Chemotherapy for cancer has always greatly relied upon the use of cytotoxic
agents. These agents exert their activity in the process of nuclear DNA and RNA
replication, and their activity in sensitive models leads to cell death and subsequent
tumor shrinkage. Although a number of human tumor types can nowadays be cured
by treatment involving cytotoxic agents, the overall clinical balance of efficacy and
toxicity of these agents remains disappointing.
In contrast to the situation with cytotoxic agents, where introduction as
anticancer agent is usually preceded by large-scale random screening procedures,
more recent research has focussed on anticancer agents for which development and
design was preceded by the identification of specific tumor-related molecular targets
or processes. These targets and processes are located either intracytoplasmic, in the
cell membrane, or even completely outside the tumor cell itself. Examples of these
molecular targets and processes are the intracytoplasmic polyamine synthesis
pathway and farnesyl transferase pathway, the activity of various transmembrane
signal transduction pathways, and the enzymatic breakdown of the extracellular
matrix and the process of tumor-related angioneogenesis, respectively.
Numerous animal studies with these new so-called rationally designed
anticancer agents, aiming at one of the above targets, yielded no or only minor
toxicity. The predictive value of results of animal studies for the human situation,
however, is relatively limited. Nevertheless, in theory, when performing clinical
studies with such compounds, toxicity may turn out to be absent or only mild. As a
resultant, defining dose limiting toxicity as an endpoint for phase I studies may not be
possible, and consequently, defining a recommended dose for additional activity
testing might proof to be difficult.
Many of these new anticancer agents were shown in preclinical studies to
have a cytostatic rather than cytotoxic effect. Although in a limited number of these
studies tumor regressions were noted, growth inhibition was the most frequently seen
effect. Although, as said, such results cannot easily be extrapolated to the human
situation, it may still be anticipated that these agents are not likely to induce tumor
regression in clinically detectable tumor masses. Because of this, performing phase II
studies might not make too much sense.
Taken these considerations together, it is obvious that the design of clinical
studies with new cytostatic agents needs a thorough reappraisal.
This thesis involves clinical phase I studies performed in this shifting field of
anticancer treatment. It outlines several of the problems described above and reports
on efforts made to suggest alternative study endpoints
