The effectiveness of vinblastine was increased by orders of magnitude
Scientists at the Scripps Research Institute, working under the leadership of Dr. Dale Boger, have developed a method to increase the effectiveness of vinblastine, one of the most successful anti–cancer drugs developed in recent decades. In terms of effectiveness, the synthesized derivatives surpass the drug used in the clinic by tens or even hundreds of times. Moreover, they do not cause the resistance that occurs with relapses of the disease. The authors hope that the approach described by them will improve another popular chemotherapy drug – vincristine.
Vinblastine and vincristine are natural alkaloids produced by a plant known as pink periwinkle. In folk medicine, the leaves of this plant have long been used to treat a wide range of diseases, including diabetes and hemorrhoids, and in the 1960s, researchers at Eli Lilly found that alkaloids to plants have a powerful cytostatic effect.
Both compounds selectively destroy rapidly dividing malignant cells by binding to the cellular protein tubulin. This leads to disruption of synthesis and destruction of tubulin–containing microtubules - structural elements of the cell that play a key role in the process of its division.
Since the 1960s, vinblastine in combination with other chemotherapy drugs has been successfully used to treat lymphomas, as well as cancer of the seminal glands, ovaries, mammary glands, bladder and lungs. Vincristine is widely used in combined protocols for the treatment of pediatric acute lymphoblastic leukemia and non-Hodgkin's lymphomas. Both compounds are currently isolated from vegetable raw materials, in which it is contained in negligible amounts (0.0001% of dry weight). Until now, it was believed that the production of their derivatives was beyond the capabilities of organic chemistry methods, but the authors managed to overcome this barrier.
The resulting vinblastine derivatives exceeded all expectations. In addition to their exceptionally high efficiency, unlike the original drug, they do not cause the development of resistance due to the ability of malignant cells to synthesize P-glycoprotein. This protein removes the drug from the cells, and as soon as the target cells begin to synthesize it in sufficient quantities, vinblastine loses its effectiveness.
Testing on 15 lines of human malignant cells (including breast, lung, colon, prostate and ovarian cancer cells), conducted by the laboratory of the largest pharmaceutical company Bristol-Myers Squibb, confirmed the previously obtained results. The obtained vinblastine derivatives exceeded its effectiveness by 10-200 times, depending on the shape of the tumor and which chemical grouping (NR2) was attached to the main backbone of the synthetic drug molecule.
According to the authors, the potential of the compounds they have obtained is extraordinary. They hope that the method of modification of complex organic compounds developed by them will bring antitumor therapy to a new level.
Article by Timothy J. Barker et al. Potent Vinblastine C20' Ureas Displaying Additionally Improved Activity Against a Vinblastine-Resistant Cancer Cell Line is published in the journal ACS Medicinal Chemistry Letters.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the Scripps Research Institute:
Scripps Research Institute Scientists Create Extremely Potent and Improved New Derivatives of Successful Anticancer Drug.20.09.2013