A highly promising molecular constellation, discovered in the field of pharmaceutical cancer research, is now better understood in terms of its efficacy, thanks to years of laboratory testing. Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig have determined the biological activity of the tubulysin molecule. Tubulysin is one of the most powerful cell division inhibitors known to science. Abnormally high, pathological cell division is what makes cancer so dangerous. The new findings are a major step forward in the pharmaceutical development of this important substance.One of the problems with highly poisonous, so-called cytotoxic, substances, like tubulysin, is that, initially at least, a pharmaceutical application would seem out of the question. The substance inhibits the growth of all human cells, not just degenerated, cancerous cells. "From the clinical perspective, this problem is expressed in severe side effects," explains Dr. Florenz Sasse, a biologist at the Helmholtz Institute. These can include alopecia because the substance also attacks the skin cells responsible for hair growth, or, changes in the blood count, leading to an absence of phagocytes, making patients more susceptible to subsequent infections. Problems like these can only be avoided if researchers find a way to alter the substance at the molecular level so that it targets tumor cells exclusively. In the case of tubulysin, chemists in the United States, in conjunction with Florenz Sasse, have made the crucial contribution. They have jointly been able to illustrate just where "tinkering" on the molecule can alter its design and synthesis properties."Tubulysin is a difficult molecule in every respect," notes Dr. Sasse. "It's formed by soil bacteria as a metabolic by-product. We discovered tubulysin in 1994, but because it's a by-product it's difficult to produce in significant amounts." "What's more," she says, "the molecule has been optimized for its function by the bacteria over a long period of evolution. That means for us that individual molecular components cannot be easily varied. If we alter the structure, we lose the potency."However, after a U.S. research group in 2006 managed to reproduce tubulysin synthetically in a test tube, it became possible for scientists to study which parts of the molecule were important for its biological activity. It is now feasible to alter specific areas of the molecule without diminishing its potency, while, at the same time, improving its cancer-fighting qualities. It can now also be attached to other substances, which transport it directly to a tumor growth. "This way, explains Sasse, "we can regulate the toxicity of tubulysin.""There is, however, a long road of development ahead of us before a targeted cancer therapy without side effects is achieved," says Dr. Sasse.Original Article:Andrew W. Patterson, Hillary M. Peltier, Florenz Sasse and Jonathan A. Ellmann (2007): Designs, Synthesis and Biological Properties of Highly Potent Tu 1 bulysin D Analogues. Chem. Eur. J. 2007, 13, 9543-9541
Pictures: Cancer cells withour (download 1) and with (download 2) Tubulysin treatment. blue: Nucleus, green: Cytoskeleton. Photographer: Florenz Sasse
