No abstract

Background: The re-occurrence of an inflammatory skin reaction which is limited to previously irradiated areas after the administration of a promoting agent is called radiation recall dermatitis. Despite a number of case reports no systematic analysis about the frequency of the phenomenon exists. Therefore we performed an observation study in order to obtain information about this phenomenon in clinical practice. Patients and Methods: 142 patients who underwent palliative radiotherapy were included in the study. The skin reaction at the day of completion of radiotherapy was documented and the patients were followed until cytotoxic chemotherapy was administered or at least 6 months. Results: 91 patients received different types of chemotherapy. In 8 patients a radiation recall dermatitis was observed, corresponding to a frequency of 8.8%. The radiation skin reactions occurred within 6 weeks after the completion of radiotherapy which corresponded to the time-period most of the chemotherapies were applied in. The grade of observed radiation recall dermatitis ranged from a mild erythema to a severe exfoliative dermatitis. Conclusion: The radiation recall dermatitis is a reaction of moderate frequency among adult cancer patients. Its possible severity as well as consecutive therapeutic consequences argue for its consideration in clinical settings.

No abstract

Kodym, E., Kodym, R., Choy, H. and Saha, D. Sustained Metaphase Arrest in Response to Ionizing Radiation in a Non-small Cell Lung Cancer Cell Line. Radiat. Res. 169, 46-58 (2008). In solid tumors, non-apoptotic forms of tumor cell inactivation such as mitotic catastrophe appear to be predominant in the response to DNA-damaging agents. Despite its importance, the underlying molecular mechanisms of mitotic catastrophe have been only partially elucidated. We found that a large fraction of HCC2279 non-small cell lung cancer cells underwent mitotic catastrophe after irradiation. Cells were arrested in metaphase with chromosomal damage indicated by DNA fragments displaced from the metaphase plate and considerable numbers of residual gamma-H2AX foci. Although TP53 was nonfunctional, we detected a prompt radiation response on the level of checkpoint kinases. In contrast, CDC25A was the only checkpoint phosphatase that was responsive to radiation. CDC25B was not detectable, and CDC25C was constitutively phosphorylated at serine 216, leading to its cytoplasmic sequestration and functional inactivation. Therefore, radiation-induced mitotic catastrophe in HCC2279 cells appears to be induced by a combination of relative insufficiencies in the p53-mediated and checkpoint kinase-mediated pathways leading to premature entry into mitosis. Displaced chromosome fragments triggering an intra-M checkpoint in cells entering mitosis presumably result in a sustained metaphase arrest. The phenomenon found in these cells, which were derived directly from a human patient, might be responsible for therapy-induced genetic instability of tumors.

The early development of vertebrate embryos is characterized by rapid cell proliferation necessary to support the embryo’s growth. During this period, the embryo must maintain a balance between ongoing cell proliferation and mechanisms that arrest or delay the cell cycle to repair oxidative damage and other genotoxic stresses. The ATM (Ataxia-Telangiectasia Mutated) kinase is a critical regulator of the response to DNA damage, acting through downstream effectors such as P53 and checkpoint kinases to mediate cell-cycle checkpoints in the presence of DNA damage. Mice and humans with inactivating mutations in ATM are viable, but have increased susceptibility to cancers. The possible role of ATM in limiting cell proliferation in early embryos has not been fully defined. One target of ATM and checkpoint kinases is the Cdc25 phosphatase, which facilitates cell cycle progression by removing inhibitory phosphates from cyclin-dependent kinases. We have identified a zebrafish mutant, standstill, with an inactivating mutation in cdc25a. Loss of cdc25a in the zebrafish leads to accumulation of cells in late G2 phase. We find that the novel family member, cdc25d, is essential for early development in the absence of cdc25a, establishing for the first time that cdc25d is active in vivo in zebrafish. Surprisingly, we find that cell cycle progression in cdc25a mutants can be rescued by chemical or genetic inhibition of ATM. Checkpoint activation in cdc25a mutants occurs despite the absence of increased DNA damage, highlighting the role of Cdc25 proteins to balance constitutive ATM activity during early embryonic development.