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1.
Cancer Cell ; 1(4): 325-37, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12086848

RESUMO

We have engineered a human adenovirus, ONYX-411, that selectively replicates in human tumor cells, but not normal cells, depending upon the status of their retinoblastoma tumor suppressor protein (pRB) pathway. Early and late viral gene expression as well as DNA replication were significantly reduced in a functional pRB-pathway-dependent manner, resulting in a restricted replication profile similar to that of nonreplicating adenoviruses in normal cells both in vitro and in vivo. In contrast, the viral life cycle and tumor cell killing activity of ONYX-411 was comparable to that of wild-type adenovirus following infection of human tumor cells in vitro as well as after systemic administration in tumor-bearing animals.


Assuntos
Adenovírus Humanos/genética , Proteínas de Ciclo Celular , Ciclo Celular/genética , Proteínas de Ligação a DNA , Vetores Genéticos/genética , Neoplasias Experimentais/terapia , Fatores de Transcrição/genética , Replicação Viral/genética , Proteínas E1A de Adenovirus/genética , Proteínas E1A de Adenovirus/metabolismo , Adenovírus Humanos/patogenicidade , Animais , Antineoplásicos , Replicação do DNA , DNA Viral/genética , Vírus Defeituosos , Fatores de Transcrição E2F , Fibroblastos/fisiologia , Regulação Viral da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Knockout , Neoplasias Experimentais/patologia , Regiões Promotoras Genéticas , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Taxa de Sobrevida , Transplante Heterólogo , Células Tumorais Cultivadas/patologia
2.
Mol Cancer Ther ; 16(2): 285-299, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27980108

RESUMO

Upregulation of MYC is a common driver event in human cancers, and some tumors depend on MYC to maintain transcriptional programs that promote cell growth and proliferation. Preclinical studies have suggested that individually targeting upstream regulators of MYC, such as histone deacetylases (HDAC) and phosphoinositide 3-kinases (PI3K), can reduce MYC protein levels and suppress the growth of MYC-driven cancers. Synergy between HDAC and PI3K inhibition in inducing cancer cell death has also been reported, but the involvement of MYC regulation is unclear. In this study, we demonstrated that HDAC and PI3K inhibition synergistically downregulates MYC protein levels and induces apoptosis in "double-hit" (DH) diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, CUDC-907, a small-molecule dual-acting inhibitor of both class I and II HDACs and class I PI3Ks, effectively suppresses the growth and survival of MYC-altered or MYC-dependent cancer cells, such as DH DLBCL and BRD-NUT fusion-positive NUT midline carcinoma (NMC) cells, and MYC protein downregulation is an early event induced by CUDC-907 treatment. Consistently, the antitumor activity of CUDC-907 against multiple MYC-driven cancer types was also demonstrated in animal models, including DLBCL and NMC xenograft models, Myc transgenic tumor syngeneic models, and MYC-amplified solid tumor patient-derived xenograft (PDX) models. Our findings suggest that dual function HDAC and PI3K inhibitor CUDC-907 is an effective agent targeting MYC and thus may be developed as potential therapy for MYC-dependent cancers. Mol Cancer Ther; 16(2); 285-99. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes myc , Inibidores de Histona Desacetilases/farmacologia , Neoplasias/genética , Neoplasias/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Camundongos , Camundongos Transgênicos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Proteólise , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cancer Res ; 63(20): 6900-8, 2003 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-14583489

RESUMO

ONYX-015 has been used successfully in the clinic as a cancer therapeutic in combination with chemotherapy. The combination of ONYX-015 and chemotherapy appears to be more efficacious than either regimen alone. In this study, we try to enhance this combination by "arming" ONYX-015 with a therapeutic transgene, an approach more commonly used with nonreplicating viruses in the context of gene therapy. We chose the prodrug converting enzyme carboxylesterase (CE), which converts the camptothecin derivative CPT-11 (irinotecan) to the much more potent chemotherapeutic SN-38. The transgene was introduced into three distinct positions in the E3 region of the adenovirus genome to allow either early or late expression during the virus life cycle. We demonstrate that each of these ONYX-015-based adenoviruses expresses an active CE enzyme that can efficiently convert CPT-11 to SN-38. Furthermore, the cytotoxicity of CE-expressing viruses, but not control viruses, is enhanced significantly in the presence of the prodrug. Finally, we demonstrate that we can achieve transgene expression and activity in vivo in a human tumor xenograft model, and that treatment with a CE-expressing virus in combination with CPT-11 enhances survival of tumor-bearing mice. These results indicate that the addition of a prodrug converting enzyme may be a feasible approach to additionally enhance the efficacy of replicating adenoviruses as cancer therapeutics.


Assuntos
Adenoviridae/genética , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Carboxilesterase/genética , Carboxilesterase/metabolismo , Pró-Fármacos/farmacocinética , Adenoviridae/fisiologia , Animais , Camptotecina/farmacologia , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Neoplasias do Colo/terapia , Feminino , Humanos , Irinotecano , Camundongos , Camundongos Nus , Pró-Fármacos/farmacologia , Coelhos , Transgenes , Replicação Viral , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Virol ; 77(4): 2640-50, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12552003

RESUMO

Mutants of human adenovirus 5 (Ad5) with enhanced oncolytic activity were isolated by using a procedure termed bioselection. Two mutants, ONYX-201 and ONYX-203, were plaque purified from a pool of randomly mutagenized Ad5 that was repeatedly passaged in the human colorectal cancer cell line HT29, and they were subsequently characterized. ONYX-201 and ONYX-203 replicated more rapidly in HT29 cells than wild-type Ad5, and they lysed HT29 cells up to 1,000-fold more efficiently. The difference was most profound when cells were infected at a relatively low multiplicity of infection, presumably due to the compounding effects of multiple rounds of infection. This enhanced cytolytic activity was observed not only in HT29 cells but also in many other human cancer cell lines tested. In contrast, the cytotoxicity of the bioselected mutants in a number of normal primary human cells was similar to that of wild-type Ad5, thus enhancing the therapeutic index (cytotoxicity in tumor cells versus that in normal cells) of these oncolytic agents. Both ONYX-201 and -203 contain seven single-base-pair mutations when compared with Ad5, four of which were common between ONYX-201 and -203. The mutation at nucleotide 8350, shared by both mutant viruses, was shown to be essential for the observed phenotypes. This mutation was mapped to the i-leader region of the major late transcription unit, resulting in the truncation of 21 amino acids from the C terminus of the i-leader protein. This work demonstrates that bioselection is a powerful tool for developing novel tumor-selective oncolytic viruses. Other potential applications of this technology are discussed.


Assuntos
Adenovírus Humanos/genética , Adenovírus Humanos/patogenicidade , Seleção Genética , Adenovírus Humanos/fisiologia , Efeito Citopatogênico Viral , Humanos , Mutagênese , Inoculações Seriadas , Células Tumorais Cultivadas , Virologia/métodos , Replicação Viral
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