fti-277 and Neoplasms

Recently, we have shown that RhoB suppresses EGFR-, ErbB2-, Ras- and Akt-mediated malignant transformation and metastasis. In this paper, we demonstrate that the novel antitumor agents farnesyltransferase inhibitors (FTIs) and geranylgeranyltransferase I inhibitors (GGTIs) upregulate RhoB expression in a wide spectrum of human cancer cells including those from pancreatic, breast, lung, colon, bladder and brain cancers. RhoB induction by FTI-277 and GGTI-298 occurs at the transcriptional level and is blocked by actinomycin D. Reverse transcription-PCR experiments documented that the increase in RhoB protein levels is due to an increase in RhoB transcription. Furthermore, treatment with FTIs and GGTIs of cancer cells results in HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter. Thus, promoter acetylation is a novel mechanism by which RhoB expression levels are regulated following treatment with the anticancer agents FTIs and GGTIs.

Topics: Acetylation; Alkyl and Aryl Transferases; Antineoplastic Agents; Benzamides; Enzyme Inhibitors; Farnesyltranstransferase; Histone Acetyltransferases; Histone Deacetylase 1; Histone Deacetylases; Histones; Humans; Methionine; Neoplasms; Promoter Regions, Genetic; Protein Processing, Post-Translational; Reverse Transcriptase Polymerase Chain Reaction; rhoB GTP-Binding Protein; RNA, Neoplasm; Tumor Cells, Cultured; Up-Regulation

Enormous progress has been made in the past 5 years in our understanding of the gene products governing the response of mammalian cells to ionizing radiation. Many of these are potential targets for enhancing the effectiveness of radiotherapy. However, a major barrier to such efforts is the requirement for a preferential effect on tumor vs. normal cells. Such a requirement can only come about by exploiting a known difference between tumor and normal cells.. This review highlights three differences between tumor and normal cells that are being exploited with fractionated radiotherapy.. The three strategies to enhance preferentially tumor response to radiotherapy are inhibition of ras activity using farnesyltransferase inhibitors (FTIs), inhibition of epidermal growth factor receptors (EGFRs), and the use of drugs that preferentially kill hypoxic cells. Each of these strategies exploits a known difference between at least some tumors and their surrounding normal tissues, and each has shown encouraging results when combined with fractionated radiation in preclinical studies.. For each of the three strategies to enhance preferentially the sensitivity of cancers, the preclinical and early clinical data are promising for their successful application in radiotherapy.

Topics: Alkyl and Aryl Transferases; Antibodies, Monoclonal; Antineoplastic Agents; Cell Division; Cell Hypoxia; Dose Fractionation, Radiation; Enzyme Inhibitors; ErbB Receptors; Farnesyltranstransferase; Genes, ras; Head and Neck Neoplasms; Humans; Methionine; Neoplasms; Radiation Tolerance; Radiation-Sensitizing Agents; Signal Transduction; Tirapazamine; Triazines; Tumor Cells, Cultured