Prolonged systemic circulation of chimeric oncolytic adenovirus Ad5/3-Cox2L-D24 in patients with metastatic and refractory solid tumors.

Eighteen patients with refractory and progressive solid tumors were treated with a single round of triple modified oncolytic adenovirus (Ad5/3-Cox2L-D24). Ad5/3-Cox2L-D24 is the first non-Coxsackie-adenovirus receptor-binding oncolytic adenovirus used in humans. Grades 1-2 flu-like symptoms, fever, and fatigue were seen in most patients, whereas transaminitis or thrombocytopenia were seen in some. Non-hematological grades 3-5 side effects were seen in one patient with grade 3 ileus. Treatment resulted in high neutralizing antibody titers within 3 weeks. Virus appeared in serum 2-4 days after treatment in 83% of patients and persisted for up to 5 weeks. One out of five radiologically evaluable patients had partial response (PR), one had minor response (MR), and three had progressive disease (PD). Two patients scored as PD had a decrease in tumor density. Tumor reductions not measurable with Response Evaluation Criteria In Solid Tumors (RECIST) were seen in a further four patients. PR, MR, stable disease, and PD were seen in 12, 23.5, 35, and 29.5% of tumor markers analyzed, respectively (N=17). Ad5/3-Cox2L-D24 appears safe for treatment of cancer in humans and extended virus circulation results from a single treatment. Objective evidence of anti-tumor activity was seen in 11/18 (61%) of patients. Clinical trials are needed to extend these findings.

Ad5/3-9HIF-Delta24-VEGFR-1-Ig, an infectivity enhanced, dual-targeted and antiangiogenic oncolytic adenovirus for kidney cancer treatment.

Despite good safety data in clinical trials, oncolytic adenoviruses have not been efficient enough to make them a viable treatment alternative for cancers. As more potent viruses are being made, transcriptional and transductional targeting to tumor tissues becomes increasingly appealing. To improve antitumor efficacy, oncolytic adenoviruses can be armed with therapeutic transgenes, such as the antiangiogenic soluble vascular endothelial growth factor receptor 1-Ig fusion protein. We hypothesized that an infectivity enhanced, targeted, vascular endothelial growth factor receptor 1-Ig armed oncolytic adenovirus would exhibit improved specificity and antitumor effect in murine kidney cancer models. Two hypoxia inducible factor-sensitive promoters were evaluated for renal cancer specificity using a novel in vivo dual luciferase-imaging system. Earlier data had shown usefulness of the 5/3-serotype chimera capsid modification for kidney cancer. Therefore, we constructed Ad5/3-9HIF-Delta24-VEGFR-1-Ig, which showed good specificity and oncolytic effect on renal cancer cells in vitro and resulted in antitumor efficacy in a subcutaneous in vivo model, in which vascular endothelial growth factor receptor 1-Ig expression and a concurrent antiangiogenic effect were confirmed. In an intraperitoneally disseminated kidney cancer model, significantly enhanced survival was observed when compared with control viruses. These results suggest that a targeted, antiangiogenic, oncolytic adenovirus might be a valuable agent for testing in kidney cancer patients.

An overall perspective of X-ray damage to a DNA oligomer mediated by reactive oxygen species.

The products produced by X irradiation of an oxygenated aqueous solution containing d(CpApTpG) were analyzed by NMR spectroscopy and mass spectrometry. Thirteen different base modifications were detected, including a novel product formed by the addition of oxygen to guanine. Seven different strand break products were identified, including strands having 5'-phosphoryl groups, 3'-phosphoryl groups and groups having 3'-phosphoglycolates as termini. The products produced in largest yield contained base modifications: Pyrimidine bases degraded to a formamido moiety, the 8-oxo-7,8-dihydroguanine (8-oxoguanine) lesion, and double base lesions in which both the 8-oxo-7,8-dihydroguanine lesion and a formamido remnant are present.

Spinal cord dose is higher than expected in head and neck radiation.

Myelopathy is a feared consequence of radiation therapy. Risk factors are multifocal; therefore, total dose calculation is crucial. We evaluated the contribution of scatter radiation to obtain an accurate cumulative spinal cord dose. Twenty patients undergoing three field head and neck radiation by Cobalt or 6 MV Linac had a total cord dose calculated from direct and scatter radiation. The cord was removed from the radiation field at tumor doses no higher than 4,400 cGy. Total tumor dose ranged from 5,400-7,400 cGy (mean 6060). All patients achieved the prescribed dose and none were lost to follow up (mean 36 months). It was found that scatter radiation can contribute as much as 20% extra dose to the spinal cord. Mean extra dose was 9% (range 1%-20%). This additional dose ranged from 52-810 cGy (mean 339 cGy). No apparent difference was seen with Cobalt or Linac source. Our conclusion was that significant additional dose is delivered to the spinal cord by scatter radiation and that scatter may contribute more to the development of myelopathy than previously believed.

Isolation and characterization of the products of anoxic irradiation of d(CpGpTpA).

An improved method for separating the products of DNA oligomers irradiated in aqueous solution has been devised. Altogether 39 products were isolated from the tetramer d(CpGpTpA) X-irradiated in dilute anoxic solution. Of these, 16, including most of the major products, were identified through the use of proton nmr spectroscopy. The identified products fall into four categories: (1) base products, (2) strand scission products, (3) base modifications and (4) tandem lesion. A tandem lesion in which the methyl carbon atom of thymine is covalently linked to the guanine C8 carbon atom was produced in larger yield than any of the simple base modifications.