Intracellular Targeting of Oncogenes: A Novel Approach for Cancer Therapy
It is now well established that cancer is a multistep disease. In the case of colon cancer, we know of at least five steps in the process of moving from a normal cell to a tumor cell.1 Each step occurs at a very low frequency but can be accelerated or obv
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Intracellular Targeting of Oncogenes: ANovel Approach for Cancer Therapy Olivier Cochet, Isabelle Delumeau, Mireille Kenigsberg, Nadege Gruel, Fabien Schweighoffer, Laurent Bracco, Jean Luc Teillaud and Bruno Tocque
Introduction
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t is now well established that cancer is a multistep disease. In the case of colon cancer, we know of at least five steps in the process of moving from a normal cell to a tumor cell.1 Each step occurs at a very low frequency but can be accelerated or obviated by environmental or genetic factors. This process may be explained at a molecular level by the need for a tumor cell to sustain several mutations in its genome, each of which is required to alter a distinct target whose activation yields a subset of the phenotypic changes necessary for conversion to the fully tumorigenic state. Are there as many distinct mechanisms of transformation as there are oncogenes? In vitro and in vivo experiments showed that there are two central cellular growth regulatory pathways that must be disrupted in order for the cell to proceed to full oncogenic transformation. There is ample testimony to the fact that oncogenic retroviruses carrying single oncogenes are potently tumorigenic. The biological model of two genetic changes required for transformation is best exemplified by the cooperation between the ras and P53 genes 2 and provides a challenge to those studying the biochemistry of their encoded proteins. How can the biological effects of such mutated proteins be circumvented to induce tumor regression? Strategies for neutralizing the effects of these proteins by expressing synthetic genes in target tumors can now be envisioned. We will discuss in this chapter some of the approaches aimed at blocking the oncogenic functions of genes such as ras, and at neutralizing the oncogenic function of the P53 mutant forms using single chain antibodies.
Ras as a Target for Cancer Treatment The discovery that ras genes are mutated in a large proportion of human tumors has generated considerable hope for cancer treatment (see ref. 3 for review). Indeed, mutated ras oncogenes have been associated with tumor progression,
Intrabodies: Basic Research and Clinical Gene Therapy Applications, edited by Wayne A. Marasco.© 1998 Springer-Verlag and R.G. Landes Company.
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Intrabodies: Basic Research and Clinical Gene Therapy Applications
metastasis and increased resistance to chemotherapy and radiotherapy."'5 One can expect some beneficial clinical input in the near future coming from any of the therapeutic approaches discussed below. Isoprenylation of Ras proteins is an absolute requirement for their membrane anchorage and transforming activity. 6 In a series of post-translational modifications, isoprenylation of cysteine'86 occurs first and is followed by the removal of the three last amino acids, and finally, by carboxymethylation of the isoprenylated and now C-terminal cysteine.? These findings opened up the possibility that specific inhibitors of Ras might be identified which have a selective toxicity for tumors
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