MGI Pharma MOGN New patents, anti cancer Message Board

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Biotech / Medical : MGI Pharma MOGN New patents, anti cancer

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To: JOSEPH VON MEISTER who wrote (201)	9/16/1997 12:50:00 AM
From: Miljenko Zuanic	of 1826

To all: Richard H., No harm done. Darci, dose per m^2 (in correlation with toll) is more accurate than dose per kg. More and more cancer trials are using this dosing calculation. Few notes regards the MGI-114 (hope it will help); 1. From patent: HMAF is sesquiterpenes class molecule and it is analog of the Illudin S(M). First, to eliminate fast metabolism and side profile/toxicity (fast binding to glutathione) one hydroxyl group (in cyclopentyl ring) is eliminated and this ring is aromatized, and other active hydroxyl group is protected by acetyl group (acyl). Second, to enhance cells uptake and metabolism-induced activation they used 6-hydroxymethyl derivative. This modification didn't effect significantly cancer cells toxicity but significantly reduce toxicity to normal cells. The problem (pharmacodinamic) is stability of the acetyl group towards premature hydrolysis in to illudofulvene S active metabolite (hydroymethylfulvene, HMF-AM)? IMO, this is a main reason that MGI went carefully in to PI trials to investigate drug performance/metabolism, and I am giving them a credit for it. 2. Illudin S toxicity: ncbi.nlm.nih.gov and ncbi.nlm.nih.gov 3. John is correct that rats didn't show side effects, but dogs did. I do not agree that we are similar to each of then regards the drugs stability/metabolism processes. Each drug has its own story and one have to be careful when study drug(s) in human PI trials. 4. Metabolism of the Illudin S: ncbi.nlm.nih.gov and ncbi.nlm.nih.gov 5. Mode of action is toward helicase-deficient DNA cross-linking (similar to cisplatin) which is unique. This property has Illudofulvene S active (and unstable) metabolite, not illudine/illodofulvene itself. ncbi.nlm.nih.gov ncbi.nlm.nih.gov 6. Dainippon know well what they are licensing (upper abstracts) and field comfortable with drug pre-clinical profile. They also repeated experiments on cancer grow inhibition before licensing. By this analysis, my 0.02 cents, if MGI can achieve half efficiency (with current MGI-114 dose) compared to animal study, there are no problem. Any side effects will be manageable. Still it will be nice to hear some explanation from IR at MGI. mz

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