| |
|
| |
poptosis, or cell 'suicide,' is a backup system that
prevents runaway division by alerting a cell to DNA damage and initiating
self-destruction. Although apoptosis is bad for the cell, it is ultimately
good for the body, which this way rids itself of damaged genetic material.
Learning more about apoptosis is key to fully understanding cancer, and
ultimately to developing strategies based on harnessing this process as
a cancer therapy.
At the University of Chicago, NIDCR- and NCI-funded scientists are studying whether alterations in the susceptibility of tumor cells to undergo apoptosis contribute to the development, progression, or recurrence of oral and pharyngeal cancer. Their current studies focus on the bcl-2 gene family. Within the family are genes that code for proteins that suppress cell death, such as bcl-2 and bcl-xl, while others promote apoptosis. So far, the scientists have correlated overexpression of bcl-xl in human oral cancer tissue with a poor prognosis, and overexpression of bcl-2 with a more hopeful outcome. These findings are consistent with their earlier work on breast cancer. Those studies showed that bcl-xl overexpression was associated with a higher tumor grade and increased number of positive lymph nodes, and tumors expressing bcl-2 were of a lower grade and a smaller size.
For their latest studies on bcl-xl, the scientists created a transgenic mouse model that overexpresses the protein in the mouth, throat, and skin. When the animals' skin was exposed to known carcinogens, approximately 70 percent of them developed invasive skin cancer, whereas only 18 percent of the control group developed the disease. The scientists are now beginning studies of the oral mucosa using a similar transgenic model. Can a cell be tricked into dying? Ultimately, the scientists hope to be able to answer this question as they learn more about the apoptotic process and the so-called 'cell survival genes' that code for proteins like bcl-xl.
A three-gene 'cocktail' is the focus of a unique gene therapy strategy set to be tested soon by NIDCR grantees at Johns Hopkins University. The herpes simplex virus thymidine kinase (HSV-tk) "suicide" gene and genes for two cytokines -- interleukin-2 (IL-2) and granulocyte macrophage colony stimulating factor (GM-CSF) -- will be delivered via an adenovirus into a mouse model of oral cancer. The scientists speculate the therapies will act synergistically. Here is why: The HSV-tk therapy causes oral cancer cells to commit 'suicide' in the presence of certain anti-herpetic drugs such as ganciclovir. As that occurs, the tumor cells release cellular debris and antigens recognized by immune cells. The HSV-tk/ganciclovir therapy, then, not only works to reduce tumor size, but also sets the stage for tumor-specific immune activity by IL-2 and GM-CSF. In turn, the two cytokines stimulate specific immune cells that are able to recognize and help destroy tumor cells.
Further along in the research pipeline is an apoptosis-based therapy
using the p53 gene. Clinical investigators at the M.D. Anderson Cancer Center
and Introgen Pharmaceuticals, Inc., recently completed a study on the safety
of p53 gene therapy in a small number of patients with head and neck cancer.
The study was a dose-escalation trial in which the investigators used an
adenovirus to deliver normal p53 gene into the patients' tumors. All the
patients had advanced, recurrent cancers of the head and neck and had failed
conventional treatment. The researchers found that the gene therapy was
not only free of serious side effects, it actually resulted in tumor regression
in some patients. With its safety now documented, scientists can move the
p53 treatment to the next stage of clinical testing.