We have cloned the entire human adenovirus type 5 (Ad5) genome into the pBR322 plasmid in two segments: the BamHI-A fragment (21 kb) and the BamHI-B fragment (15 kb). We have also generated a series of clones with smaller Ad5 DNA inserts, all containing the left-end of the viral genome. One such clone, pXCl, containing the left 16% of the Ad5 DNA molecule, has been shown to transform rodent cells by DNA transfection. We have used the transposable element Tn5 as an insertion mutator to isolate pXCl mutants containing Tn5 inserted at a large number of sites. By assaying transforming activity of selected pXC::Tn5 plasmids we have identified Ad5 sequences which are essential for DNA-mediated transformation. Our results with these mutants and with a plasmid pCD1, containing a deletion within the Ad5-transforming region, indicate that sequences present in both early region 1a and the N-terminal region of early region 1b are essential for DNA-mediated transformation.

Adenoviruses, Human↗

PubMedDate not supplied

Quantitative analysis of regions of adenovirus E1A products involved in interactions with cellular proteins.

Human adenovirus E1A proteins and oncogene products of several other DNA tumour viruses derive much of their oncogenic potential from interactions with cellular polypeptides. E1A proteins form complexes with p105Rb and a related p107 polypeptide, and with at least three other proteins (p60cycA, p130, and p300); all may be required for cell transformation. Using a series of E1A deletion mutants, we have carried out a quantitative analysis of the binding patterns of cellular proteins to E1A products. Binding of most of the proteins was affected at least partially by mutations within the amino terminal 25 residues, amino acids 36-69 within conserved region 1 (CR1), and residues 121-138 in conserved region 2 (CR2). However, the specific binding characteristics of each protein varied considerably. p300 was the only species for which binding was totally eliminated by deletions at the amino terminus. Removal of regions within CR1 eliminated binding of all species except p107 and p60cycA. Deletion of portions of CR2 reduced or eliminated binding of all proteins except p300. Thus, whereas cellular polypeptides generally were found to interact with the same three regions of E1A proteins, specific interactions varied considerably.

Adenovirus E1A Proteins↗

PubMedDate not supplied

A multicentric phase II clinical trial on intra-arterial hepatic radiotherapy with 90yttrium SIR-spheres in unresectable, colorectal liver metastases refractory to i.v. chemotherapy: preliminary results on toxicity and response rates.

BACKGROUND: In patients locally progressing after two lines of chemotherapy, some locoregional approaches showed encouraging results in terms of local control of disease. The aim of our study was to evaluate toxicity, clinical response and quality of life in 48 patients with unresectable colorectal liver metastases submitted to selective internal radiotherapy (SIRT). MATERIALS AND METHODS: Up to now 35 patients with unresectable colorectal liver metastases, refractory to two lines of chemotherapy, underwent intra-arterial infusion of resin microspheres with yttrium-90 (SIR-spheres). Pre-treatment evaluation included a CT scan, blood tests, a PET scan and arteriography of celiac trunk, hepatic and superior mesenteric artery; extrahepatic uptakes and pulmonary shunts more than 10% were excluded by a Scinti-scan. The gastroduodenal artery was embolized before the SIR-spheres injection. Other exclusion criteria were liver dysfunction and anatomical vascular anomalies. The clinical response was evaluated by CT-scan following the RECIST criteria. Median follow-up was 4 months. RESULTS: Median number of metastases was 4 (range, 1-15), 38% of cases presenting hepatic involvement < 25%. The median SIRT dose delivered was 1.7 GBq. Median pulmonary shunt was 6%. No operative mortality occurred; early toxicity (within 48 hours) was 20.6%, shown as fever, acute pain and leucocytosis. The late toxicity was 24.1% with chronic pain, jaundice and nausea being the most frequent. All the toxic events were graded 2 or 3 according to the WHO scale. Preliminary results were available in terms of clinical response after 6 weeks: 12.5% had a partial response, 75% a stable disease, while progression of disease, was observed in 12.5% of the patients. CONCLUSION: SIRT is a safe treatment in terms of acute and late toxicity. Intra-arterial microspheres could represent a good therapeutic option for patients with progressing liver metastases only, after two lines of systemic chemotherapy.

Antineoplastic Agents↗

PubMedDate not supplied

Hepatic arterial infusion (HAI) for unresectable liver metastases (ULM) from colorectal carcinoma.

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Adult↗