A potent replicative delta-24 adenoviral vector driven by the promoter of human papillomavirus 16 that is highly selective for associated neoplasms.
BACKGROUND
Several human epithelial neoplasms are associated with high-risk strains of human papillomavirus (HPV) such as cervical, anorectal, and other carcinomas. For some tumor types the current therapeutic tools are only palliative. Conditionally replicative adenoviruses (CRAds) are promising antineoplastic agents, which also can trigger confined antitumor effects.


METHODS
We constructed a series of CRAds driven by the upstream regulatory promoter region (URR) of an Asian-American variant of HPV-16, which contained different mutations at the E1A region (dl1015 and/or Delta24) and wild-type. All vectors were tested in vitro for viral replication and cytotoxicity. Viral DNA replication and E1A expression were also assessed by quantitative PCR. Finally, we confirmed the antitumoral efficacy of this vector in injected and non-injected xenotransplanted cervical tumors in a murine model for tumor regression and survival studies.


RESULTS
A vector denominated Ad-URR/E1ADelta24 displayed a potent cytopathic effect associated with high selectivity for HPV+ cell lines. We found that the oncolytic effect of this CRAd was comparable to Ad-wt or Ad-Delta24, but this efficacy was significantly attenuated in HPV- cell lines, an effect that was contributed by the URR promoter. Ad-URR/E1ADelta24 was very effective to control tumor growth, in both, injected and non-injected tumors generated with two different HPV+ cell lines.


CONCLUSIONS
CRAd Ad-URR/E1ADelta24 is a highly selective vector for HPV+ cell lines and tumors that preserves the oncolytic efficacy of Ad-wt and Ad-Delta24. Our preclinical data suggest that this vector may be useful and safe for the treatment of tumors induced by HPV, like cervical cancers.
Delgado-Enciso
Iván
I
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico.
Cervantes-García
Daniel
D
Martínez-Dávila
Irma A
IA
Ortiz-López
Rocío
R
Alemany-Bonastre
Ramón
R
Silva-Platas
Christian I
CI
Lugo-Trampe
Angel
A
Barrera-Saldaña
Hugo A
HA
Galván-Salazar
Héctor R
HR
Coronel-Tene
Christian G
CG
Sánchez-Santillán
Carlos F
CF
Rojas-Martínez
Augusto
A
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000260:Adenoviruses, Human / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006367:HeLa Cells; D052162:Human papillomavirus 16 / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000628:therapy; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D011401:Promoter Regions, Genetic; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014779:Virus Replication
D017500:Adenovirus E1A Proteins