The research, led by George Thomas, PhD, professor at the University of Cincinnati's (UC) Genome Research Institute, and Heidi Lane of Novartis Institutes for Biomedical Research, appears in the March 25, 2005, issue of the journal Cell.
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 these studies at UC's Genome Research Institute, where further studies continue.
"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 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 a grant from Novartis Institutes for Biomedical Research and the Novartis Foundation, and by grants from 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.
Additional study authors include Iwan Beuvink and Frederic Zilbermann, both of the Friedrich Miescher Institute for Biomedical Research, and Anne Boulay, Jonathan Hall, Francois Natt, Terence O'Reilly and Stephan Ruetz, all of Novartis Institutes for Biomedical Research.