The research, led by George Thomas, PhD,
professor at UC's Genome Research Institute, and Heidi Lane, of
Novartis Institutes for Biomedical Research, appeared in the March 25
issue of the journal Cell.
"The use of DNA-damaging agents has
revolutionized chemotherapy against a wide variety of cancers," says
Dr. Thomas. "However, a narrow therapeutic window, combined with
possible severe side effects, has greatly limited their broader use."
These factors, says Dr. Thomas, have
probably contributed to recent reports of the under-dosing of patients
and the failure to blunt the disease.
When cancer cells are treated with a
DNA-damaging agent, a cancer-suppressing gene known as the "guardian of
the cell" (a protein called p53) responds by either killing the cell,
if the damage is too severe, or allowing the cancer cell to repair the
damaged DNA. If the DNA is repaired, cells can continue to multiply.
The dilemma is that high doses of
DNA-damaging agents can be toxic, and doses that are too low allow for
DNA repair and further cell growth. Thus, says Dr. Thomas, there is a
need for drugs that can sensitize cells to lower doses of DNA-damaging
agents to guarantee cell death, but without the toxic side effects.
The researchers studied the results of
combining a DNA-damaging agent called cisplatin with RAD001, a
derivative of the immunosuppressive drug rapamycin. Used in organ
transplant patients, rapamycin and its derivatives have shown promising
anti-tumor activity in phase I and II clinical trials.
RAD001 lowers the amount of DNA-damaging
agent needed by blocking p53's DNA-repair function, automatically
killing the cancer cells when agents like cisplatin are introduced.
"These findings provide the rationale for
combining DNA-damaging agents with sensitizing agents like RAD001,"
says Dr. Thomas. "Since about 50 percent of all solid tumors contain
p53, such a drug combination could dramatically improve the treatment
of solid tumors."
The research was funded by grants from
Novartis Institutes for Biomedical Research and the Novartis
Foundation, the Collaborative Cancer Research Project of the Swiss
Cancer League, and the National Cancer Institute Mouse Models of Human
Cancer Consortium. Dr. Thomas is a consultant for Novartis Institutes
for Biomedical Research.
Dr. Thomas and a co-author, Stefano
Fumagalli, PhD, began this research while working at the Friedrich
Miescher Institute for Biomedical Research in Basel, Switzerland, and
completed it at UC's Genome Research Institute, where further studies