Adenoviral Gene Transfer of the Human Inducible Nitric Oxide Synthase Gene Enhances the Radiation Response of Human Colorectal Cancer Associated with Alterations in Tumor Vascularity

Wang, Zifa; Cook, Tracy; Alber, Sean; Liu, Kaihong; Kovesdi, Imre; Watkins, Simon C.; Vodovotz, Yoram; Billiar, Timothy R.; Blumberg, David

doi:10.1158/0008-5472.can-03-1307

Cited by 62 publications

(45 citation statements)

References 37 publications

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“…2 The combination of gene therapy and radiation has also demonstrated synergistic antitumor effects both in vitro and in vivo in several tumor models. 6,13 The combination of an oncolytic adenoviral vector with Taxol produces an additive antitumor effect in preclinical studies in mouse xenograft tumor models. 4 Thus, combination treatment has great potential for translation into effective clinic therapy in the immediate future.…”

Section: Discussionmentioning

confidence: 99%

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

Dilley

Reddy

et al. 2005

Cancer Gene Ther

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Conditionally replicating adenoviruses that selectively replicate in tumor cells, but not in normal cells, are being explored as virotherapeutic agents for cancer. A prostate-specific oncolytic adenovirus, CG7870 is currently being evaluated in phase 1/2 clinical trials for the treatment of prostate cancer. To decrease the effective dose and further increase the therapeutic efficacy of CG7870, the combination of virotherapy with radiation therapy was explored in this study. CG7870 is an oncolytic adenovirus in which tumor-specific promoters are driving the expression of E1A and E1B proteins. The effects of combined treatment with CG7870 and radiation on cultured cells were determined in cytotoxicity and virus yield assays. The antitumor efficacy of CG7870 (1 Â 10 7 particles/mm 3 of tumor), 10 Gy of local radiation or both was evaluated in established subcutaneous LNCaP xenografts in nude mice. In vitro, the dual agent treatment resulted in synergistically enhanced potency at suboptimal doses of radiation and virus. Virus yield in irradiated cells increased relative to yield in nonirradiated cells without compromising the specificity of the vector for its target cell types. In vivo, CG7870 treatment alone suppressed tumor growth and extended tumor nonprogression time. The average tumor-volume of the groups treated with CG7870 only and radiation only was 121 and 126% of baseline, respectively, 39 days after treatment. The average tumor-volume of the combination group was 34% of baseline 39 days after a single dose of treatment. No significant body weight loss was observed in any treatment group. There was a significant drop in serum level of prostate-specific antigen (PSA) in the combination group compared to the group treated with either agent alone. In mice treated with CG7870 only or radiation only, serum PSA levels changed to 26 and 383% of baseline, respectively, by study day 46. In contrast, PSA levels in mice treated with CG7870 plus radiation decreased to less than 11% of baseline by study day 46. Histological analysis of tumor sections collected from the combination group revealed enhanced necrosis and more apoptotic cells. Combination of CG7870 with radiotherapy significantly increased antitumor efficacy compared to either agent alone. These results suggest that CG7870 in combination with radiation has improved antitumor efficacy at lower doses and with no additional side effects.

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Section: Discussionmentioning

confidence: 99%

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

Dilley

Reddy

et al. 2005

Cancer Gene Ther

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“…The usefulness of cancer therapy using NO, including inducible NO synthase gene therapy and administration of NO donor, was recently confirmed in animal models (45)(46)(47). Consequently, NO therapy has received considerable attention and is currently undergoing clinical evaluation for cancer prevention (48).…”

Section: Discussionmentioning

confidence: 99%

“…Specific MEK1/2 inhibitors can inhibit the expression of phospho-ERK1/2 for various lengths of time in vitro (36)(37)(38). CI-1040, a MEK1/2 inhibitor, reduced tumor growth by 31.3% in mice inoculated with papillary thyroid carcinoma (PTC) cells carrying a BRAF mutation and by 47.5% in mice inoculated with PTC cells bearing a RET/ PTC1 rearrangement (39). Cl-1040 has been tested in other cancers, including colon cancer, breast cancer, non-small cell lung cancer (NSCLC), and melanoma, and was well tolerated by patients in phase I-II trials (40,41).…”

Section: Discussionmentioning

confidence: 99%

NO donor and MEK inhibitor synergistically inhibit proliferation and invasion of cancer cells

Furuhashi

Sugita

Horino³

et al. 2011

Int J Oncol

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Abstract.Nitric oxide (NO) shows tumoricidal activity. We had previously reported that NO downregulates the phosphatidylinositol-3-kinase/Akt pathway, but upregulates the MEK/ERK pathway downstream of growth factor signaling. We hypothesized that NO donor and MEK inhibitor in combination synergistically inhibit the viability of cancer cells compared to either NO donor or MEK inhibitor alone. We determined the effects of S-nitrosoglutathione (GSNO, NO-donor) and U0126 (MEK inhibitor) on insulin-like growth factor-I (IGF-I) and epidermal growth factor (EGF) signaling, proliferation and invasion in cancer cell lines. GSNO inhibits phosphorylation of IGF-I receptor (IGF-IR), EGF receptor (EGFR) and Akt, but upregulates ERK1/2 phosphorylation in MIAPaCa-2 and HCT-116 cells after stimulation by IGF-I and EGF. On the other hand, U0126 inhibits phosphorylation of ERK1/2, but upregulates phosphorylation of IGF-IR and EGFR in MIAPaCa-2 and HCT-116 cells. The combination of GSNO and U0126 downregulates phosphorylation of IGF-IR, EGFR, Akt and ERK1/2 after stimulation by IGF-I and EGF. GSNO as well as U0126, inhibits the proliferation of MIAPaCa-2, HCT-116, Panc-1, MCF-7, HT-29 and AGS cells in a dose-dependent manner. GSNO and U0126 in combination synergistically inhibit proliferation and invasion of cancer cells. These results indicate that the combined treatment of NO donor and MEK inhibitor may be promising in cancer therapy.

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“…(27). It has been reported that the adenoviral gene transfer of the iNOS gene enhances the radiation response of human colorectal cancer associated with alterations in tumor vascularity (28).…”

Section: Discussionmentioning

confidence: 99%

A novel chenodeoxycholic derivative HS-1200 enhances radiation-induced apoptosis in MCF-7 cells

Yee

Song²,

Jeong³

et al. 2007

Oncol Rep

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Adenoviral Gene Transfer of the Human Inducible Nitric Oxide Synthase Gene Enhances the Radiation Response of Human Colorectal Cancer Associated with Alterations in Tumor Vascularity

Abstract: ABSTRACT

Cited by 62 publications

References 37 publications

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

NO donor and MEK inhibitor synergistically inhibit proliferation and invasion of cancer cells

A novel chenodeoxycholic derivative HS-1200 enhances radiation-induced apoptosis in MCF-7 cells

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