Conditionally replication competent adenoviruses (Ads) that selectively replicate in cancer cells and simultaneously express a therapeutic cytokine, such as melanoma differentiation associated gene- 7/Interleukin-24 (mda-7/IL-24), a Cancer Terminator Virus (CTV-M7), hold potential for treating human cancers. To enhance the efficacy of the CTV-M7, we generated a chimeric Ad.5 and Ad.3 modified fiber bipartite CTV (Ad.5/3-CTV-M7) that can infect tumor cells in a Coxsackie Adenovirus receptor (CAR) independent manner, while retaining high infectivity in cancer cells containing high CAR. Although mda-7/IL-24 displays broad-spectrum anticancer properties, pancreatic ductal adenocarcinoma (PDAC) cells display an intrinsic resistance to mda-7/IL-24-mediated killing due to an mda-7/IL-24 mRNA translational block. However, using a chemoprevention gene therapy (CGT) approach with perillyl alcohol (POH) and a replication incompetent Ad to deliver mda-7/IL-24 (Ad.mda-7) there is enhanced conversion of mda-7/IL-24 mRNA into protein resulting in pancreatic cancer cell death in vitro and in vivo in nude mice containing human PDAC xenografts. This combination synergistically induces mda-7/IL-24-mediated cancer-specific apoptosis by inhibiting anti-apoptotic Bcl-xL and Bcl-2 protein expression and inducing an endoplasmic reticulum (ER) stress response through induction of BiP/GRP-78, which is most evident in chimeric-modified non-replicating Ad.5/3- mda-7- and CTV-M7-infected PDAC cells. Moreover, Ad.5/3-CTV-M7 in combination with POH sensitizes therapy-resistant MIA PaCa-2 cell lines over-expressing either Bcl-2 or Bcl-xL to mda-7/IL-24-mediated apoptosis. Ad.5/3-CTV-M7 plus POH also exerts a significant antitumor 'bystander' effect in vivo suppressing both primary and distant site tumor growth, confirming therapeutic utility of Ad.5/3-CTV-M7 plus POH in PDAC treatment, where all other current treatment strategies in clinical settings show minimal efficacy.

Background:A novel, short duration, palliative radiotherapy schedule for inoperable head and neck cancer was evaluated in terms of palliation of cancer-related symptoms and acute toxicities.Materials and Methods:Thirty-six patients with inoperable head and neck cancer were included in the study (2010-2012). All patients received 40 Gy in 10 fractions (equivalent dose: 49.8 Gy in conventional fractionation) with 2 fractions per week. Treatment-related toxicity was assessed using Radiation Therapy Oncology Group criteria. Functional Assessment of Cancer Therapy (Head and Neck, FACT H and N) quality of life (QOL) tool was administered before starting and at the completion of radiotherapy. Mean value before and after treatment was compared (paired t-test, P = 0.05, two-tailed for significance).Results:Thirty-three patients (male: 29, female: 4, mean age: 57.8 ± 9.7 years) were included in the analysis (three patients discontinued treatment due to socioeconomic reasons). All patients had advanced inoperable head and neck cancers (27% IVA, 61% IVB, 9% IVC, TNM stage and 3% recurrent disease). Distressing pain at primary site (42%), dysphagia (18%), neck swelling (30%), and hoarseness (10%) were common presentations. Incidence of grade III mucositis and dermatitis and pain was 18%, 3%, and 24%, respectively. Planned radiotherapy without any interruptions was completed by 73% patients. QOL assessment showed improvement in social well-being (17.4 vs. 20.01, P = 0.03), but no significant change was observed in head and neck specific score (25.1 vs. 25.0, P = NS) after treatment. Reduction of pain was observed in 88% patients and 60% patients had improvement of performance status. Median overall survival of the cohort was 7 months.Conclusions:The study shows that this short duration palliative radiotherapy schedule is a clinically viable option for advanced inoperable head and neck cancer to achieve significant palliation of the main presenting symptoms like pain, dysphagia, and throat pain.

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