, eight patients; ER positive and PR unknown, two patients; and ER and PR unknown, three patients. Dose-limiting toxicity was not observed. Treatment was well tolerated with mild to moderate hot flashes in 18 of 32 patients (56%) at all dose levels. Transvaginal ultrasound performed at baseline and after 12 weeks of treatment showed no endometrial thickening. Of the 32 patients evaluable for response, six patients had stable disease for at least 6 months with a median duration of 7.7 months (range, 6.2 months to 33.8 months). The pharmacokinetics of LY353381.HCl were generally linear with respect to time and studied dose range. CONCLUSION: As predicted in preclinical testing, daily oral LY353381.HCl is safe, is well tolerated at all tested dose levels, and may be clinically beneficial in patients with extensively pretreated metastatic breast cancer. Further studies with LY353381 to evaluate the efficacy in patients with or without prior exposure to tamoxifen and fewer overall prior regimens are under way.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/farmacologia , Piperidinas/farmacologia , Tiofenos/farmacologia , Análise Atuarial , Adulto , Idoso , Neoplasias da Mama/patologia , Relação Dose-Resposta a Droga , Endométrio/efeitos dos fármacos , Antagonistas de Estrogênios/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Piperidinas/uso terapêutico , Tiofenos/uso terapêuticoRESUMO
BACKGROUND: The Hsp90s contain a conserved pocket that binds ATP/ADP and plays an important role in the regulation of chaperone function. Occupancy of this pocket by several natural products (geldanamycin (GM) and radicicol) alters Hsp90 function and results in the degradation of a subset of proteins (i.e. steroid receptors, Her2, Raf). We have used the structural features of this pocket to design a small molecule inhibitor of Hsp90. RESULTS: The designed small molecule PU3 competes with GM for Hsp90 binding with a relative affinity of 15-20 microM. PU3 induces degradation of proteins, including Her2, in a manner similar to GM. Furthermore, PU3 inhibits the growth of breast cancer cells causing retinoblastoma protein hypophosphorylation, G1 arrest and differentiation. CONCLUSIONS: PU3 is representative of a novel class of synthetic compounds that binds to Hsp90 and inhibits the proliferation of cancer cells. These reagents could provide a new strategy for the treatment of cancers.
Assuntos
Nucleotídeos de Adenina/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Desenho de Fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Receptor ErbB-2/efeitos dos fármacos , Benzoquinonas , Ligação Competitiva , Diferenciação Celular/efeitos dos fármacos , Feminino , Humanos , Lactamas Macrocíclicas , Ligação Proteica , Quinonas/metabolismo , Receptor ErbB-2/metabolismo , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
17-allyl-aminogeldanamycin (17-AAG) is an ansamycin antibiotic that binds to a highly conserved pocket in the Hsp90 chaperone protein and inhibits its function. Hsp90 is required for the refolding of proteins during cellular stress and the conformational maturation of certain signaling proteins. 17-AAG has antitumor activity in cell culture and animal xenograft models and is currently in clinical trial. It causes an RB-dependent G(1) arrest, differentiation, and apoptosis. RB-negative cells arrest in mitosis and undergo apoptosis. Hsp90 plays an important role in the cellular response to environmental stress. Therefore, we tested whether the regulation of Hsp90 function by 17-AAG could sensitize cells to cytotoxic agents. 17-AAG sensitized tumor cells to Taxol and doxorubicin. Taxanes cause growth arrest in mitosis and apoptosis. The addition of 17-AAG to cells after exposure to Taxol significantly increased both the activation of caspases 9 and 3 and apoptosis. In cells with intact RB, exposure to 17-AAG before Taxol resulted in G(1) arrest and abrogated apoptosis. Schedule dependence was not seen in cells with mutated RB, because both agents blocked cells in mitosis. Schedule- or RB-dependence was also not observed when cells were treated with 17-AAG and doxorubicin, a DNA-intercalating agent that acts on different phases of the cell cycle. These findings suggest that inhibition of Hsp90 function by 17-AAG enhances the apoptotic effects of cytotoxic agents. The sequence of drug administration and the RB status significantly influence efficacy.
