Scientists have discovered a way to make significant improvements to a popular cancer cell-killing drug called vinblastine, according to a study published in the journal ACS Medicinal Chemistry Letters.
Researchers from the The Scripps Research Institute (TSRI) say that their modified versions of the drug revealed 10 to 200 times greater potency, compared with standard vinblastine, and it even overcame the drug-resistance that some vinblastine users experience.
They add that their modifications may also boost the effectiveness of vincristine, a drug closely related to vinblastine.
Vinblastine has been used as a successful chemotherapy drug in combination with other treatments since the 1960s. It is widely used to treat lymphomas, as well as testicular, ovarian, breast, bladder and lung cancers.
Vincristine is a widely used chemotherapy drug, commonly used in combination regimes to treat childhood acute lymphoblastic leukemia and non-Hodgkin lymphomas.
Both drugs are natural products of the Madagascar periwinkle - a pink-flowered herb. They both selectively kill cancer cells by binding to a cellular protein called tubulin, which interrupts the build-up and breakdown of tubulin-containing chains called microtubules.
Microtubules are the structural elements of cells that play an important part in cell division. When their normal activity is interrupted, cancer cells stop dividing and die.
New method created to 'modify organic compounds'
Researchers say they have made significant improvements to chemotherapy drug vinblastine, which uses natural products of the Madagascar periwinkle.
According to the researchers, because the compounds of these drugs are plant-derived, scientists were not able to access them using current biotechnology or genetic engineering methods, and they were seen as "too complex to be prepared by laboratory organic chemistry techniques."
But the researchers from TSRI have created a "three-step preparation process" from commercially available chemicals using chemistry they developed for this purpose.
The study authors say that one problem with both vinblastine and vincristine is that when used for long periods of treatment, they can trigger a form of drug resistance.
This is caused by a molecule called P-glycoprotein (Pgp). This protein removes infiltrating drug molecules from the cancer cells. When the cancer cells evolve to produce higher levels of Pgp, the drugs then fail to reach the concentrations needed to continue killing them.
However, last year, the researchers created a new method that enabled the modifications of organic compounds such as vinblastine.
This new method meant they were able to make new vinblastine "analogues," leading to the discovery of a modification that limits the drug's potency against resistant Pgp-overproducing cancer cells, compared with non-resistant cancer cells.
Modified drugs up to 200 times more effective
For this most recent study, variations of this modification were analyzed. This led to the discovery of several analogues that were able to kill resistant cells just as effectively as standard vinblastine kills non-resistant cancer cells.
The researchers say that these new analogues were also between 10 and 200 times more potent than vinblastine when it came to killing non-resistant cancer cells.
Furthermore, when the analogues were tested in the laboratory of a major drug company, the results were repeated in a larger set of clinically important human tumor cell lines. The researchers say this confirmed that the reason the new analogues showed greater potency is because of their increased ability to bind to tubulin.
Dale L. Boger, professor and chair at TSRI and lead study author, says:
"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.
So we have something here that's really unique, and we discovered it only because of the novel chemistry we developed."
The researchers believe that the development of these new compounds will lead to even better chemotherapy treatments for cancer sufferers.
"These new compounds should improve on what are already superb anticancer drugs," Prof. Boger adds.
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