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The p53 protein is an inducible transcription factor with multiple anti-proliferative roles in response to genotoxic damage; unprogrammed proliferative stimuli; and deprivation of oxygen, nutrients, or ribonucleotides. Inactivation of the TP53 gene by mutation or deletion is the most common event in human cancer. Loss of p53 function compromises genetic homeostasis in cells exposed to mutagens and prevents normal cytotoxic responses to cancer therapies. Genetic and pharmacological approaches are being developed with the ultimate goal of restoring or controlling p53 functions in cancer patients.Genetic interventions aiming at expressing wild-type TP53 in cancer cells, either by retroviral or adenoviral transfer, have met limited clinical success. However, recently, the use of a defective adenovirus (ONYX-015) that selectively kills p53-incompetent cells has shown promising effects in pre-clinical and clinical studies. Pharmacological methods are under development to either stimulate wild-type p53 protein function or induce p53 mutant proteins to resume wild-type functions. These methods are based on small chemicals (CP-31388, PRIMA-1), peptides (CDB3), or single-chain Fv antibody fragments corresponding to defined p53 domains. In addition, detection of mutant TP53 may also serve as a marker for early cancer detection, prediction, and prognosis. In this review, we discuss the mechanisms underlying these approaches and their perspectives for cancer therapy. [ABSTRACT FROM AUTHOR]

The relationship between P-glycoprotein expression and malignancy is controversial. We have recently found that, in osteosarcoma, multidrug resistance (MDR) is associated with a less aggressive behavior, both in vitro and in clinical settings. In this study, we evaluated whether P-glycoprotein overexpression has a cause-effect relationship with the reduced metastatic potential of MDR cells, or rather reflects a more complex phenotype. MDR1 gene-transfected osteosarcoma cell clones, showing different levels of P-glycoprotein expression, were analysed for their in vitro characteristics and their tumorigenic and metastatic ability in athymic mice. Apart from the different levels of P-glycoprotein, no significant change in the expression of surface antigens or in the differentiative features were observed in the MDR1 gene transfectants compared to the parental cell lines or control clones, obtained by transfection with neo gene alone. In contrast to controls, however, MDR1 transfectants showed a significantly lower ability to grow in semi-solid medium and were completely unable to grow and give lung metastases in athymic mice. These findings indicate that P-glycoprotein overexpression is causally associated with a low malignant potential of osteosarcoma cells, and open new insights on the role and functions of P-glycoprotein activity. [ABSTRACT FROM AUTHOR]