Silicon Investor (SI) -- The First Internet Community

STOCKTALK

We've detected that you're using an ad content blocking browser plug-in or feature. Ads provide a critical source of revenue to the continued operation of Silicon Investor. We ask that you disable ad blocking while on Silicon Investor in the best interests of our community. If you are not using an ad blocker but are still receiving this message, make sure your browser's tracking protection is set to the 'standard' level.

Biotech / Medical : Kosan BioSciences -- KOSN -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (392)	12/18/2003 9:48:38 AM
From: tuck	Read Replies (1) \| Respond to of 933

>>Cancer Res. 2003 Dec 1;63(23):8393-9. Combination treatment with 17-N-allylamino-17-demethoxy geldanamycin and acute irradiation produces supra-additive growth suppression in human prostate carcinoma spheroids. Enmon R, Yang WH, Ballangrud AM, Solit DB, Heller G, Rosen N, Scher HI, Sgouros G. Memorial Sloan-Kettering Cancer Center, New York, New York. Failure to control localized prostate cancer can result not only in localized disease progression but also distant metastatic spread. Whereas significant advances in both surgical technique and radiation therapy have improved local control rates with decreased morbidity, consistent long-term control remains elusive. This study investigates the potential of 17-N-allylamino-17-demethoxy geldanamycin (17AAG), a geldanamycin derivative, to sensitize tumor cells to ionizing radiation, permitting a significant improvement to targeted radiotherapies of prostate carcinoma. As a monotherapeutic, 17AAG functions to modulate the action of heat shock protein 90, ultimately affecting a multitude of cellular signaling pathways. It is in Phase I trial and has shown promise in controlling prostate cancer progression. Human prostate tumor cells (LNCaP and CWR22Rv1) were grown as spheroids and incubated for 96 h with increasing doses of 17AAG immediately before and after 2 or 6 Gy low linear energy transfer (LET), high dose-rate irradiation (Cs-137 irradiator). Twelve or 24 spheroids (initial diameter, 150-200 micro m) were used per experiment. Response was determined by spheroid volume measurements taken over at least 40 days, after treatment. Incubation of either cell line with 17AAG (</=1000 nM) or irradiation (</=6 Gy) alone resulted in transient median growth delays ranging from 2 to 9 days (relative to controls). Combining treatments produced dose- and cell line-dependent supra-additive responses. For LNCaP spheroids, the combination of 2 Gy and 100 nM 17AAG resulted in growth delays additive of the treatments individually; however, increasing either the radiation to 6 Gy or the 17AAG concentration to 1000 nM led to synergistic interactions. Similarly, synergy was noted in CWR22Rv1 studies at only 6 Gy and 1000 nM 17AAG. Terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) and Ki67 staining of spheroid sections revealed the increased growth control to be a function of spheroids failing to re-enter the cell cycle. For all 6 Gy experiments, cells remaining from each of the spheroids that failed to regrow were transferred to adherent dishes to evaluate clonogenicity; growth-controlled spheroids also failed to form colonies within 2 weeks of being plated. These results suggest that significant gains in treatment effectiveness may be obtained by combining these treatment modalities, warranting additional preclinical investigation.<< Cheers, Tuck

To: scaram(o)uche who wrote (392)	1/9/2004 1:24:09 AM
From: tuck	Read Replies (1) \| Respond to of 933

Anybody fell like doing an IP search regarding Morphochem and epothilones? Have they been mentioned as competition before? morphochem.de Hofle is their collaborator in this area: >>J Nat Prod. 2001 Jul;64(7):847-56. New natural epothilones from Sorangium cellulosum, strains So ce90/B2 and So ce90/D13: isolation, structure elucidation, and SAR studies. Hardt IH, Steinmetz H, Gerth K, Sasse F, Reichenbach H, Hofle G. Gesellschaft fur Biotechnologische Forschung mbH, Mascheroder Weg 1, D-38124 Braunschweig, Germany. In addition to epothilones A (1) and B (2), 37 natural epothilone variants and epothilone-related compounds were isolated from the culture broth of a 700 L fermentation of Sorangium cellulosum, strain So ce90/B2. Of these, only the 12,13-desoxyepothilones, epothilone C (14) and D (15), were produced in significant amounts (3-6 mg/L); the 21-hydroxy derivatives and epothilones E (3) and F (4), in low and variable amounts due to further degradation by the producing organism. Most of the other epothilone variants were produced only in 1-100 microg/L amounts. The new compounds are very similar in structure to the parent compounds 1, 2 and 14, 15 and are presumably the result of the imperfect selectivity of the biosynthetic enzymes for acetate and propionate. Further, epothilones containing an oxazole moiety (10-13) in the side chain instead of a thiazole as well as ring-expanded 18-membered macrolides, epothilones I (30-35), and a ring contracted 14-membered macrolide, epothilone K (36), were found as very minor metabolites. The mutant strain, So ce90/D13, instead of macrolactones, produced short-chain carboxylic acids 40, 41, and 42 bearing the characteristic thiazole side chain. The structures of the new epothilones were elucidated on the basis of comprehensive NMR and MS data. The new epothilone variants were tested in a cytotoxicity assay with mouse fibroblasts (cell line L929), and structure-activity relationships were established. Several new natural epothilones showed activity comparable to 1 and 2, but in no case exceeded that of 2.<< So they don't appear to be trying anything with Epothilone D, and haven't found anything better than Epothilone B, at least not yet. Might have to keep an eye on 'em though. Cheers, Tuck