Assuntos
Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Proteínas de Choque Térmico HSP90/efeitos dos fármacos , Proteína do Retinoblastoma/fisiologia , Antineoplásicos Fitogênicos/farmacologia , Benzoquinonas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/fisiopatologia , Caspase 3 , Caspase 9 , Caspases/efeitos dos fármacos , Caspases/metabolismo , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/fisiologia , Humanos , Lactamas Macrocíclicas , Mitose/fisiologia , Paclitaxel/farmacologia , Proteína do Retinoblastoma/genética , Rifabutina/análogos & derivados , Rifabutina/farmacologia , Fatores de Tempo , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
BACKGROUND: The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K-AKT-mTOR) signalling pathway is aberrantly activated in several cancers. Notch signalling maintains cell proliferation, growth and metabolism in part by driving the PI3K pathway. Combining the mTOR inhibitor ridaforolimus with the Notch inhibitor MK-0752 may increase blockade of the PI3K pathway. METHODS: This phase I dose-escalation study (NCT01295632) aimed to define the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of combination oral ridaforolimus (rising doses starting at 20 mg, 5 days/week) and oral MK-0752 (1800 mg once weekly) in patients with solid tumours. No intrapatient dose escalation was permitted. RESULTS: Twenty eight patients were treated on study. Ridaforolimus doses were escalated from 20 to 30 mg/day. Among 14 evaluable patients receiving ridaforolimus 20 mg, one DLT (grade 2 stomatitis, second episode) was reported. Among eight evaluable patients receiving ridaforolimus 30 mg, three DLTs were reported (one each grade 3 stomatitis, grade 3 diarrhoea, and grade 3 asthenia). The MTD was 20 mg daily ridaforolimus 5 days/week+1800 mg weekly MK-0752. The most common drug-related adverse events included stomatitis, diarrhoea, decreased appetite, hyperglycaemia, thrombocytopenia, asthenia and rash. Two of 15 (13%) patients with head and neck squamous cell carcinoma (HNSCC) had responses: one with complete response and one with partial response. In addition, one patient experienced stable disease ⩾6 months. CONCLUSIONS: Combined ridaforolimus and MK-0752 showed activity in HNSCC. However, a high number of adverse events were reported at the MTD, which would require careful management during future clinical development.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Derivados de Benzeno/administração & dosagem , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/patologia , Esquema de Medicação , Europa (Continente) , Feminino , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons , Propionatos/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Carcinoma de Células Escamosas de Cabeça e Pescoço , Sulfonas/administração & dosagem , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Estados UnidosRESUMO
In recent years, the most frequent indication for high-dose autologous stem-cell-supported chemotherapy in the United States has been breast cancer. This approach is applied in "high-risk," early-stage disease as adjuvant treatment, and with either curative or palliative intent in metastatic disease. Among both lay persons and medical professionals, high-dose therapy is broadly viewed as standard and appropriate, even though the results of the largest prospective randomized studies are not yet available. This view is based on extrapolation from preclinical data, a fundamental belief that "more is better," a faith in high technology, and the results of numerous pilot and phase I and II trials. Because high-dose therapy is promising, but also more difficult to administer than standard therapy, controversy rages in all circles concerning its use. Unless and until we have the results of properly randomized, prospective studies, this controversy will likely continue. Against this background, we will review the theoretical basis for high-dose treatment in breast cancer, the translation of this laboratory science into the clinic, usual treatment approaches, the available data, ongoing clinical trials, and future research directions.
