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Biotech / Medical : KDUS, who knows this company? -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (65)	1/8/1998 1:14:00 AM
From: Dave K	Read Replies (1) \| Respond to of 117

Still they made a lot of folks smile last year. Maybe they had some guidance (good or bad) on arriving at the $3 billion value. Geze !. Pity this thread so quiet. Was hoping someone could shed some light on Axiom. Looks like Jay III came and left. Oh well.

To: scaram(o)uche who wrote (65)	1/27/1998 2:11:00 AM
From: Dave K	Read Replies (1) \| Respond to of 117

Some neat yeast and bug stuff. Thought we could lament together...with Sibi and Kboom weak. Last sentence sounds cool. nejm.org ------------------------------------------------------------------------ The New England Journal of Medicine -- January 8, 1998 -- Volume 338, Number 2 ------------------------------------------------------------------------ Emerging Uses for Genomic Information in Drug Discovery ----------------------------------------------------------------------- Geneticists who study yeast, worms, and fruit flies have long recognized that an effective way to identify genes with functional relevance to a particular biologic process is to screen large numbers of mutagenized organisms. Researchers have recently used these primitive organisms to pinpoint genetic mechanisms in human diseases. This approach has succeeded mainly because genome-sequencing projects have discovered numerous invertebrate homologues of human genes. The gene involved in basal-cell carcinoma, for example, was cloned in part through its similarity to the patched gene of the fruit fly Drosophila melanogaster. (1,2) New work on two breast-cancer-susceptibility genes, BRCA1 and BRCA2, is a superb example of how information gained from primal organisms can point to the molecular origins of human cancer. BRCA1 and BRCA2 have attracted widespread attention because, when mutated, they become risk factors for breast cancer. The function of these genes was unclear, however, until certain proteins they interact with were noted to have homologues in yeast. (3,4) Both human genes are related to Rad51, a gene found originally in yeast, where it participates in DNA recombination and the repair of radiation-induced breaks in DNA. These new findings indicate that mutations of BRCA1 and BRCA2 may well disable the mechanism that repairs breaks in double-stranded DNA. (5) The genetic instability such a defect can cause plausibly explains the connection between BRCA mutations and susceptibility to breast cancer. Equally important, the same invertebrate organisms that offered the clue to the function of the BRCA genes may also serve to identify targets for new therapeutic agents against breast cancer. The prospect that knowledge of the molecular defect in breast cancer can be used in this way stems from a new method of developing anticancer drugs. The usual primary targets of small-molecule drugs are enzymes and receptor-ligand pairs. Finding selective inhibitors of these molecules is relatively straightforward, but many of the genetic abnormalities in human cancer are loss-of-function mutations that eliminate or severely reduce the biochemical activities governed by these proteins. The inhibition of molecules that have already lost their activity would have no therapeutic benefit. The new strategy, called synthetic lethal screening, relies on finding secondary molecular targets -- genes with no essential relation to the gene that is primarily affected in the disease. (5) In a typical assay of this type, cells with a mutation in the gene of primary interest that has little or no effect on the viability of the organism are again mutagenized and then screened for cells that die if they carry both mutations (Figure 1). (6) Standard techniques can be used to identify the secondary gene, which, when mutated, specifically kills cells harboring the primary mutation. Two examples show how this approach works. The first involves the DNA mismatch-repair pathway in yeast. Mismatch-repair proteins find and excise misaligned nucleotides in a newly replicated strand of DNA. Defects in three human mismatch-repair genes, MLH1, MSH2, and PMS2, confer a predisposition to colon cancer, as well as several other cancers. It would obviously be beneficial to find a protein whose inactivation by a drug resulted in the selective killing of tumor cells with a defect in mismatch repair. Synthetic lethal screening in yeast has revealed that cells with mutations in the mismatch-repair genes MLH1, MSH2, and PMS1 are selectively killed by mutations in the genes for DNA polymerases (delta) and (epsilon). (7) These enzymes catalyze DNA replication, and in the process they proofread the growing strand of nucleic acids for errors in the genetic code. The results in yeast reveal the possibility of selectively killing colon-cancer cells with a defective mismatch-repair pathway by interfering with another system, the DNA polymerases. The second example involves a homologue of the gene for transforming growth factor (beta) (TGF-(beta)) in fruit flies that is called decapentaplegia (dpp). In mammals, TGF-(beta) has been implicated in cell proliferation, tumor progression, and a variety of inflammatory processes. A mutation in dpp alone is not lethal, but the combination of mutations in dpp and a novel gene called Mad (for "mothers against dpp") proved fatal to fruit-fly cells. (8) This result suggests opportunities for killing cells with a mutant TGF-(beta) gene by interfering with a protein that has a secondary relation to TGF-(beta). Synthetic lethal screening is more powerful than biochemical screening because in principle it can identify any gene that, if mutated, causes the death of cells with a nonlethal "primary" mutation, such as a mutation in BRCA1. With synthetic lethal screening, investigators can scan the entire genome of an organism to find the best target for the selective killing of cells with a particular primary genetic defect. The discovery that mutations in BRCA1 and BRCA2 interfere with the repair of breaks in double-stranded DNA suggests that synthetic lethal screening has the potential to identify molecular targets for the treatment of breast cancer due to such mutations. Whether such screening could also be used to prevent cells with mutant BRCA genes from ever evolving into breast cancer -- a new form of chemoprevention -- is a possibility worth considering. Genetic screening in yeast, worms, and fruit flies and whole-genome analyses are quickly emerging as powerful tools that can accelerate the pace at which anticancer drugs are developed. Stephen H. Friend, M.D., Ph.D. Fred Hutchinson Cancer Research Center Seattle, WA 98104 Allen Oliff, M.D. Merck Research Laboratories West Point, PA 19486