The team’s modified versions of vinblastine showed 10 to 200 times greater potency than the clinical drug. Even more significantly, these new compounds overcome the drug resistance that emerges upon treatment relapse, which renders continued or subsequent vinblastine treatment ineffective in some patients.
The TSRI researchers expect that similar modifications will boost the effectiveness of vincristine, a closely related drug that is commonly used against childhood leukemias and Hodgkin’s disease.
“These new compounds should improve on what are already superb anticancer drugs,” said Dale L. Boger, who is the Richard and Alice Cramer Professor and Chair of the Department of Chemistry at TSRI. Boger and members of his laboratory reported the discovery in a paper recently published online ahead of print by the journal ACS Medicinal Chemistry Letters.
Vinblastine and vincristine are natural products of a pink-flowered herb known as the Madagascar periwinkle. Although the leaves of the plant had been used in traditional medicines for a range of other conditions, from diabetes to hemorrhoids, drug researchers at Eli Lilly found in the 1960s that the two compounds showed excellent potential as anticancer agents.
Both were found to selectively kill cancer cells by a mechanism that many other cancer drugs, including taxol, epothilones, and colchicine, have followed since—they bind a cellular protein called tubulin in a way that interferes with the buildup and breakdown of tubulin-containing chains called microtubules—structural elements of cells that play a key role in cell division. When the normal dynamics of their microtubules are disrupted, fast-dividing cancer cells stop dividing and die.
Since the 1960s, vinblastine has been used successfully in combination with other chemotherapy drugs against lymphomas as well as testicular, ovarian, breast, bladder and lung cancers. Vincristine is routinely used in combination regimes against childhood acute lymphoblastic leukemia and non-Hodgkin lymphomas. Both compounds are presently isolated from cultivated fields of the plants that make them naturally, but in trace amounts (0.0001% of the dry leaf weight). Since they are plant-derived natural products, they cannot be accessed using existing biotechnology or genetic engineering methods and, prior to the TSRI efforts, they were viewed as far too complex to be prepare by laboratory organic chemistry techniques. The authors developed a remarkable three-step preparation from commercially available chemicals using chemistry that they invented specifically for this purpose.
A significant limitation of vinblastine and vincristine is that, with extended treatment, they may evoke a powerful form of drug resistance. This resistance comes from a doorkeeper-type molecule called P-glycoprotein (Pgp), which transports infiltrating drug molecules out of the cancer cells. As cancer cells evolve to produce more and more Pgp, drugs fail to reach effective concentrations in cells and cancerous growth resumes. For years, medicinal chemists have tried to find modified versions—“analogues”—of these drugs that would overcome Pgp-mediated resistance, but without success.
Developing Extraordinary Potency
Last year, however, in a landmark paper in Organic Letters, Boger and his colleagues described a broad new method for modifying organic compounds like vinblastine, and demonstrated the method by making previously inaccessible variants of the drug. “Although it is a versatile method, we developed it specifically so that we could start making these vinblastine analogues that couldn’t be made before,” Boger said.
As his team used the method to make more new vinblastine analogues, the scientists discovered a type of modification to the drug that limits its usual drop in potency against resistant, Pgp-overproducing cancer cells as compared to non-resistant cancer cells. For the new study, the team explored variations of that modification and eventually found several analogues that were as good at killing resistant cells as ordinary vinblastine is at killing non-resistant cancer cells.
These new analogues were also many times more potent than vinblastine against non-resistant cells—which are the kinds of cancer cells almost all patients have at diagnosis. The laboratory of a major drug company, Bristol-Myers Squibb, was able to repeat these results in a larger set of clinically important human tumor cell lines, and Boger’s team confirmed that the new analogues’ greater potency corresponds to their greater ability to bind to tubulin.
“The potency of these analogues is extraordinary—they show activity down at the 100 picomolar level [100 trillionths of a mole] against some cell lines,” said Boger. “So we have something here that’s really unique, and we discovered it only because of the novel chemistry we developed.”
The other contributors to the paper, “Potent Vinblastine C20’ Ureas Displaying Additionally Improved Activity Against a Vinblastine-Resistant Cancer Cell Line,” were the lead author Timothy J. Barker, and Katharine K. Duncan and Katerina Otrubova, all of TSRI at the time of the study.Funding for the study came in part from the National Institutes of Health (grants CA042056, CA115526, CA165303).
Mika Ono | EurekAlert!
Researchers release the brakes on the immune system
18.10.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn
Norovirus evades immune system by hiding out in rare gut cells
12.10.2017 | University of Pennsylvania School of Medicine
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
18.10.2017 | Materials Sciences
18.10.2017 | Physics and Astronomy
18.10.2017 | Physics and Astronomy