Assuntos
Antineoplásicos/administração & dosagem , Transplante de Medula Óssea , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Esquema de Medicação , Feminino , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema de Registros , Resultado do Tratamento , Estados UnidosRESUMO
The breast cancer mortality rate is falling, most likely because of a combination of early detection, refined surgical and radiation therapy techniques, and improved systemic therapy efficacy. The proper integration and application of these treatment modalities present evolving challenges for clinicians. Systemic therapy, in particular, is changing rapidly with the advent of new chemotherapy drugs, new classes of agents, and new therapeutic regimens. The most recent studies suggest that optimal outcomes are possible through the broad but appropriate use of hormone therapy and chemotherapy to prevent relapse and possibly prevent second primary tumors. The choice of therapy for patients remains a matter for careful consideration and discussion in each individual case.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Metástase Neoplásica , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Indução de Remissão , Resultado do TratamentoRESUMO
Myocytes were isolated from the ventricles of neonatal rat hearts and cultured for 1-3 days. Newly formed cell pairs were used to examine the conductance of gap junctions, gj. Measurements were performed using a dual voltage-clamp method in conjunction with a whole-cell, tight-seal recording. Exposure to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA, 100-160 nM) led to a decrease in gj. Single-channel events recorded immediately before complete uncoupling yielded a single-channel conductance, gamma j, of 40.5 pS, implying that TPA affects the channel kinetics rather than gamma j. TPA-induced uncoupling was observed at subphysiological levels of cytosolic Ca2+ (pipette solution = 18 nM), not at physiological levels (pipette solution = 170 nM). The effects of TPA could not be mimicked by 250 microM 1-oleoyl-2-acetyl-glycerol (OAG). Preincubation with TPA (up to 24 h) revealed no changes in gj attributable to down-regulation of protein kinase C, PKC. Pretreatment with PKC inhibitors, staurosporine or PKCI, prevented the TPA-dependent decrease in gj. TPA-dependent uncoupling was not impaired by 4-bromophenacyl bromide, an inhibitor of phospholipase A2, PLA2; conversely, an arachidonic acid-dependent decrease in gj was not prevented by PKCI. This suggests that gj regulation does not involve an interaction between PLA2 and PKC.
Assuntos
Animais Recém-Nascidos , Junções Intercelulares/fisiologia , Miocárdio/ultraestrutura , Acetato de Tetradecanoilforbol/farmacologia , Alcaloides/farmacologia , Animais , Ácido Araquidônico/farmacologia , Cálcio/metabolismo , Cálcio/farmacologia , Células Cultivadas , Citosol/metabolismo , Diglicerídeos/farmacologia , Condutividade Elétrica , Ventrículos do Coração/ultraestrutura , Junções Intercelulares/efeitos dos fármacos , Cinética , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Ratos , Ratos Wistar , EstaurosporinaRESUMO
One of the major challenges of early-stage breast cancer is to select the adjuvant therapy that ensures the most benefits and the least harm for the patient. The definition of accurate predictive factors is therefore of paramount importance. So far the choice of adjuvant therapy has been based on the number of affected lymph nodes and the hormone receptor status of the patient. This paper evaluates the use of other tumor-related markers as predictive factors for adjuvant therapy. These include HER2, p53 and Bcl-2, cathepsin B, p27, proliferating cell nuclear antigen (PCNA), cyclin D, Ki-67, and vascular endothelial growth factor (VEGF).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Quimioterapia Adjuvante , Feminino , Humanos , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor ErbB-2/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
A 35-kDa protein (designated p35) showing antigenic homology with an N-terminal epitope on the SV-40 large T-antigen oncoprotein was purified from transformed cardiomyocytes. Sequence analysis of several tryptic peptides indicated that p35 was not homologous to previously described sequences. Polyclonal antibody raised against synthetic peptide containing one of the tryptic fragments was used in Western blot analyses to ascertain the tissue-specific pattern of p35 expression. p35 was expressed ubiquitously in adult mouse tissues, and was detected in both embryonic and transformed cardiomyocyte preparations. Subcellular fractionation studies indicated that p35 is an integral membrane protein. Expression of p35 appeared to be regulated by growth conditions as evidenced by a transient decrease in protein levels following the addition of serum to quiescent NIH 3T3 cells.