DNA repair capacity as a risk factor for non-melanocytic skin cancer—a molecular epidemiological study

Capacity to repair UV-induced DNA damage was studied by use of a host cell reactivation assay in T lymphocytes isolated from 86 cases and 87 controls (aged 44-68 years) who were participants in a population-based case-control study of basal cell (BCC) or squamous cell (SCC) carcinoma of the skin in Geraldton, Western Australia. Lymphocytes were cultured and transfected with either control or UV-irradiated plasmids (254 mm, 350 J/m²) containing a reporter gene [the chloramphenicol-acetyltransferase (CAT) gene], and the repair capacity was determined by measuring CAT gene expression in protein extracts prepared from the transfected cells. DNA repair activity was 1.07 (95% confidence interval 0.94-1.26) times greater in BCC cases than in controls for each 350 J/m² increment in UV dose to the plasmids, and 1.04 (95% confidence interval 0.85-1.26) times greater in SCC cases than in controls, though the differences were not statistically significant. DNA repair activity showed little association with age, sex and viability of the lymphocytes, though it was positively associated with their blastogenic rate (p=0.055).     

Syrian hamster as a permissive immunocompetent animal model for the study of oncolytic adenovirus vectors

Oncolytic adenoviruses represent an innovative approach to cancer therapy. These vectors are typically evaluated in immunodeficient mice with human xenograft tumors. However, in addition to being immunodeficient, this model is limited because normal and cancerous mouse tissues are poorly permissive for human adenovirus replication. This prompted us to search for a model that more accurately reflects the use of oncolytic adenoviruses in cancer patients. To this end, we developed a novel Syrian hamster model that is both immunocompetent and replication-permissive. We found that human adenovirus replicates well in Syrian hamster cell lines and confirmed replication in the lungs. Oncolytic adenovirus injection showed efficacy in three different hamster tumor models. Furthermore, i.t. oncolytic adenovirus injection resulted in suppression of primary and metastatic lesions, i.t. replication and necrosis, vector entrance into the bloodstream, replication in the liver and lungs, and anti-adenovirus antibody induction. Our findings show that the Syrian hamster is a promising immunocompetent model that is permissive to human adenovirus replication in tumors as well as normal tissues. Therefore, the Syrian hamster model may become a valuable tool for the field of oncolytic adenovirus vectors in which vector safety and efficacy can be evaluated.     

The pig as an animal model for the study of nitrosamine metabolism

Surgical procedures have been developed that permit the sampling of portal blood, bile and hepatic blood in intact pigs. Animals so prepared have been used to study liver metabolism and biliary excretion of N-nitrosodimethylamine (NDMA) following oral and intravenous dosing.     

The infant mouse as a in vivo model for the detection and study of DNA damage-induced changes in the liver

The present work describes the use of the infant (4-wk-old) mouse as an animal model for the study of DNA damage-induced G(1) checkpoint response, changes in p53 protein levels, and multiple gene expression changes after DNA damage has been induced in the liver. Hepatocytes in the infant B6C3F1 mouse had a proliferation index that was 27 times greater than that of the 12-wk-old B6C3F1 mouse (57.4 vs. 2.1%, respectively). Eight hours after infant mice were exposed to the DNA damaging agents bleomycin (100 mg/kg, i.p.) or 10 Gy of whole body gamma irradiation, the G(1)/S ratio significantly increased from 21 (control) to 66 and 75, respectively, because of the induction of the G(1)/S checkpoint response. One hour after whole body irradiation of infant mice the levels of the p53 protein, phosphoserine 18-p53 and phosphoserine 23-p53 increased dramatically and tended to peak at 1 h in the liver, whereas the p21(WAF1) protein increased more slowly and tended to peak at 2 h after irradiation. The mRNA expression of the p53-response genes p21, murine double minute clone 2 (mdm2), and cyclin G was increased at 2 h after irradiation but was decreased by 8 h postirradiation, relative to the 2-h time-point. The expression of insulin-like growth factor binding protein-1 (IGFBP-1) and growth-regulated oncogene 1 (GRO1) increased at 2 and 8 h postirradiation. This work characterizes various parameters in the infant mouse, thus validating the use of this model to study in vivo DNA damage-induced cell-cycle-related changes.     

