Combination Therapy Of Ftis Or Ggtis With Cytotoxic Anticancer Drugs Is More Efficacious Than Monotherapy

Evidence from our research and that of others (46-48) indicated that FTIs' antitumor effect is often cytostatic and reversible. This suggested that combination therapy may be beneficial. Furthermore, there are several reasons why combination therapy with FTIs or GGTIs and other clinically used anticancer drugs with different mechanisms ofaction may prove to be more beneficial than monotherapy. First, because a tumor is made up of a heterogeneous population of cells with different genetic...

Cancer Drug Discovery and Development Beverly A Teicher Series Editor

Matrix Metalloproteinase Inhibitors in Cancer Therapy, edited by Neil J. Clendeninn and Krzysztof Appelt, 2000 9. Tumor Suppresor Genes in Human Cancer, edited by David E. Fisher, 2000 8. Farnesyltransferase Inhibitors in Cancer Therapy, edited by Said M. Sebti and Andrew Hamilton, 2000 7. Platinum-Based Drugs in Cancer Therapy, edited by Lloyd R. Kelland and Nicholas P. Farrell, 2000 6. Signaling Networks and Cell Cycle Control The Molecular Basis of Cancer and Other Diseases, edited by J....

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Significant loss in potency, presumably owing to an unfavorable steric interaction with the FTase active site. The N-methyl derivative 14 was comparable in potency to the unsub-stituted analog compound 8 and encouraged us to explore other hydrophobic groups on the nitrogen ofthe imidazole ring. Two compounds (15 and 16) were prepared incorporating abenzyl group via reductive amination of 1-benzyl-4- and 1-benzyl-5-imidazole car-boxaldehydes with 1 followed by deesterification of the methionine...

Not All Ras Proteins Are The Same

Because mutated alleles of K-ras which encodes K-Ras4A and K-Ras4B owing to alternative splicing and N-ras, are found in human tumors more commonly than H-ras 19 , FTI analyses were extended to rodent fibroblast cells transformed by oncogenic forms of K-Ras4B and N-Ras. In light of the relative ease with which FTIs could block H-Ras prenylation, both K-Ras and N-Ras proteins showed surprising resistance to FTI-mediatedinhibitionofprenylation 53-55,88 . Furthermore, although inhibitionoftheir...

Characterization Of Ftase And Ggtase I In Saccharomyces Cerevisiae

Identification of S. cerevisiae Genes Encoding FTase and GGTase I As shown in Table 1, S. cerevisiae FTase consists of two subunits that are encoded by Dpr1 Ram1 and Ram2. These genes were identified from the study of the processing of yeast Ras proteins and identification ofmutants defective in the processing 13-16 . The overall processing ofthe Ras2 protein leading to its membrane association can be divided into a series of modification events 17-19 . First, Ras2 is synthesized in the...

Peptidomimetic Inhibitors Of Ftase

Because CAAX tetrapeptides are farnesylated by FTase as efficiently as the corresponding full-length protein and also are potent 10-200 nM competitive inhibitors of FTase 22 , several groups have targeted the CAAX tetrapeptide as an anticancer drug development strategy. The major efforts have involved improving stability of the tetrapeptides toward proteolytic degradation and increasing their cellular uptake 23 . Our strategy focused on the CA1A2X motif from K-Ras4B CVIM. We reasoned that the...

Peptidomimetics

The finding that CAAX tetrapeptides contain the primary determinants for enzyme recognition ledto the synthesis ofa number ofpeptides, such as FTIs, using the principles of rational drug design. The demonstration that tetrapeptides with aromatic amino-acid substitutions at the second aliphatic amino-acid position two residues away from the cysteine group were nonsubstrate FTIs aroused interest in developing low-molecular weight CAAX peptidomimetics as a principal strategy for FTase inhibition...