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1.
Cancer Res ; 79(8): 1996-2008, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30723115

RESUMO

Expression of the TAM (TYRO3, AXL, MER) family of receptor tyrosine kinases (RTK) has been associated with cancer progression, metastasis, and drug resistance. In immune cells, TAM RTKs can dampen inflammation in favor of homeostatic wound-healing responses, thus potentially contributing to the evasion of cancer cells from immune surveillance. Here we characterize the small-molecule RXDX-106 as a selective and potent pan-TAM RTK inhibitor with slow dissociation kinetics and significant antitumor activity in multiple syngeneic tumor models. Expression of AXL and MER on both immune and tumor cells increased during tumor progression. Tumor growth inhibition (TGI) following treatment with RXDX-106 was observed in wild-type mice and was abrogated in immunodeficient mice, suggesting that the antitumor activity of RXDX-106 is, in part, due to the presence of immune cells. RXDX-106-mediated TGI was associated with increased tumor-infiltrating leukocytes, M1-polarized intratumoral macrophages, and activation of natural killer cells. RXDX-106 proportionally increased intratumoral CD8+ T cells and T-cell function as indicated by both IFNγ production and LCK phosphorylation (pY393). RXDX-106 exhibited its effects via direct actions on TAM RTKs expressed on intratumoral macrophages and dendritic cells, leading to indirect activation of other immune cells in the tumor. RXDX-106 also potentiated the effects of an immune checkpoint inhibitor, α-PD-1 Ab, resulting in enhanced antitumor efficacy and survival. Collectively, these results demonstrate the capacity of RXDX-106 to inhibit tumor growth and progression and suggest it may serve as an effective therapy against multiple tumor types. SIGNIFICANCE: The pan-TAM small-molecule kinase inhibitor RXDX-106 activates both innate and adaptive immunity to inhibit tumor growth and progression, indicating its clinical potential to treat a wide variety of cancers.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/imunologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirimidinas/farmacologia , Quinolinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , c-Mer Tirosina Quinase/antagonistas & inibidores , Imunidade Adaptativa , Animais , Apoptose , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Neoplasias do Colo/patologia , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Artigo em Inglês | MEDLINE | ID: mdl-15043157

RESUMO

IMPDH inhibitors have potential antimicrobial, anticancer and immunomodulatory effects. Nucleoside inhibitors of IMPDH exert their inhibitory effects via nucleoside 5'-MPs. Conversion of nucleoside analogs to NMPs by cellular nucleoside kinases is not assured, and usually is inefficient. In order to bypass cellular phosphorylation, a series of azole nucleoside 5'-MP mimics (P1Ms) based on ribavirin, EICAR and bredinin were synthesized and screened against human and C. albicans IMP dehydrogenises. P1Ms 8, 16, 25, 28 and 29 demonstrated substantial IMPDH inhibition with Ki values in low micromolar range.


Assuntos
Inibidores Enzimáticos/síntese química , IMP Desidrogenase/antagonistas & inibidores , Nucleotídeos/síntese química , Inibidores Enzimáticos/química , Nucleotídeos/química
3.
Fertil Steril ; 77(1): 98-100, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11779597

RESUMO

OBJECTIVE: To determine if a fixed-dose stimulation protocol with monitoring limited to a single ultrasound can provide acceptable outcomes in assisted reproduction technologies (ART) procedures in appropriately selected patients. DESIGN: Prospective study of all minimally monitored ART cycles from 1996 through 1998. SETTING: University ART program. PATIENTS: Eligibility included Institutional Review Board consent, age 18-37, basal FSH < or = 10, normal semen parameters, and regular menses. IVF (n = 81) and GIFT (n = 14). INTERVENTIONS: A single ultrasound was performed after 8 or 9 days of stimulation in a fixed-schedule long luteal phase leuprolide protocol. No hormone levels were obtained. Human chorionic gonadotropin was administered when at least 2 follicles were projected to reach 18 mm. MAIN OUTCOME MEASURES: Pregnancy, delivery, and implantation rates. RESULTS: The clinical pregnancy rates were 51% for IVF and 36% for GIFT. Delivery rates were 42% for IVF and 29% for GIFT. The implantation rates for IVF were 23% and 17% for GIFT. No patient was admitted for ovarian hyperstimulation. CONCLUSIONS: We were able to achieve satisfactory pregnancy and delivery rates in properly selected patients with a minimal monitoring protocol, limited to a single ultrasound near the end of a fixed-stimulation regimen. The reduced time commitment and cost led to a very high patient acceptance of this approach.


Assuntos
Fertilização In Vitro/estatística & dados numéricos , Técnicas de Reprodução Assistida/estatística & dados numéricos , Adulto , Colorado , Custos e Análise de Custo , Implantação do Embrião , Feminino , Transferência Intrafalopiana de Gameta/estatística & dados numéricos , Humanos , Infertilidade Feminina/etiologia , Monitorização Fisiológica/economia , Monitorização Fisiológica/métodos , Gravidez/estatística & dados numéricos , Resultado da Gravidez , Técnicas de Reprodução Assistida/economia
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