ReviewThe role of p53 in treatment responses of lung cancer
Section snippets
Genetic alterations in lung cancers
Multiple genetic and molecular changes characterize LC development [6]. Among these, overexpression of insulin-like growth factor receptor (IGF-R) is found in about 95% of all SCLC and in 80% of all NSCLC generating high growth factor signalling [7], [8]. Furthermore, 30% of all NSCLCs have a mutation in the oncogene K-ras resulting in a constitutive active p21-Ras protein and continuous signalling through the mitogen-activated protein kinase (MAPK) or the phosphatidylinositol-3 (PI3K) kinase
The role of p53 in DNA damage surveillance and DNA repair
The treatment modalities used in LC therapy include radiation as well as chemotherapy and to a large extent, these treatments exert their function by causing different types of DNA damage. It is therefore appropriate to address the function of p53 in DNA damage surveillance and DNA repair when addressing the importance of p53 as a predictive marker of LC behavior and treatment responses.
Several DNA damage repair and detection systems contribute to a network through which DNA damages are
The influence of p53 on radiation responses in lung cancer
Upon radiation cells can respond with growth arrest or be triggered to death of multiple types, i.e., mitotic catastrophe, apoptosis, necrosis, and autophagy. Although p53 is activated in response to radiation in experimental cell systems, it is important to point out that some but not all radiation-induced cell deaths are dependent on functional p53. Thus if the p53-mediated effect within cells mainly is induction of apoptosis, as it is in cells of hematopoietic origin, functional p53 has been
The influence of p53 status on chemotherapy response in lung cancer
In preclinical studies of LC cell lines, the influences of p53 status on responses to the DNA-crosslinking agent cisplatin have been conflicting. Thus, p53 wild-type expressing NSCLC cells which were inoculated in nude mice regressed upon treatment with cisplatin whereas NSCLC expressing mutated p53 did not [64]. The necessity of wild-type p53 for the cytotoxic response to cisplatin as well as to topoisomerase inhibitors etoposide and camptothecin in NSCLC cell lines was also addressed by Hwang
P53-replacement therapies in LC treatment
Given the high frequency of mutation in p53 in LC, concomitant treatment with different classes of chemotherapy and p53 gene replacement strategies has been tested in preclinical as well as in clinical settings (as reviewed in [107]). In preclinical studies with LC cell lines expressing mutated p53, p53 replacement strategy has improved chemotherapy and radiotherapy responses [108], [109].
Phase I and II clinical trials in NSCLC patients have been initiated world wide either with p53-replacement
Conclusions
A summary of preclinical data on the value of p53 status as a predictive marker of sensitivity of lung cancer to radiation or chemotherapy is contradictory. It may be that the different lung cancer cell lines studied have other signalling defects downstream of p53 which can influence the outcome of treatment-induced p53-mediated signalling events. Moreover, in part the discrepancies among the studies can be explained by different assessment methodology used. More studies in which clonogenic
Acknowledgments
Work in the authors’ laboratory is supported by grants from the Swedish and Stockholm Cancer Societies, The Swedish Research Council, Swedish Heart and Lung Foundation, and by the European Commission (QLK3-CT-2002-01956). We apologize to authors whose primary references could not be cited due to space limitations.
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