Bendamustine as a model for the activity of alkylating agents

Attempts to administer personalized standard cytotoxic chemotherapy based on individual patient characteristics have been disappointing. Alkylating agents are one of the oldest classes of anticancer medicine with a wide variety of molecular actions and thus the potential for broad utility. Bendamustine hydrochloride, a new addition to this class, was previously developed in the 1960s and has now been trialled in hematological malignancies and many solid tumor types as monotherapy or in combination with the known standard of care. It appears to occupy a particular role in resistant or refractory hematological disease and it was approved by the US FDA for the treatment of chronic lymphocytic leukemia in March 2008. Further trials will reveal whether it is likely to become incorporated into front-line regimens in non-Hodgkin's lymphoma and other malignancies.     

Tcl1 as a model for lymphomagenesis

Mature leukemias and lymphomas are a heterogeneous group of lymphoproliferative neoplasias characterized by the accumulation of mature lymphocytes in lymph nodes, other lymphoid tissues, and peripheral blood. In this article we discuss molecular mechanisms leading to the pathogenesis of two major types of mature leukemias and lymphomas: mature T-cell leukemia and chronic lymphocytic leukemia.     

Brain metastasis as a late manifestation of ovarian carcinoma

CHEN Y‐L., CHENG W‐F., HSIEH C‐Y. & CHEN C‐A. (2011) European Journal of Cancer Care 20 , 44–49
Brain metastasis as a late manifestation of ovarian carcinoma This paper aims to evaluate the clinical characteristics of ovarian cancer patients with cerebral metastases. Ten ovarian cancer patients with brain metastases were retrospectively identified from a total of 539 ovarian cancer patients. Their characteristics before and at the time of diagnosis of cerebral metastases were analysed. The survival of them was also measured. Ten (1.9%) of the 539 ovarian cancer patients had brain metastases in the study period. Nine had stage III or IV tumours with either moderate or poor histological differentiation. The mean time from diagnosis of ovarian cancer to documentation of central nervous system metastasis was 24.3 months, which was 11.1 months if other sites of metastasis were involved before cerebral relapse. All of the patients with intra‐cranial tumours suffered from associated neurological defects and relived by treatments. The median survival time after diagnosis of central nervous system involvement was 3 months. In this study, all ovarian cancer patients with cerebral metastases had clinical neurological symptoms. Physicians should pay more attention to ovarian cancer patients with neurological defects and arrange brain imaging studies for the early diagnosis of brain metastases and prompt management to improve quality of life.     

DNA repair as a determinant of tumour chemosensitivity

Differently from target-based anticancer drugs, molecular mechanisms of actions are not well-known in many of the classical antineoplastic agents. With the exception of vinca alkaloids and taxanes, all of the classical antineoplastic agents work on DNA metabolism in cells and can therefore be categorised as 'DNA metabolism inhibitor'. Cellular sensitivity against these drugs largely depends on various activities in DNA metabolism, particularly in DNA repair. However, DNA repair as a determinant of drug sensitivity had long received little attention. DNA mismatch repair (MMR) is now regarded as an important determinant to alter cellular sensitivities against various drugs including fluoropyrimidines, platinum compounds and topoisomerase inhibitors. However, molecular mechanisms of this connection are still unknown. In particular, the relationship between MMR and 5-fluorouraci (l 5-FU) sensitivity is now being approached by examining the tumour MMR status and clinical outcomes in colorectal cancer patients treated with 5-FU-based adjuvant chemotherapies. However, reported results lack consistency, possibly due to the methodological problems in assays used to determine the MMR status. On the other hand, nucleotide excision repair (NER) is also regarded as an important determinant of cisplatin (CDDP) sensitivity. Expression of ERCC 1, a component of this complex multi-protein system, has been reported to be a determinant of prognosis in CDDP-treated non-small-cell lung cancer patients. In order to establish the significance of DNA repair as a determinant of tumour chemosensitivity, further basic studies, particularly ones approached from biochemical viewpoints, are required. Clinical studies supported by accurate assay techniques are also needed.     

