BUFFALONew work on the role of schedule and dose in
determining the efficacy of two classes of drugsthymidylate synthase
and topoisomerase I inhibitorswas described by Youcef M. Rustum, PhD, at the Vanderbilt University Symposium.
Dr. Rustum is senior vice president for scientific affairs and graduate
education at Roswell Park Cancer Institute in Buffalo.
The thymidylate synthase inhibitors include fluorouracil,
capecitabine (Xeloda), and raltitrexed (Tomudex). The topoisomerase I inhibitor
singled out was irinotecan (Camptosar).
Hypotheses Being Tested
"The following hypotheses about efficacy are being
tested," Dr. Rustum explained. "First, that optimal therapeutic
synergy is drug dose and schedule dependent. Next, that recruitment of cells
into S-phase is a key determinant for selection and curative therapy with
irinotecan/fluorouracil combinations. Third, that overexpression of BAX will
enhance cell susceptibility to drug-induced apoptosis."
The role of treatment schedule
and dose was studied in rat colon
cancer models using three schedules: concurrent irinotecan/fluorouracil,
fluorouracil followed 24 hours later by irinotecan, and irinotecan followed 24
hours later by fluorouracil. "The highest cure rate is with irinotecan
followed in 24 hours by fluorouracil," Dr. Rustum said. "There was
significant, dose-dependent interaction between irinotecan and
fluorouracil." A 50 mg/m2 dose of irinotecan put cells into S-phase, but a
100 mg/m2 dose put them into G2-phase.
In combinations of raltitrexed, fluorouracil, and capecitabine,
the therapeutic effect occurred regardless of which drug followed irinotecan,
Dr. Rustum noted. Irinotecan renders the tumor vulnerable to DNA inhibition by
the second agent administered, said Dr. Rustum.
A number of mechanisms are thought to contribute to the
therapeutic synergy of irinotecan followed by thymidylate synthase (TS)
inhibitors. A key step in this process is mediated by dihydropyrimidine
dehydrogenase (DPD). "High levels of DPD are associated with resistance to
fluoropyrimidine therapy. Under certain conditions, DPD is down-regulated by
irinotecan," Dr. Rustum said.
DPD inhibition also mediates the therapeutic efficacy of
capecitabine. "Inhibition of DPD makes resistant tumors susceptible to
and reverses resistance, but only
in tumors with high levels of DPD,"
Dr. Rustum said.
With regard to the modulation of tumor markers by irinotecan,
Dr. Rustum said that recruitment of cells into S-phase is concentration and
time dependent. "Up-regulation of BAX and wild-type p53 protein expression
by irinotecan occurs in tumors with pre-existing baseline levels of these
markers as a time-dependent effect. Down-regulation of DPD and thymidylate
synthase occurs only in tumors
with higher levels of these enzymes, markers associated with resistence to
fluorouracil. This process is also time and concentration dependent. Finally,
we found that induction of tumor-associated apoptosis was significant when
irinotecan preceded fluorouracil by 24 hours."
Dr. Rustum outlined a number of questions for future
Is recruitment of cells into S-phase drug specific?
Is recruitment of cells into S-phase by irinotecan a
sufficient mechanism predictive for the observed therapeutic synergy of the
irinotecan/ fluorouracil sequential combination?
Are cells synchronized into S- phase more sensitive to
antimetabolites? Can this be used to overcome resistance?