RESUMEN
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.
Asunto(s)
Anticarcinógenos/administración & dosificación , Clorhidrato de Erlotinib/administración & dosificación , Naproxeno/administración & dosificación , Recurrencia Local de Neoplasia/prevención & control , Neoplasias Experimentales/prevención & control , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Animales , Anticarcinógenos/efectos adversos , Butilhidroxibutilnitrosamina/toxicidad , Carcinógenos/toxicidad , Progresión de la Enfermedad , Esquema de Medicación , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/métodos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib/efectos adversos , Femenino , Humanos , Naproxeno/efectos adversos , Recurrencia Local de Neoplasia/patología , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/patología , Quimioterapia por Pulso , Ratas , Factores de Tiempo , Tiempo de Tratamiento , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/inducido químicamente , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
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.
Asunto(s)
Bencenosulfonatos/farmacología , Neoplasias Mamarias Experimentales/prevención & control , Receptor ErbB-2/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Ácidos Aminosalicílicos/farmacología , Animales , Antracenos/toxicidad , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Neoplasias Mamarias Experimentales/etiología , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Virus del Tumor Mamario del Ratón/genética , Ratones , Ratones Transgénicos , Piperidinas/toxicidad , Ratas , Ratas Sprague-Dawley , Células Tumorales CultivadasRESUMEN
(2E,4E,6Z,8Z)-8-(3',4'-Dihydro-1'(2H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid, 9cUAB30, is a selective rexinoid for the retinoid X nuclear receptors (RXR). 9cUAB30 displays substantial chemopreventive capacity with little toxicity and is being translated to the clinic as a novel cancer prevention agent. To improve on the potency of 9cUAB30, we synthesized 4-methyl analogs of 9cUAB30, which introduced chirality at the 4-position of the tetralone ring. The syntheses and biological evaluations of the racemic homolog and enantiomers are reported. We demonstrate that the S-enantiomer is the most potent and least toxic even though these enantiomers bind in a similar conformation in the ligand binding domain of RXR.