CHARLOTTESVILLE, VirginiaAdministering camptothe-cins, such as
irinotecan (Camptosar), or giving 5-fluorouracil (5-FU) at the right
time of day might reduce toxicity and permit use of significantly
higher doses. Tyvin A. Rich, MD, Department of Radiation Oncology at
the University of Virginia in Charlottesville, Virginia, discussed
this chronotolerance data during a workshop sponsored by the
University of Texas M. D. Anderson Cancer Center and Pharmacia Oncology.
Camptothecins are potent radiation sensitizers in vivo, and
radiation sensitization is dependent on dose and schedule, Dr.
Rich explained. Acute toxicity is time dependent, and data
support a clinical protocol testing chronomodulated irinotecan
administration with irradiation.
Preclinical studies in mice showed that weight loss increased and
survival decreased if irinotecan was given at night, during the
nocturnal animals most active period. This risk period
coincides with the peak proliferative period of intestinal mucosa.
Dr. Rich said that moving the dose to the animals less-active
period reduced gastrointestinal toxicity but did not affect
Less Toxic During Down Time
The timing of 5-FU/leucovorin can also affect overall survival. This
is apparently due to much lower rates of mucositis, diarrhea, and
neutropenia when given at 5:00 AM, during the animals less
Pancreatic cancer phase II studies have shown that toxicity of
5-FU/leucovorin can be reduced by changing the time of dosing.
S-phase agents are likely to be more toxic during the day in
humans, since cell proliferation in the intestine is more active
during the day. To reduce toxicity, choose a time when the cells are
preferentially out of cycle, Dr. Rich said.
There is no evidence for circadian-dependent tumor response
with 9-aminocamptothecin (9-AC) and radiation therapy. Because of
circadian-dependent toxicity, we might be able to dose-escalate
radiosensitizers by as much as 30% through chronomodulation, and this
may permit an improved therapeutic index for irinotecan and radiation
therapy, Dr. Rich concluded.