MEMPHIS‘‘Camptothecin activity is schedule dependent and
is very S-phase-specific at concentrations we can achieve in vivo," Peter
J. Houghton, PhD, said while summarizing the results of preclinical studies
with camptohecins. "Protracted administration is optimal, and threshold
concentrations are critical," he continued. Dr. Houghton is chairman of
the Department of Molecular Pharmacology at St. Jude Children’s Research
Hospital in Memphis.
Dr. Houghton illustrated the schedule dependence of topotecan
(Hycamtin) in a comparison of daily vs alternate-day dosing (Figure 1). He said
that 30% to 40% of tumors are "dramatically dependent on dose
scheduling" and that cellular determinants of response may be less
important than these pharmacokinetics in many situations.
Camptothecin analogs are being evaluated for possible
therapeutic efficacy in xenograft models in which human tumors are grafted into
immune-deficient mice. Studies with irinotecan (Camptosar) showed that 5 days
of treatment had much less effect than 10 days of treatment at half the dose.
"Mice are poor models for toxicity but can be used to evaluate antitumor
effects," Dr. Houghton said. "This is done by relating clinically
achievable systemic exposure levels to those that produce antitumor effects in
the xenograft model.
Clinical Studies Designed
Based on these data, clinical studies were designed to test
topotecan in a phase II study of 22 children with stage IV neuroblastoma. Dr.
Houghton said that the schedule of administration was derived directly from the
xenograft model results (daily x 5 x 2). Treatment produced partial responses
in 13 of 22 children (59%) and stable disease in 9 patients.
Irinotecan has similarly progressed to a phase I study in 23
children with refractory or relapsed solid tumors, with the schedule of
administration derived again from the xenograft model (daily x 5 x 2). Dr.
Houghton said that diarrhea was the dose-limiting toxicity and that hematologic
toxicity was minimal. The cumulative area under the curve of SN-38 (the active
metabolite of irinotecan) was two- to fourfold higher than observed in adult
studies. ‘‘There were 5 partial responses and 17 patients with disease
improvement that did not qualify as a partial response," Dr. Houghton
said. The maximum tolerated dose was 20 mg/m2/dose, and cumulative dose per
cycle was 200 mg/m2.
Based on these studies, Dr. Houghton said that preclinical
studies of combination therapy are underway with topotecan plus vincristine,
irinotecan plus the methylating agent temozolamide (Temodar), and irinotecan
plus the EGF receptor antagonist ZD1839 (Iressa).
"Temozolamide in combination with irinotecan is appealing
because there are nonoverlapping organ toxicities and a potential mechanism for
interaction," Dr. Houghton said. The synergy is only partly dependent on
O6-methylguanine-DNA methyltransferase (MGMT) and efficacy may vary according
to tumor MGMT activity levels.
Schedule Dependent Synergy
"In preclinical trials, we have seen synergy in tumors
with high MGMT levels and in tumors deficient in mismatch repair
mechanisms," Dr. Houghton said. "Temozolamide combined with
irinotecan produces greater than additive antitumor activity against eight of
the nine xenograft lines tested. Synergy is schedule dependent. Dosing of
temozolamide plus irinotecan should be sequential: temozolamide should be given
first, then irinotecan."
In summary, Dr. Houghton said that camptothecins are very
active in preclinical models, but that activity is highly schedule dependent.
"Irinotecan and topotecan are highly active against childhood solid
tumors, and systemic exposures and schedules consistent with activity in model
systems yield a high response rate in children," he said.