Cancer dormancy: a model of early dissemination and late cancer recurrence

Cancer dormancy is a stage in tumor progression in which residual disease remains occult and asymptomatic for a prolonged period of time. Dormant tumor cells can be present as one of the earliest stages in tumor development, as well as a stage in micrometastases, and/or minimal residual disease left after an apparently successful treatment of the primary tumor. The general mechanisms that regulate the transition of disseminated tumor cells that have lain dormant into a proliferative state remain largely unknown. However, regulation of the growth from dormant tumor cells may be explained in part through the interaction of the tumor cell with its microenvironment, limitations in the blood supply, or an active immune system. An understanding of the regulatory machinery of these processes is essential for identifying early cancer biomarkers and could provide a rationale for the development of novel agents to target dormant tumor cells. This review focuses on the different signaling models responsible for early cancer dissemination and tumor recurrence that are involved in dormancy pathways.     

Early and late effects of fractionated irradiation and the kinetics of repair in rat lung

The thorax of WAG/Rij rats was irradiated with fractionated doses of X rays. Irradiation schedules were designed either to allow virtually complete repair of sublethal damage between subsequent fractions by fractionating at 6-h intervals, or to result in incomplete repair by allowing only 1-h intervals between subsequent fractions. Combination of the data from both experimental series permitted the calculation of alpha/beta ratios and values for the repair halftime T1/2. The animals were monitored by assessment of the breathing frequency and by recording deaths. At the end of the experiments, 18 months after treatment, the hydroxyproline content of the lung tissue was determined as a biochemical indicator of radiation-induced fibrosis, and an histopathological analysis was performed. Early endpoints, indicative of radiation-induced pneumonitis, resulted in an alpha/beta ratio of 3.5 Gy and a T1/2 value of 0.95 h. Late endpoints were presumed to be indicative of radiation-induced fibrosis. Based on the combined analysis of data from three different late endpoints, the mean alpha/beta ratio was 2.3 Gy, and the T1/2 value was 1.13 h. The difference in alpha/beta ratio and T1/2 value between early and late endpoints was not significant, since the 95% confidence limits were overlapping. For each individual early or late endpoint as well as for the two early or the three late endpoints combined, there was a trend for lower alpha/beta ratios and higher T1/2 values associated with low doses per fraction. However, widely overlapping confidence limits indicated that again the differences were not significant.     

Latent-time estimation for late cutaneous and subcutaneous radiation reactions in a single-follow-up clinical study

In this paper, an analysis of the fractionation sensitivity and latency of subcutaneous fibrosis and telangiectasia in a clinical series is presented. The series comprised 163 breast cancer patients who, from 1978 to 1980, received postmastectomy irradiation delivered in 12 fractions, with 2 fractions per week over a period of 37 to 46 days. The total dose was specified either as a maximum absorbed dose of 51.36 Gy, or as a minimum target dose of 36.6 Gy specified at the level of the mid-axilla. From 1981 to 1982, 66 patients received a minimum target dose of 40.92 Gy in 22 fractions administered as 5 fractions per week over 29 to 35 days. Late complications were evaluated prospectively at a single follow-up after a minimum observation time of 16 months. The clinical endpoints analyzed were subcutaneous fibrosis and telangiectasia. The data were analyzed using a mixture model that incorporates both dose fractionation and latency effects. The length of time to expression of 90% of the ultimate frequency of moderate or severe complications was 3.2 years (95% confidence limits (c.l.) [2.3,3.9] years) and 4.7 years (95% c.l. [4.0,4.8] years) for fibrosis and telangiectasia respectively, while the alpha/beta ratios were 1.9 Gy (95% c.l. [0.8,3.0] Gy) and 3.7 Gy (95% c.l. [0.2,47] Gy), respectively. For subcutaneous fibrosis the time to reach a specific grade of reaction increases with the grade, thus being consistent with the clinical impression that fibrosis progresses in severity over time. If latency and censoring effects are unaccounted for, serious underestimates of the ultimate frequency of radiation complications in groups with incomplete follow-up may result.