RESUMO
Daily dosing of either NSAIDs or EGFR inhibitors has been shown to prevent bladder cancer development in a N-butyl-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced rat model. However, these inhibitors cause gastrointestinal ulceration and acneiform rash, respectively, limiting their continuous use in a clinical prevention setting. We studied chemopreventive efficacy of pulsatile dosing of EGFR inhibitor erlotinib (42 mg/kg BW, once/week) combined with intermittent or continuous low doses of the NSAID naproxen (30 mg/kg BW/day, 3 weeks on/off or 128 ppm daily in diet) in the OH-BBN induced rat bladder cancer model. The interventions were started either at 1 or 4 weeks (early intervention) or 3 months (delayed intervention) after the last OH-BBN treatment, by which time the rats had developed microscopic bladder lesions. All combination regimens tested as early versus late intervention led to the reduction of the average bladder tumor weights (54%-82%; P < 0.01 to P < 0.0001), a decrease in tumor multiplicity (65%-85%; P < 0.01 to P < 0.0001), and a decrease in the number of rats with large palpable tumors (>200 mg; 83%-90%; P < 0.01 to P < 0.0001). Levels of signal transduction markers, Ki-67, cyclin D1, IL1ß, pSTAT3, and pERK, were significantly (P < 0.05 to P < 0.001) reduced in the treated tumors, demonstrating their potential utility as predictive markers for efficacy. These findings demonstrate that significant chemopreventive efficacy could be achieved with alternative intervention regimens designed to reduce the toxicity of agents, and that starting erlotinib and/or naproxen treatments at the time microscopic tumors were present still conferred the efficacy.
Assuntos
Anticarcinógenos/administração & dosagem , Cloridrato de Erlotinib/administração & dosagem , Naproxeno/administração & dosagem , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Experimentais/prevenção & controle , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Anticarcinógenos/efeitos adversos , Butilidroxibutilnitrosamina/toxicidade , Carcinógenos/toxicidade , Progressão da Doença , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/efeitos adversos , Feminino , Humanos , Naproxeno/efeitos adversos , Recidiva Local de Neoplasia/patologia , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/patologia , Pulsoterapia , Ratos , Fatores de Tempo , Tempo para o Tratamento , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/patologiaRESUMO
Signal transducer and activator of transcription 3 (STAT3) plays a key role in the transformation of normal cells to cancerous cells. Although inhibitors of STAT3 have been shown to suppress the growth of multiple cancer types in vitro and in vivo, such agents are of particular interest for the prevention of breast cancer, which affects over 200,000 women and claims more than 40,000 lives in the United States each year. In the present study, we employed the MMTV/Neu transgenic mouse model, which develops estrogen receptor (ER)negative, Neuoverexpressing tumors, and the SpragueDawley (SD) rat model, which develops ERpositive tumors upon exposure to the carcinogen 7,12dimethylbenz[a]anthracene (DMBA), to test the efficacy of the STAT3 inhibitor GLG302 in the prevention of mammary cancer. Orally administered GLG302 and its trizma salt derivative reduced mammary cancer incidence, multiplicity, and tumor weights in female MMTV/Neu mice, and GLG302 reduced tumor multiplicity and weights in female DMBAtreated rats. Consistent with the mechanism of action of STAT3 inhibitors, the reductions in mammary tumors were correlated with decreases in STAT3 phosphorylation and cell proliferation. These data suggest that GLG302 is a novel agent with potential for prevention of mammary cancer and support the further development of STAT3 inhibitors for this cause.
Assuntos
Benzenossulfonatos/farmacologia , Neoplasias Mamárias Experimentais/prevenção & controle , Receptor ErbB-2/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Ácidos Aminossalicílicos/farmacologia , Animais , Antracenos/toxicidade , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Neoplasias Mamárias Experimentais/etiologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Vírus do Tumor Mamário do Camundongo/genética , Camundongos , Camundongos Transgênicos , Piperidinas/toxicidade , Ratos , Ratos Sprague-Dawley , Células Tumorais CultivadasRESUMO
Two cancer chemopreventive agents, vitamin D3 and 9-cis-retinoic acid (9-cis-RA), were evaluated alone and in combination in the methylnitrosourea (MNU)-induced mammary cancer model. In this study, female Sprague-Dawley rats received MNU (50 mg/kg BW) at 50 days of age. Vitamin D3 and 9-cis-RA were administered in the diet beginning three days later. The groups were: Group 1, vehicle only; Group 2, 9-cis-RA (60 mg/kg diet); Group 3, vitamin D3 (10 microg/kg diet); Group 4, vitamin D3 (3.3 microg/kg diet); Group 5, 9-cis-RA (60 mg/kg diet) plus vitamin D3 (10 microg/kg diet); and Group 6, 9-cis-RA (60 mg/kg diet) plus vitamin D3 (3.3 microg/kg diet). Animals were observed daily for signs of toxicity and were palpated 2x/week for mammary tumors. The study was terminated 150 days after treatment with MNU. The average number of mammary cancers was 6.7 in the animals receiving only the carcinogen. 9-cis-RA alone caused a 23% decrease in mammary cancer multiplicity, while vitamin D3 alone actually caused slight increases of 17 and 16% at 10 and 3.3 microg/kg diet dose levels, respectively. When the agents were given in combination, however, the 9-cis-RA plus the high dose of vitamin D caused a statistically significant decrease (44%) in mammary cancer number, while the 9-cis-RA plus the low dose resulted in a 37% decrease. Thus, low doses of these agents that were not effective in preventing mammary cancer when given alone appeared to be active when given in combinations. Possible interactions between the retinoic acid receptors and vitamin D receptor may be responsible for the observed inhibition of mammary carcinogenesis.