The Salk Institute says it appears to have serendipitously solved a long standing mystery about how a key class of chemotherapy drugs work, which could lead to better ways of fighting a wide variety of cancers, including tumors of the breast, ovaries, colon, lung and prostate.
The discovery was made by molecular biologist Jan Karlseder and research associate Makoto Hayashi while they were studying the basic nature of telomeres, the protective caps on the ends of chromosomes. Scientists believe teleomeres play a role in cancer and aging.
During its research, the Karlseder group unexpectedly found that a type of cancer drug known as a mitotic inhibitor damages telomeres.
This microscope image shows chromosomes in human lung cells exhibiting telomere damage caused by Colcemid, a drug that arrests cell division. The Salk scientists discovered the molecular pathway that initiates a stress response upon treatment with chemotherapy drugs, resulting in a cessation of cell growth or cell death. Salk Institute.
"We knew that mitotic inhibitors kill cancer cells, but we didn't know how that happens," said Karlseder. "Now we understand that these drugs inflict damage on telomeres, which causes a response that kills cells."
The finding was published online today in the journal Nature Structural and Molecular Biology.
"This is a completely unexpected finding ..." said Steven Artandi, an oncologist at the Stanford University. "This study suggests new approaches to enhance the efficacy of mitotic inhibitors in the treatment of human cancer."
The discovery goes a long way toward explaining one of the bigger ironies in medicine; doctors have long prescribed mitotic inhibitors like Taxol and Vincristrine without knowing precisely how the drugs destroy cancer.
"Not knowing how this type of chemotherapy works has made it harder to produce better drugs, and to reduce the devastating side effects, like hair loss and nausea," Karlseder said. "Now that we understand the molecular pathways induced by mitotic inhibitors we can attempt to design synergistic treatments that could be much more effective."
Physicians need better treatments. Chemotherapy is a form of poison that doesn't always kill all of the cancer in a person's body. That means that even if a single cell survives the tumors can regrow. Karlseder's discovery, and those made by other researchers, point to the need for combining different drugs to improve the chances of wiping out cancer cells that are not destroyed by a single chemotherapy approach."
SOURCE: San Diego Union Tribune 3-11-2012
Paclitaxel: Anti-tumor agent isolated from the bark of the yew tree.
Colchicine: Depolymerizes microtubules. Inhibits tubulin polymerization. Induces apoptosis.
Piperafizine A: Piperafizine A is a methylated diketopiperazine formed by the condensation of phenylalanine and produced by a number of species in the Streptomyces genus. Piperafizine A exhibits little activity in vitro but has been seen to potentiate vincristine antitumor potency. The mechanism of action has not been characterised. Recently purified metabolite. Please inquire.
Vincristine Sulfate: Vincristine.sulfate blocks mitotic spindle formation, which impedes the cell cycle in G2/M phase. Blocks binding of tubulin to microtubule proteins through depolymerization. Also acts as inducer to apoptosis; initiates Raf-1 activation & phosphorylation of Bcl-2 family proteins; and induction of p53 expression. Used as cancer chemotherapeutic agent. Plant alkaloid.
Vinblastine Sulfate: Inhibits microtubule assembly. Induces apoptosis and acts as a cancer chemotherapeutic agent.