Conditionally replicating E1B-deleted adenovirus driven by the squamous cell carcinoma antigen 2 promoter for uterine cervical cancer therapy

Abstract

Cervical cancer is the second most common type of malignant tumor among women worldwide. When the disease is confined locally, it can be controlled with surgical resection and radiotherapy. However, patients with recurrent or metastatic disease often have a poor prognosis. Measurement of serum levels of squamous cell carcinoma (SCC) antigens has been widely used as serological markers for SCC of uterine cervix. Recently, it has been demonstrated that cervical cancer patients with elevated squamous cell carcinoma antigen-2 (SCCA2) expression in tumor cells carry a poor prognosis. Here, by using a luciferase reporter assay, we show that SCCA2 promoter was active in SCCA2-producing human cervical cancer cell lines, including Cx, Cxwj, SiHa and HeLa cells, but relatively quiescent in normal cervical epithelial cells. We then developed a conditionally replicating adenovirus, designated Ad-KFH, under the transcriptional control of the SCCA2 promoter. This E1B-55 kDa-deleted oncolytic adenovirus replicated specifically in and lysed SCCA2-producing cervical cancer cells. Furthermore, in a peritoneal metastatic tumor model, Ad-KFH retarded Cxwj tumor growth in NOD/severe combined immunodeficient mice and prolonged survival of tumor-bearing mice, especially when combined with cisplatin. These results suggest that Ad-KFH may provide a new strategy of gene therapy for advanced or recurrent uterine cervical cancer.

The use of a human papillomavirus 18 promoter for tissue-specific expression in cervical carcinoma cells

“…Gene therapy using tissue-specific promoters has been reported to be a promising tool for treating cancers [8]. Few studies have explored this possibility for the treatment of cervical cancer; however, a SCCA2 promoter [20] and an HPV16 promoter [21] have been utilised to direct tissue-restricted gene expression in cervical carcinoma cells. The malignant phenotype of HPV-positive cervical cancers is dependent on the continuous expression of E6 and E7 via the P 105 promoter [22].…”

A Solanum incanum extract (SR-T100) regresses vulvar condyloma acuminatum and induces distinct autophagic and apoptotic responses in different types of HPV-infected cells

“…Cell lines were maintained in Dulbecco's modified Eagle's medium (Invitrogen, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (Sigma Chemical Co., St. Louis, MO, USA), 20 mM HEPES, and 50 mg/ml gentamicin. For primary epithelial cells, normal uterine cervical cells were derived from patients who had undergone hysterectomy and were cultured in serum-free keratinocyte medium (Keratinocyte-SFM; Invitrogen) as previously described [12]. The 3-methyladenine (3-MA), pepstatin A (PSTA), wortmannin (WT), trans-epoxysuccinyl-L-leucylamido-(4-guanidino)-butane (E-64), benzyloxycarbonyl-valyl-alanyl-aspartic acid (O-methyl)-fluoromethylketone z (Z-VAD-FMK), monodansylcadaverine (MDC), and anti-β-actin antibody (clone AC-15; 1:25,000) were obtained from Sigma Chemical Co. DiOC6(3) was purchased from Molecular Probes.…”

Oncolytic adenovirus mediated Survivin RNA interference and 5-fluorouracil synergistically suppress the lymphatic metastasis of colorectal cancer

“…Oncolytic virus virotherapy has been proved by many studies to be effective against various types of malignancies (8)(9)(10)(11). ONYX-015, a well known E1B-55 kDa deleted adenovirus, has been used in clinical trials and achieved encouraging results, but the therapeutic efficacy of ONYX-015 is limited when used alone (12,13).…”