miércoles, 11 de julio de 2012

Experimental Drug Based on Plant Toxin Targets and Kills Tumor Cells ▲ NCI Cancer Bulletin for July 10, 2012 - National Cancer Institute

NCI Cancer Bulletin for July 10, 2012 - National Cancer Institute


Experimental Drug Based on Plant Toxin Targets and Kills Tumor Cells

Researchers have engineered a drug that can deliver a potent cell-killing toxin to tumors while largely sparing normal tissues. The drug, known as G202, shrank xenograft tumors of several human cancers in mice, including prostate, breast, kidney, and bladder cancer, and had relatively few toxic effects. On the basis of these findings, reported June 27 in Science Translational Medicine, researchers have initiated an early-phase clinical trial of G202 in patients with advanced cancer.
G202 delivers its toxic payload—a potent analog of the plant substance thapsigargin—to tumors by binding specifically to a protein known as prostate-specific membrane antigen (PSMA). PSMA is found in high levels in most prostate cancers. It is also found in tumor endothelial cells, which line blood vessels in a variety of solid tumors but not in normal endothelial cells. PSMA is an enzyme that spans the cell membrane and can cut proteins in specific places.
Researchers designed G202 so that it not only binds to PSMA but is also a target for PSMA's protein-cutting activity. G202 is an inactive "prodrug," and PSMA causes the release of the active, cell-killing thapsigargin analog from the prodrug form. This release takes place outside the cell, in the tumor microenvironment. Once released, the thapsigargin analog is taken up by nearby tumor cells, where it inhibits a protein known as the SERCA pump. Shutting down the SERCA pump floods the cell with calcium and triggers programmed cell death.
Unlike commonly used chemotherapy drugs, which typically work by killing rapidly dividing cells, "[thapsigargin] and its analogs can kill both rapidly proliferating and nonproliferating cells with equal potency," wrote Drs. Samuel Denmeade and John Isaacs of Johns Hopkins University and their colleagues. This ability, they noted, makes a thapsigargin-based drug particularly suitable for treating prostate cancer because most cancer cells in metastatic prostate cancer are not dividing.
Safety studies of G202 that are required before the drug can be tested in humans showed that it caused transient reversible kidney toxicity in rats and monkeys. G202 did not cause bone marrow toxicity—a common side effect of traditional cell-killing chemotherapy—in mice, rats, or monkeys.
Also in the Journals: Cells Most Vulnerable to HPV Identified
Researchers have identified a distinct population of cervical cells that are targeted by cancer-causing types of human papillomavirus (HPV), according to a study published June 26 in the Proceedings of the National Academy of Sciences.
These cells sit at the junction between the interior and exterior epithelial surfaces of the cervix and have a unique appearance and gene expression profile. The researchers showed that specific biomarkers of these junction cells were expressed in HPV-associated precancers and cancers. Forced expression of proteins coded for HPV (HPV oncoproteins) in other cell types did not cause the expression of junction cell biomarkers. And researchers did not find junction cell biomarkers in HPV-associated vaginal, vulvar, or penile precancers.
By examining tissue from women who had surgery to remove cervical tissue followed several months later by a hysterectomy, the researchers found that cells expressing the junction cell markers did not return once they were removed. These findings raise the possibility that removing junction cells may prevent cervical cancer, although further research is needed to understand how these cells change during a woman's life.

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