N-Acetyl Calicheamicin g1

Calicheamicins are a group of enediyne antitumor antibiotics. Calicheamicins target DNA and cause strand scission.Story behind Calicheamicns: In the mid 1980’s a Lederle Lab scientist was on vacation in Texas and took a chalky soil sample from an area near the town of Kerrville that the locals call the “calichi pits”. Back in the lab a strain of the Actinomycete bacteria, Micromonospora echinospora, was isolated from this soil sample and was found to produce a novel antibiotic later named calicheamicin. Calicheamicin is fabulously potent. The good news was that only a couple of calicheamicin molecules could easily kill a cancer cell (almost totally unheard of in efficacy and a thousand times more potent than some of the best clinical antitumor drugs, like adriamycin). The bad news was that only a couple of calicheamicin molecules could also easily kill a normal cell. In fact, calicheamicin kills everything it touches: bacteria, fungi and viruses, eukaryotic cells and eukaryotic organisms like mice and people. Studies on calicheamicin by George Ellestad and Nada Zein, who among other scientists at at Lederle Laboratories*, showed why calicheamicin was so fabulously potent: it had a highly unusual mode of action. Calicheamicin acts as a “chemical nuclease”. Calicheamicin is similar to an enzyme (it’s really a chemical catalyst); it is able to repeatedly bind to DNA and make double strand breaks. Exposure to just a few molecules of calichaemicin can chop an entire genome into hamburger. It took ten years of hard work to get there, resulting in the development of gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth). The gemtuzumab ozogamicin antibody binds CD33, a myeloid-specific cell surface protein that targets the calicheamicin for the treatment of acute myeloid leukemia (AML). But frustrating everyone involved, gemtuzumab ozogamicin did not turn out to be the magic bullet. Ten years post launch gemtuzumab ozogamicin was removed from the market in the United States at the request of the U.S. Food and Drug Administration (FDA). After years of clinical experience the FDA concluded that the drug was still too toxic, although it is still being used in Japan and studies continue to support the re-approval of this agent - novel projects may bring Calicheamicins back into the game....