ZIB

Hits per page

hits 1 - 2 | 2 hits

Sorting

Electronic Resource

Effects of SCH 59228, an orally bioavailable farnesyl protein transferase inhibitor, on the growth of oncogene-transformed fibroblasts and a human colon carcinoma xenograft in nude mice (1999)

Liu, Ming ; Bryant, Matthew S. ; Chen, Jianping ; [et al.]

Springer

Cancer chemotherapy and pharmacology 43 (1999), S. 50-58

add to mindlist on the mindlist

Details

ISSN: 1432-0843

Keywords: Key words SCH 59228 ; Orally bioavailable ; Tricyclic farnesyl-transferase-inhibitor ; Ras ; Xenograft

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract The products of the Ha-, Ki-, and N-ras proto-oncogenes comprise a family of 21 kDa guanine nucleotide-binding proteins which play a crucial role in growth factor signal transduction and in the control of cellular proliferation and differentiation. Activating mutations in the ras oncogenes occur in a wide variety of human tumors. Ras proteins undergo a series of posttranslational processing events. The first modification is addition of the 15-carbon isoprene, farnesyl, to a Cys residue near the carboxy-terminus of Ras. Prenylation allows the Ras oncoprotein to localize to the plasma membrane where it can initiate downstream signalling events leading to cellular transformation. Inhibitors of the enzyme which catalyzes this step, farnesyl protein transferase (FPT), are a potential class of novel anticancer drugs which interfere with Ras function. SCH 59228 is a tricyclic FPT inhibitor which inhibits the farnesylation of purified Ha-Ras with an IC50 of 95 nM and blocks the processing of Ha-Ras in Cos cells with an IC50 of 0.6 M. SCH 59228 has favorable pharmacokinetic properties upon oral dosing in nude mice. The in vivo efficacy of SCH 59228 was evaluated using a panel of tumor models grown in nude mice. These included several rodent fibroblast lines expressing mutationally-activated (val12) forms of the Ha-Ras oncogene. In some cases, these proteins contain their native C-terminal sequence (CVLS) which directs farnesylation. In one model, the C-terminal sequence was altered to CVLL, making the expressed protein a substrate for a distinct prenyl transferase, geranylgeranyl protein transferase-1. When dosed orally at 10 and 50 mg/kg (four times a day, 7 days a week) SCH 59228 significantly inhibited tumor growth of cells expressing farnesylated Ha-Ras in a dose-dependent manner; over 90% growth inhibition was observed at the 50 mg/kg dose. Tumor growth of cells expressing the geranylgeranylated form of Ha-Ras was less potently inhibited. Growth of tumors derived from a rodent fibroblast line expressing activated Ki-Ras containing its native C-terminal sequence (CVIM), which preferentially directs farnesylation, was also inhibited by SCH 59228. Inhibition in the Ki-Ras model was less than that observed in the Ha-Ras model. In contrast, tumors derived from cells transformed with the mos oncogene were not significantly inhibited even at the highest dose level. SCH 59228 also significantly and dose-dependently inhibited the growth of human colon adenocarcinoma DLD-1 xenografts (which express activated Ki-ras). These results indicate that SCH 59228 possesses in vivo antitumor activity upon oral dosing in tumor models expressing activated ras oncogenes. This is the first report of oral antitumor activity with an FPT inhibitor. These results are discussed in light of recent observations on alternative prenylation of some Ras isoforms.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002800050862

Permalink

Library	Location	Call Number	Volume/Issue/Year	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

Electronic Resource

GC/MS analysis of biologically important aromatic amines. Application to human dosimetry (1987)

Stillwell, W. G. ; Bryant, Matthew S. ; Wishnok, John S.

Chichester : Wiley-Blackwell

Biological Mass Spectrometry 14 (1987), S. 221-227

add to mindlist on the mindlist

Details

ISSN: 0887-6134

Keywords: Chemistry ; Analytical Chemistry and Spectroscopy

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology

Notes: Human exposure to aromatic amines may be monitored by measuring the amount of sulfinamide adduct bound to hemoglobin. In order to develop a sensitive and selective method for measuring aromatic amines present in low concentrations the mass spectra of the pentafluoropropionamide derivatives of a series of aromatic amines were determined under various ionization conditions. With electron ionization the aromatic amine derivatives typically yield intense molecular ions with fragmentation leading to elimination of C2F5 and COC2F5. Higher molecular weight polycyclic aromatic amines, e.g., 6-aminochrysene, give prominent molecular ions as well as intense ions corresponding to M-174 (loss of CNHCOC2F5). With positive chemical ionization using methane as reagent gas the derivatives give protonated molecular ions as the base peaks, as well as the associated ions at M + 29 and M + 41. Negative ion chemical ionization yields, primarily, peaks corresponding to the loss of HF from the molecular anions. Negative ion chemical ionization with selected ion monitoring is generally more suitable than positive chemical ionization or electron ionization for the quantitative analysis of aromatic amines present in biological samples in the mid femtomolar range. Exposure of human subjects to aromatic amines was determined via basic hydrolysis of the isolated sulfinic acid amide hemoglobin adducts. Analysis of the derivatized extracts by gas chromatography/negative ion chemical ionization/mass spectrometry demonstrated the presence of aniline, ortho-, meta-, and para-toluidine, 2-naphthylamine, and 4-aminobiphenyl. The hemoglobin adduct levels of these amines in both cigarette smokers and nonsmokers were determined. The mean values of the adduct levels of ortho- and para-toluidine, 2-naphthylamine, and 4-aminobiphenyl were higher in smokers than in nonsmokers, while the mean adduct values of aniline and meta-toluidine were similar in both groups. Adducts of 2-, 3-, 4-ethylaniline, 2,3-, 2,4-, 2,5-, 2,6-dimethylaniline, and 3-aminobiphenyl have been detected in smokers' blood. 1-Aminoanthracene, 9-aminophenanthrene, and 6-aminochrysene have not been detected. GC/MS procedures were also used to determine the extent of binding of aniline-2,3,4,5,6-d5 to hemoglobin in rats administered aniline-d5.

Additional Material: 4 Ill.